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Fecci, Peter Edward

Overview:

As the Director of both the Brain Tumor Immunotherapy Program and the Center for Brain and Spine Metastasis at Duke University, I focus our programmatic interests on the design, optimization, and monitoring of immune-based treatment platforms for patients with intracranial tumors, whether primary or metastatic. Within this broad scope, however, my own group looks more specifically at limitations to immunotherapeutic success, with a particular focus on understanding and reversing T cell dysfunction in patients with glioblastoma (GBM) and brain metastases. We employ a systematic approach to categorizing T cell dysfunction (Woroniecka et al, Clin Cancer Res 2018 Aug 15;24(16):3792-3802), and whereas our earlier work addressed concerns for regulatory T cell-induced tolerance, we now heavily study T cell ignorance and exhaustion, as well. Regarding the former, we recently published the novel phenomenon of S1P1-mediated bone marrow T cell sequestration in patients with intracranial tumors (Chongsathidkiet et al, Nat Medicine 2018 Sep;24(9):1459-1468). Regarding the latter, we have likewise recently identified and characterized exhaustion as a significant limitation to T-cell function within GBM (Woroniecka et al, Clin Cancer Res 2018 Sep 1;24(17):4175-4186). I very much look to collaboratively integrate our approaches with others investigating innovative treatment options. I continue my focus on combining strategies for reversing T cell deficits with current and novel immune-based platforms as a means of deriving and improving rational and precise anti-tumor therapies. It is my sincerest desire to forge a career focused on co-operative, multi-disciplinary, organized brain tumor therapy. Ultimately, my goal is to help coordinate the efforts of a streamlined and effective center for brain tumor research and clinical care. I hope to play some role in ushering in a period where the science and treatment arms of brain tumor therapy suffer no disjoint, but instead represent the convergent efforts of researchers, neuro-oncologists, medical oncologists, radiation oncologists, biomedical engineers, and neurosurgeons alike. I hope to see such synergy become standard of care.

Positions:

Associate Professor of Neurosurgery

Neurosurgery
School of Medicine

Assistant Research Professor in Immunology

Immunology
School of Medicine

Associate Professor in Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 2007

M.D. — Duke University School of Medicine

Ph.D. 2007

Ph.D. — Duke University

Internship, General Surgery

Massachusetts General Hospital

Residency, Neurosurgery

Massachusetts General Hospital

Postdoctoral Fellow

Dana Farber Cancer Institute

Instructor, Neurosurgery

Massachusetts General Hospital

News:

Grants:

Duke CTSA (KL2)

Administered By
Institutes and Centers
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
May 02, 2018
End Date
April 30, 2023

Duke CTSA (TL1)

Administered By
Institutes and Centers
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
May 02, 2018
End Date
April 30, 2023

Medical Scientist Training Program

Administered By
School of Medicine
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1997
End Date
June 30, 2022

A Novel Clinical Challenge in Brain Tumor Immunology: T cell Sequestration

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
December 15, 2016
End Date
November 30, 2021

Identification of actionable networks promoting breast cancer progression and brain metastasis

Administered By
Pharmacology & Cancer Biology
AwardedBy
Department of Defense
Role
Collaborator
Start Date
September 01, 2018
End Date
August 31, 2021

Translational Research in Surgical Oncology

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Co-Mentor
Start Date
January 01, 2002
End Date
August 31, 2021

The Role of CD155 in Leptomeningeal Dissemination and Oncolytic Virus Susceptibility in the Medulloblastoma Microenvironment

Administered By
Neurosurgery
AwardedBy
Department of Defense
Role
Significant Contributor
Start Date
August 01, 2018
End Date
July 31, 2021

Laser Ablation using Robotic Neuroblate System (LAANTERN)

Administered By
Neurosurgery
Role
Principal Investigator
Start Date
March 01, 2016
End Date
December 31, 2020

Lost and Found: The Bone Marrow as Counterproductive Site of T cell Sequestration in GBM

Administered By
Neurosurgery
AwardedBy
Sontag Foundation
Role
Principal Investigator
Start Date
October 01, 2015
End Date
September 30, 2019

Validation of Novel Therapeutic Approach for Leptomeningeal Metastases

Administered By
Neurosurgery
Role
Co Investigator
Start Date
August 01, 2018
End Date
July 31, 2019

NINDS Research Education Programs for Residents and Fellows in Neurosurgery

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
March 01, 2009
End Date
June 30, 2019

LITT and Short Course Radiation for Patients with GBM Requiring Standard Treatment Alternatives (LASR)

Administered By
Duke Cancer Institute
Role
Principal Investigator
Start Date
April 27, 2017
End Date
April 26, 2019

Directed Chemotherapy Delivery for Leptomeningeal Metastases

Administered By
Neurosurgery
Role
Co Investigator
Start Date
September 01, 2016
End Date
August 31, 2017
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Awards:

Paper of the Year. American Association of Physicists in Medicine.

Type
Scholarly Society
Awarded By
American Association of Physicists in Medicine
Date
January 01, 2017

Visting Scholar. National Institutes of Health.

Type
National
Awarded By
National Institutes of Health
Date
January 01, 2017

Duke Health Scholars Award. Duke University School of Medicine.

Type
University
Awarded By
Duke University School of Medicine
Date
January 01, 2016

Prince Mahidol Youth Mentor Award. Prince Mahidol Award Foundation.

Type
International
Awarded By
Prince Mahidol Award Foundation
Date
January 01, 2016

Alpha Omega Alpha. Alpha Omega Alpha Medical Honor Society.

Type
Scholarly Society
Awarded By
Alpha Omega Alpha Medical Honor Society
Date
January 01, 2015

Resident Advocate Award. Duke University Department of Neurosurgery.

Type
Department
Awarded By
Duke University Department of Neurosurgery
Date
January 01, 2015

Sontag Distinguished Scientist Award. Sontag Foundation.

Type
Scholarly Society
Awarded By
Sontag Foundation
Date
January 01, 2015

Matson Award for Best Basic Science Research. New England Neurosurgical Society.

Type
Scholarly Society
Awarded By
New England Neurosurgical Society
Date
January 01, 2013

Preuss Award for Neuro-Oncologic Research. Congress of Neurological Surgeons.

Type
Scholarly Society
Awarded By
Congress of Neurological Surgeons
Date
January 01, 2013

NIH Loan Repayment Program Award. National Institutes of Health.

Type
National
Awarded By
National Institutes of Health
Date
January 01, 2011

Resident Teaching Award. Tufts University School of Medicine.

Type
Department
Awarded By
Tufts University School of Medicine
Date
January 01, 2008

Neurosurgery Award. Duke University Department of Neurosurgery.

Type
Department
Awarded By
Duke University Department of Neurosurgery
Date
January 01, 2007

Keynote Speaker. Society for Neuro-Oncology.

Type
Scholarly Society
Awarded By
Society for Neuro-Oncology
Date
January 01, 2006

Eugene A. Stead Scholar. Duke University School of Medicine.

Type
University
Awarded By
Duke University School of Medicine
Date
January 01, 2001

Medical Scientist Training Program Fellowship. National Institutes of Health.

Type
National
Awarded By
National Institutes of Health
Date
January 01, 2001

Cornell-Diamante Scholarship. Cornell University.

Type
University
Awarded By
Cornell University
Date
January 01, 1999

Merrill Presidential Scholar. Cornell University.

Type
University
Awarded By
Cornell University
Date
January 01, 1999

Nanaline H. Duke Scholar. Duke University School of Medicine.

Type
University
Awarded By
Duke University School of Medicine
Date
January 01, 1999

Publications:

Sinonasal Quality of Life Outcomes After Extended Endonasal Approaches to the Skull Base.

Introduction  Endoscopic endonasal skull base surgery (EESBS) leads to significant alterations in sinonasal anatomy and physiology. However, there is limited data available on quality of life (QOL) outcomes following EESBS. Methods  A retrospective review of patients undergoing EESBS from January 2014 to April 2017 was performed. Records were reviewed for clinical history, operative details, and 22-item Sinonasal Outcomes Test (SNOT-22) scores. Unadjusted and adjusted linear regression models were utilized to compare change in SNOT-22 scores from baseline in patients who underwent a simple sella approach (SA) or an extended beyond sella approach (BSA). Results  A total of 108 patients were in the SA group, while 61 patients were in the BSA group. SNOT-22 scores were available at baseline and 3 months for 84 patients, while 6-month scores were available for 49 patients. SNOT-22 scores for all patients were not significantly different at 3 months ( p  = 0.40) or at 6 months ( p  = 0.58). Unadjusted linear regression model did not show an association between the type of approach and change in SNOT-22 score at 3 months ( p  = 0.07) and 6 months ( p  = 0.28). Adjusted regression model showed a significant decrease in SNOT-22 scores at 3 months ( p  = 0.04) for the BSA group, but there was no significant change in SNOT-22 score at 6 months ( p  = 0.22). Conclusion  Patients undergoing EESBS had no significant change in outcomes at 3 and 6 months. A more extensive BSA was not associated with worse QOL outcomes as measured by SNOT-22.

Authors
Choi, KJ; Ackall, FY; Truong, T; Cheng, TZ; Kuchibhatla, M; Zomorodi, AR; Codd, PJ; Fecci, PE; Hachem, RA; Jang, DW
MLA Citation
Choi, Kevin J., et al. “Sinonasal Quality of Life Outcomes After Extended Endonasal Approaches to the Skull Base..” J Neurol Surg B Skull Base, vol. 80, no. 4, Aug. 2019, pp. 416–23. Pubmed, doi:10.1055/s-0038-1675592.
PMID
31316887
Source
pubmed
Published In
Journal of Neurological Surgery Part B: Skull Base
Volume
80
Issue
4
Publish Date
2019
Start Page
416
End Page
423
DOI
10.1055/s-0038-1675592

Lymphopenia and Bone Marrow T-cell Sequestration Accompanying Stroke are Mediated by T-cell S1P1 Loss

Authors
DeChant, C; Chongsathidkiet, P; Wilkinson, D; Wang, H; Kemeny, H; Polania, JW; Cui, X; Laskowitz, D; Fecci, P
MLA Citation
DeChant, Cosette, et al. “Lymphopenia and Bone Marrow T-cell Sequestration Accompanying Stroke are Mediated by T-cell S1P1 Loss.” Journal of Neurosurgery, vol. 131, no. 1, AMER ASSOC NEUROLOGICAL SURGEONS, 2019.
Source
wos
Published In
Journal of Neurosurgery
Volume
131
Issue
1
Publish Date
2019

Targeting Immunostimulatory Pathways in Combination with Checkpoint Blockade Improves Survival in Murine Glioma

Authors
Woroniecka, K; Dechant, C; Rhodin, K; Chongsathidkiet, P; Wilkerson, D; Cui, X; Fecci, P
MLA Citation
Woroniecka, Karolina, et al. “Targeting Immunostimulatory Pathways in Combination with Checkpoint Blockade Improves Survival in Murine Glioma.” Journal of Neurosurgery, vol. 131, no. 1, AMER ASSOC NEUROLOGICAL SURGEONS, 2019.
Source
wos
Published In
Journal of Neurosurgery
Volume
131
Issue
1
Publish Date
2019

The Evolving Modern Management of Brain Metastasis.

The incidence of brain metastases is increasing as cancer therapies improve and patients live longer, providing new challenges to the multidisciplinary teams that care for these patients. Brain metastatic cancer cells possess unique characteristics that allow them to penetrate the blood-brain barrier, colonize the brain parenchyma, and persist in the intracranial environment. In addition, brain metastases subvert the innate and adaptive immune system, permitting evasion of the antitumor immune response. Better understanding of the above mechanisms will allow for development and delivery of more effective therapies for brain metastases. In this review, we outline the molecular mechanisms underlying development, survival, and immunosuppression of brain metastases. We also discuss current and emerging treatment strategies, including surgery, radiation, disease-specific and mutation-targeted systemic therapy, and immunotherapy.

Authors
Fecci, PE; Champion, CD; Hoj, J; McKernan, CM; Goodwin, CR; Kirkpatrick, JP; Anders, CK; Pendergast, AM; Sampson, JH
MLA Citation
Fecci, Peter E., et al. “The Evolving Modern Management of Brain Metastasis..” Clin Cancer Res, June 2019. Pubmed, doi:10.1158/1078-0432.CCR-18-1624.
PMID
31213459
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Publish Date
2019
DOI
10.1158/1078-0432.CCR-18-1624

Fostering Antecedent T-cell Activation with 41BB Agonism Licenses Checkpoint Blockade in Murine Glioma

Authors
Woroniecka, K; Dechant, C; Rhodin, K; Chongsathidkiet, P; Wilkinson, D; Cui, X; Fecci, P
MLA Citation
Woroniecka, Karolina, et al. “Fostering Antecedent T-cell Activation with 41BB Agonism Licenses Checkpoint Blockade in Murine Glioma.” Journal of Neuropathology and Experimental Neurology, vol. 78, no. 6, OXFORD UNIV PRESS INC, 2019, pp. 529–529.
Source
wos
Published In
Journal of Neuropathology and Experimental Neurology
Volume
78
Issue
6
Publish Date
2019
Start Page
529
End Page
529

Author Correction: Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors.

In the version of this article originally published, the figure callout in this sentence was incorrect: "Furthermore, in S1P1-KI mice themselves, whereas PD-1 blockade was ineffectual as monotherapy, the effects of 4-1BB agonism and checkpoint blockade proved additive, with the combination prolonging median survival and producing a 50% long-term survival rate (Fig. 6f)." The callout should have been to Supplementary Fig. 6b. The error has been corrected in the PDF and HTML versions of the article.

Authors
Chongsathidkiet, P; Jackson, C; Koyama, S; Loebel, F; Cui, X; Farber, SH; Woroniecka, K; Elsamadicy, AA; Dechant, CA; Kemeny, HR; Sanchez-Perez, L; Cheema, TA; Souders, NC; Herndon, JE; Coumans, J-V; Everitt, JI; Nahed, BV; Sampson, JH; Gunn, MD; Martuza, RL; Dranoff, G; Curry, WT; Fecci, PE
MLA Citation
Chongsathidkiet, Pakawat, et al. “Author Correction: Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors..” Nat Med, vol. 25, no. 3, Mar. 2019. Pubmed, doi:10.1038/s41591-019-0355-0.
PMID
30670876
Source
pubmed
Published In
Nat Med
Volume
25
Issue
3
Publish Date
2019
Start Page
529
DOI
10.1038/s41591-019-0355-0

Preventing Lck Activation in CAR T Cells Confers Treg Resistance but Requires 4-1BB Signaling for Them to Persist and Treat Solid Tumors in Nonlymphodepleted Hosts.

PURPOSE: Chimeric antigen receptor (CAR) T cells have shown promise against solid tumors, but their efficacy has been limited, due in part, to immunosuppression by CD4+FoxP3+ regulatory T cells (Tregs). Although lymphodepletion is commonly used to deplete Tregs, these regimens are nonspecific, toxic, and provide only a narrow window before Tregs repopulate hosts. Importantly, CARs have also been shown to inadvertently potentiate Tregs by providing a source of IL2 for Treg consumption. We explored whether disruption of the IL2 axis would confer efficacy against solid tumors without the need for lymphodepletion. EXPERIMENTAL DESIGN: We developed second- (CD28z) and third- (CD28-4-1BBz) generation CARs targeting EGFRvIII. To eliminate secretion of IL2, 2 amino acid substitutions were introduced in the PYAP Lck-binding motif of the CD28 domain (ΔCD28). We evaluated CARs against B16 melanomas expressing EGFRvIII. RESULTS: CD28z CARs failed to engraft in vivo. Although 4-1BB addition improved expansion, CD28-4-1BBz CARs required lymphodepletion to treat solid tumors. CARs deficient in Lck signaling, however, significantly retarded tumor growth without a need for lymphodepletion and this was dependent on inclusion of 4-1BB. To evaluate CAR vulnerability to Tregs, we lymphodepleted mice and transferred CARs alone or with purified Tregs. Cotransfer with Tregs abrogated the efficacy of CD28-4-1BBz CARs, whereas the efficacy of ΔCD28-4-1BBz CARs remained unperturbed. CONCLUSIONS: In the absence of lymphodepletion, CARs targeting solid tumors are hindered by Treg immunosuppression and poor persistence. Here, CARs were modified to circumvent Treg suppression and to simultaneously improve in vivo engraftment. Modified CARs treated solid tumors without a need for lymphodepletion.

Authors
Suryadevara, CM; Desai, R; Farber, SH; Choi, BD; Swartz, AM; Shen, SH; Gedeon, PC; Snyder, DJ; Herndon, JE; Healy, P; Reap, EA; Archer, GE; Fecci, PE; Sampson, JH; Sanchez-Perez, L
MLA Citation
Suryadevara, Carter M., et al. “Preventing Lck Activation in CAR T Cells Confers Treg Resistance but Requires 4-1BB Signaling for Them to Persist and Treat Solid Tumors in Nonlymphodepleted Hosts..” Clin Cancer Res, vol. 25, no. 1, Jan. 2019, pp. 358–68. Pubmed, doi:10.1158/1078-0432.CCR-18-1211.
PMID
30425092
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
25
Issue
1
Publish Date
2019
Start Page
358
End Page
368
DOI
10.1158/1078-0432.CCR-18-1211

A NOVEL NANOTECHNOLOGY-BASED PLATFORM IMPROVES LASER INTERSTITIAL THERMAL THERAPY FOR INTRACRANIAL TUMORS

Authors
Chongsathidkiet, P; Liu, Y; Kemeny, H; Dechant, C; Odion, R; Cui, X; Rhodin, K; Tuan, V-D; Fecci, P
MLA Citation
Chongsathidkiet, Pakawat, et al. “A NOVEL NANOTECHNOLOGY-BASED PLATFORM IMPROVES LASER INTERSTITIAL THERMAL THERAPY FOR INTRACRANIAL TUMORS.” Neuro Oncology, vol. 20, OXFORD UNIV PRESS INC, 2018, pp. 89–90.
Source
wos
Published In
Neuro Oncology
Volume
20
Publish Date
2018
Start Page
89
End Page
90

PREVENTING T-CELL S1P1 INTERNALIZATION OBVIATES BONE MARROW T CELL SEQUESTRATION AND IMPROVES IMMUNOTHERAPEUTIC EFFICACY IN GBM

Authors
Chongsathidkiet, P; Woroniecka, K; Dechant, C; Kemeny, H; Cui, X; Wilkinson, D; Fecci, P
MLA Citation
Chongsathidkiet, Pakawat, et al. “PREVENTING T-CELL S1P1 INTERNALIZATION OBVIATES BONE MARROW T CELL SEQUESTRATION AND IMPROVES IMMUNOTHERAPEUTIC EFFICACY IN GBM.” Neuro Oncology, vol. 20, OXFORD UNIV PRESS INC, 2018, pp. 127–127.
Source
wos
Published In
Neuro Oncology
Volume
20
Publish Date
2018
Start Page
127
End Page
127

UPFRONT MRI-GUIDED STEREOTACTIC LASER-ABLATION IN NEWLY DIAGNOSED GLIOBLASTOMA: A MULTICENTER REVIEW OF SURVIVAL OUTCOMES COMPARED TO A MATCHED COHORT OF BIOPSY-ONLY PATIENTS

Authors
Mohammadi, A; Sharma, M; Beaumont, T; Juarez, K; Kemeny, H; Dechant, C; Seas, A; Sarmey, N; Lee, B; Jia, X; Fecci, P; Baehring, J; Moliterno, J; Chiang, V; Ahluwalia, M; Kim, A; Barnett, G; Leuthardt, E
MLA Citation
Mohammadi, Alireza, et al. “UPFRONT MRI-GUIDED STEREOTACTIC LASER-ABLATION IN NEWLY DIAGNOSED GLIOBLASTOMA: A MULTICENTER REVIEW OF SURVIVAL OUTCOMES COMPARED TO A MATCHED COHORT OF BIOPSY-ONLY PATIENTS.” Neuro Oncology, vol. 20, OXFORD UNIV PRESS INC, 2018, pp. 253–54.
Source
wos
Published In
Neuro Oncology
Volume
20
Publish Date
2018
Start Page
253
End Page
254

LASER ABLATION FOR BRAIN METASTASES: SAFETY AND PRELIMINARY OUTCOMES FROM THE LASER ABLATION OF ABNORMAL NEUROLOGICAL TISSUE USING ROBOTIC NEUROBLATE SYSTEM (LAANTERN) REGISTRY

Authors
Kamath, A; Tatter, S; Fecci, P; Chen, C; Chiang, V; Rao, G; Mohammadi, A; Judy, K; Field, M; Neimat, J; Leuthardt, E; Kim, A
MLA Citation
Kamath, Ashwin, et al. “LASER ABLATION FOR BRAIN METASTASES: SAFETY AND PRELIMINARY OUTCOMES FROM THE LASER ABLATION OF ABNORMAL NEUROLOGICAL TISSUE USING ROBOTIC NEUROBLATE SYSTEM (LAANTERN) REGISTRY.” Neuro Oncology, vol. 20, OXFORD UNIV PRESS INC, 2018, pp. 251–251.
Source
wos
Published In
Neuro Oncology
Volume
20
Publish Date
2018
Start Page
251
End Page
251

Surgical Cavities Exhibit Substantial Remodeling Post Resection of Brain Metastases: Implications for Stereotactic Radiosurgery (SRS)

Authors
Tanksley, J; Adamson, J; Torok, J; Kim, GJ; Floyd, SR; Fecci, P; Kirkpatrick, JP
MLA Citation
Tanksley, J., et al. “Surgical Cavities Exhibit Substantial Remodeling Post Resection of Brain Metastases: Implications for Stereotactic Radiosurgery (SRS).” International Journal of Radiation Oncology*Biology*Physics, vol. 102, no. 3, Elsevier BV, 2018, pp. S151–S151. Crossref, doi:10.1016/j.ijrobp.2018.06.365.
Source
crossref
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
102
Issue
3
Publish Date
2018
Start Page
S151
End Page
S151
DOI
10.1016/j.ijrobp.2018.06.365

T-cell exhaustion in glioblastoma

Authors
Woroniecka, K; Fecci, PE
MLA Citation
Woroniecka, K., and P. E. Fecci. “T-cell exhaustion in glioblastoma.” Oncotarget, vol. 9, no. 82, Oct. 2018, pp. 35287–88.
Source
scopus
Published In
Oncotarget
Volume
9
Issue
82
Publish Date
2018
Start Page
35287
End Page
35288

Hyaluronic acid based low viscosity hydrogel as a novel carrier for Convection Enhanced Delivery of CAR T cells

Authors
Atik, AF; Suryadevara, CM; Schweller, RM; West, JL; Healy, P; Herndon, JE; Congdon, KL; Sanchez-Perez, L; McLendon, RE; Archer, GE; Fecci, P; Sampson, JH
MLA Citation
Atik, Ahmet F., et al. “Hyaluronic acid based low viscosity hydrogel as a novel carrier for Convection Enhanced Delivery of CAR T cells.” Journal of Clinical Neuroscience, vol. 56, ELSEVIER SCI LTD, Oct. 2018, pp. 163–68. Wos, doi:10.1016/j.jocno.2018.06.005.
Source
wos
Published In
Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia
Volume
56
Publish Date
2018
Start Page
163
End Page
168
DOI
10.1016/j.jocno.2018.06.005

Hyaluronic acid based low viscosity hydrogel as a novel carrier for Convection Enhanced Delivery of CAR T cells.

Convection Enhanced Delivery (CED) infuses therapeutic agents directly into the intracranial area continuously under pressure. The convection improves the distribution of therapeutics such as those aimed at brain tumors. Although CED successfully delivers small therapeutic agents, this technique fails to effectively deliver cells largely due to cell sedimentation during delivery. To overcome this limitation, we have developed a low viscosity hydrogel (LVHydrogel), which is capable of retaining cells in suspension. In this study, we evaluated whether LVHydrogel can effectively act as a carrier for the CED of tumor-specific chimeric antigen receptor (CAR) T cells. CAR T cells were resuspended in saline or LVHydrogel carriers, loaded into syringes, and passed through the CED system for 5 h. CAR T cells submitted to CED were counted and the efficiency of delivery was determined. In addition to delivery, the ability of CAR T cells to migrate and induce cytotoxicity was evaluated. Our studies demonstrate that LVHydrogel is a superior carrier for CED in comparison to saline. The efficiency of cell delivery in saline carrier was only ∼3-5% of the total cells whereas delivery by the LVHydrogel carrier was much higher, reaching ∼45-75%. Migration and Cytotoxicity was similar in both carriers in non-infused samples but we found superior cytotoxicity in LVHydrogel group post-infusion. We demonstrate that LVHydrogel, a biodegradable biomaterial which does not cause acute toxicity on preclinical animal models, prevents cellular sedimentation during CED and presents itself as a superior carrier to the current carrier, saline, for the CED of CAR T cells.

Authors
Atik, AF; Suryadevara, CM; Schweller, RM; West, JL; Healy, P; Herndon Ii, JE; Congdon, KL; Sanchez-Perez, L; McLendon, RE; Archer, GE; Fecci, P; Sampson, JH
MLA Citation
Atik, Ahmet F., et al. “Hyaluronic acid based low viscosity hydrogel as a novel carrier for Convection Enhanced Delivery of CAR T cells..” J Clin Neurosci, vol. 56, Oct. 2018, pp. 163–68. Pubmed, doi:10.1016/j.jocn.2018.06.005.
PMID
30041899
Source
pubmed
Published In
J Clin Neurosci
Volume
56
Publish Date
2018
Start Page
163
End Page
168
DOI
10.1016/j.jocn.2018.06.005

T-Cell Exhaustion Signatures Vary with Tumor Type and Are Severe in Glioblastoma.

Purpose: T-cell dysfunction is a hallmark of glioblastoma (GBM). Although anergy and tolerance have been well characterized, T-cell exhaustion remains relatively unexplored. Exhaustion, characterized in part by the upregulation of multiple immune checkpoints, is a known contributor to failures amid immune checkpoint blockade, a strategy that has lacked success thus far in GBM. This study is among the first to examine, and credential as bona fide, exhaustion among T cells infiltrating human and murine GBM.Experimental Design: Tumor-infiltrating and peripheral blood lymphocytes (TILs and PBLs) were isolated from patients with GBM. Levels of exhaustion-associated inhibitory receptors and poststimulation levels of the cytokines IFNγ, TNFα, and IL2 were assessed by flow cytometry. T-cell receptor Vβ chain expansion was also assessed in TILs and PBLs. Similar analysis was extended to TILs isolated from intracranial and subcutaneous immunocompetent murine models of glioma, breast, lung, and melanoma cancers.Results: Our data reveal that GBM elicits a particularly severe T-cell exhaustion signature among infiltrating T cells characterized by: (1) prominent upregulation of multiple immune checkpoints; (2) stereotyped T-cell transcriptional programs matching classical virus-induced exhaustion; and (3) notable T-cell hyporesponsiveness in tumor-specific T cells. Exhaustion signatures differ predictably with tumor identity, but remain stable across manipulated tumor locations.Conclusions: Distinct cancers possess similarly distinct mechanisms for exhausting T cells. The poor TIL function and severe exhaustion observed in GBM highlight the need to better understand this tumor-imposed mode of T-cell dysfunction in order to formulate effective immunotherapeutic strategies targeting GBM. Clin Cancer Res; 24(17); 4175-86. ©2018 AACRSee related commentary by Jackson and Lim, p. 4059.

Authors
Woroniecka, K; Chongsathidkiet, P; Rhodin, K; Kemeny, H; Dechant, C; Farber, SH; Elsamadicy, AA; Cui, X; Koyama, S; Jackson, C; Hansen, LJ; Johanns, TM; Sanchez-Perez, L; Chandramohan, V; Yu, Y-RA; Bigner, DD; Giles, A; Healy, P; Dranoff, G; Weinhold, KJ; Dunn, GP; Fecci, PE
MLA Citation
Woroniecka, Karolina, et al. “T-Cell Exhaustion Signatures Vary with Tumor Type and Are Severe in Glioblastoma..” Clin Cancer Res, vol. 24, no. 17, Sept. 2018, pp. 4175–86. Pubmed, doi:10.1158/1078-0432.CCR-17-1846.
PMID
29437767
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
24
Issue
17
Publish Date
2018
Start Page
4175
End Page
4186
DOI
10.1158/1078-0432.CCR-17-1846

Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors.

T cell dysfunction contributes to tumor immune escape in patients with cancer and is particularly severe amidst glioblastoma (GBM). Among other defects, T cell lymphopenia is characteristic, yet often attributed to treatment. We reveal that even treatment-naïve subjects and mice with GBM can harbor AIDS-level CD4 counts, as well as contracted, T cell-deficient lymphoid organs. Missing naïve T cells are instead found sequestered in large numbers in the bone marrow. This phenomenon characterizes not only GBM but a variety of other cancers, although only when tumors are introduced into the intracranial compartment. T cell sequestration is accompanied by tumor-imposed loss of S1P1 from the T cell surface and is reversible upon precluding S1P1 internalization. In murine models of GBM, hindering S1P1 internalization and reversing sequestration licenses T cell-activating therapies that were previously ineffective. Sequestration of T cells in bone marrow is therefore a tumor-adaptive mode of T cell dysfunction, whose reversal may constitute a promising immunotherapeutic adjunct.

Authors
Chongsathidkiet, P; Jackson, C; Koyama, S; Loebel, F; Cui, X; Farber, SH; Woroniecka, K; Elsamadicy, AA; Dechant, CA; Kemeny, HR; Sanchez-Perez, L; Cheema, TA; Souders, NC; Herndon, JE; Coumans, J-V; Everitt, JI; Nahed, BV; Sampson, JH; Gunn, MD; Martuza, RL; Dranoff, G; Curry, WT; Fecci, PE
MLA Citation
Chongsathidkiet, Pakawat, et al. “Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors..” Nat Med, vol. 24, no. 9, Sept. 2018, pp. 1459–68. Pubmed, doi:10.1038/s41591-018-0135-2.
PMID
30104766
Source
pubmed
Published In
Nat Med
Volume
24
Issue
9
Publish Date
2018
Start Page
1459
End Page
1468
DOI
10.1038/s41591-018-0135-2

T-cell Dysfunction in Glioblastoma: Applying a New Framework.

A functional, replete T-cell repertoire is an integral component to adequate immune surveillance and to the initiation and maintenance of productive antitumor immune responses. Glioblastoma (GBM), however, is particularly adept at sabotaging antitumor immunity, eliciting severe T-cell dysfunction that is both qualitative and quantitative. Understanding and countering such dysfunction are among the keys to harnessing the otherwise stark potential of anticancer immune-based therapies. Although T-cell dysfunction in GBM has been long described, newer immunologic frameworks now exist for reclassifying T-cell deficits in a manner that better permits their study and reversal. Herein, we divide and discuss the various T-cell deficits elicited by GBM within the context of the five relevant categories: senescence, tolerance, anergy, exhaustion, and ignorance. Categorization is appropriately made according to the molecular bases of dysfunction. Likewise, we review the mechanisms by which GBM elicits each mode of T-cell dysfunction and discuss the emerging immunotherapeutic strategies designed to overcome them. Clin Cancer Res; 24(16); 3792-802. ©2018 AACR.

Authors
Woroniecka, KI; Rhodin, KE; Chongsathidkiet, P; Keith, KA; Fecci, PE
MLA Citation
Woroniecka, Karolina I., et al. “T-cell Dysfunction in Glioblastoma: Applying a New Framework..” Clin Cancer Res, vol. 24, no. 16, Aug. 2018, pp. 3792–802. Pubmed, doi:10.1158/1078-0432.CCR-18-0047.
PMID
29593027
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
24
Issue
16
Publish Date
2018
Start Page
3792
End Page
3802
DOI
10.1158/1078-0432.CCR-18-0047

Patterns of Clinical Use of Stereotactic Laser Ablation: Analysis of a Multicenter Prospective Registry.

BACKGROUND: Stereotactic laser ablation (SLA), also termed laser interstitial thermal therapy, is a minimally invasive procedure that is increasingly used in neurosurgery. We wished to examine how and whether SLA is changing the landscape of treatment options for neurosurgical patients. METHODS: Patients undergoing stereotactic laser ablation were prospectively enrolled in the Laser Ablation of Abnormal Neurological Tissue (LAANTERN) registry. Data from the first 100 enrolled patients are presented here. RESULTS: Clinical indications for SLA include treatment of primary intracranial tumors (48%; 81% being high-grade gliomas [HGGs]), brain metastases (BMs, 34%), epilepsy (16%), and other (2%). For HGGs, SLA was equally likely used for newly diagnosed (45%) or previously treated/recurrent lesions (55%, P = 0.54). By contrast, SLA was predominantly used as treatment for BMs in which radiation therapy/radiosurgery had failed (91%), with only 9% of SLAs performed as initial treatment for newly diagnosed lesions (P < 0.001). Of all SLAs performed, 45% of the procedures were in lieu of surgical resection, with 43% performed because the lesion was not accessible by conventional neurosurgical techniques. CONCLUSION: HGGs and BMs are the leading indications for SLA in the LAANTERN study. For HGGs, SLA is equally used in the presenting or previously treated/recurrent setting. For BMs, SLA is typically used in the recurrent setting. SLAs are equally likely to be performed for difficult-to-access lesions or in lieu of conventional open surgery.

Authors
Rennert, RC; Khan, U; Tatter, SB; Field, M; Toyota, B; Fecci, PE; Judy, K; Mohammadi, AM; Landazuri, P; Sloan, A; Leuthardt, E; Chen, CC
MLA Citation
Rennert, Robert C., et al. “Patterns of Clinical Use of Stereotactic Laser Ablation: Analysis of a Multicenter Prospective Registry..” World Neurosurg, vol. 116, Aug. 2018, pp. e566–70. Pubmed, doi:10.1016/j.wneu.2018.05.039.
PMID
29772367
Source
pubmed
Published In
World Neurosurg
Volume
116
Publish Date
2018
Start Page
e566
End Page
e570
DOI
10.1016/j.wneu.2018.05.039

Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy.

BACKGROUND: Corticosteroids are routinely utilized to alleviate edema in patients with intracranial lesions and are first-line agents to combat immune-related adverse events (irAEs) that arise with immune checkpoint blockade treatment. However, it is not known if or when corticosteroids can be administered without abrogating the efforts of immunotherapy. The purpose of this study was to evaluate the impact of dexamethasone on lymphocyte activation and proliferation during checkpoint blockade to provide guidance for corticosteroid use while immunotherapy is being implemented as a cancer treatment. METHODS: Lymphocyte proliferation, differentiation, and cytokine production were evaluated during dexamethasone exposure. Human T cells were stimulated through CD3 ligation and co-stimulated either directly by CD28 ligation or by providing CD80, a shared ligand for CD28 and CTLA-4. CTLA-4 signaling was inhibited by antibody blockade using ipilimumab which has been approved for the treatment of several solid tumors. The in vivo effects of dexamethasone during checkpoint blockade were evaluated using the GL261 syngeneic mouse intracranial model, and immune populations were profiled by flow cytometry. RESULTS: Dexamethasone upregulated CTLA-4 mRNA and protein in CD4 and CD8 T cells and blocked CD28-mediated cell cycle entry and differentiation. Naïve T cells were most sensitive, leading to a decrease of the development of more differentiated subsets. Resistance to dexamethasone was conferred by blocking CTLA-4 or providing strong CD28 co-stimulation prior to dexamethasone exposure. CTLA-4 blockade increased IFNγ expression, but not IL-2, in stimulated human peripheral blood T cells exposed to dexamethasone. Finally, we found that CTLA-4 blockade partially rescued T cell numbers in mice bearing intracranial gliomas. CTLA-4 blockade was associated with increased IFNγ-producing tumor-infiltrating T cells and extended survival of dexamethasone-treated mice. CONCLUSIONS: Dexamethasone-mediated T cell suppression diminishes naïve T cell proliferation and differentiation by attenuating the CD28 co-stimulatory pathway. However, CTLA-4, but not PD-1 blockade can partially prevent some of the inhibitory effects of dexamethasone on the immune response.

Authors
Giles, AJ; Hutchinson, M-KND; Sonnemann, HM; Jung, J; Fecci, PE; Ratnam, NM; Zhang, W; Song, H; Bailey, R; Davis, D; Reid, CM; Park, DM; Gilbert, MR
MLA Citation
Giles, Amber J., et al. “Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy..” J Immunother Cancer, vol. 6, no. 1, June 2018. Pubmed, doi:10.1186/s40425-018-0371-5.
PMID
29891009
Source
pubmed
Published In
Journal for Immunotherapy of Cancer
Volume
6
Issue
1
Publish Date
2018
Start Page
51
DOI
10.1186/s40425-018-0371-5

In Reply to Pratx and Kapp.

Authors
Oldham, M; Yoon, SW; Adamson, J; Zhang, X; Fecci, P; Dewhirst, M
MLA Citation
Oldham, Mark, et al. “In Reply to Pratx and Kapp..” Int J Radiat Oncol Biol Phys, vol. 101, no. 2, June 2018, pp. 495–96. Pubmed, doi:10.1016/j.ijrobp.2018.02.018.
PMID
29726370
Source
pubmed
Published In
Int J Radiat Oncol Biol Phys
Volume
101
Issue
2
Publish Date
2018
Start Page
495
End Page
496
DOI
10.1016/j.ijrobp.2018.02.018

Antitumor efficacy Of anti-PDL-1 In ACTH-secreting pituitary adenomas: an immunotherapeutic approach for Cushing's disease

Authors
Kemeny, H; Elsamadicy, A; Farber, S; Chongsathidkiet, P; Woroniecka, K; Cui, X; Dunn, I; Fecci, P
MLA Citation
Kemeny, Hanna, et al. “Antitumor efficacy Of anti-PDL-1 In ACTH-secreting pituitary adenomas: an immunotherapeutic approach for Cushing's disease.” Journal of Neurosurgery, vol. 128, no. 4, AMER ASSOC NEUROLOGICAL SURGEONS, 2018, pp. 81–82.
Source
wos
Published In
Journal of Neurosurgery
Volume
128
Issue
4
Publish Date
2018
Start Page
81
End Page
82

SYMPHONY: A novel synergistic nanotechnology-based platform for the improvement of laser interstitial thermal therapy

Authors
Chongsathidkiet, P; Kemeny, H; Liu, Y; Elsamadicy, A; Cui, X; Woroniecka, K; Tuan, V-D; Fecci, P
MLA Citation
Chongsathidkiet, Pakawat, et al. “SYMPHONY: A novel synergistic nanotechnology-based platform for the improvement of laser interstitial thermal therapy.” Journal of Neurosurgery, vol. 128, no. 4, AMER ASSOC NEUROLOGICAL SURGEONS, 2018, pp. 60–60.
Source
wos
Published In
Journal of Neurosurgery
Volume
128
Issue
4
Publish Date
2018
Start Page
60
End Page
60

Enhancing Radiation Therapy Through Cherenkov Light-Activated Phototherapy.

PURPOSE: This work investigates a new approach to enhance radiotherapy through a photo therapeutic agent activated by Cherenkov light produced from the megavoltage photon beam. The process is termed Radiotherapy Enhanced with Cherenkov photo-Activation (RECA). RECA is compatible with various photo-therapeutics, but here we focus on use with psoralen, an ultraviolet activated therapeutic with extensive history of application in superficial and extracorporeal settings. RECA has potential to extend the scope of psoralen treatments beyond superficial to deep seated lesions. METHODS AND MATERIALS: In vitro studies in B16 melanoma and 4T1 murine breast cancer cells were performed to investigate the potential of RT plus RECA versus RT alone for increasing cytotoxicity (local control) and increasing surface expression of major histocompatibility complex I (MHC I). The latter represents potential for immune response amplification (increased antigen presentation), which has been observed in other psoralen therapies. Cytotoxicity assays included luminescence and clonogenics. The MHC I assays were performed using flow cytometry. In addition, Cherenkov light intensity measurements were performed to investigate the possibility of increasing the Cherenkov light intensity per unit dose from clinical megavoltage beams, to maximize psoralen activation. RESULTS: Luminescence assays showed that RECA treatment (2 Gy at 6 MV) increased cytotoxicity by up to 20% and 9.5% for 4T1 and B16 cells, respectively, compared with radiation and psoralen alone (ie, Cherenkov light was blocked). Similarly, flow cytometry revealed median MHC I expression was significantly higher in RECA-treated cells, compared with those receiving radiation and psoralen alone (approximately 450% and 250% at 3 Gy and 6 Gy, respectively, P < .0001). Clonogenic assays of B16 cells at doses of 6 Gy and 12 Gy showed decreases in tumor cell viability of 7% (P = .017) and 36% (P = .006), respectively, when Cherenkov was present. CONCLUSION: This work demonstrates for the first time the potential for photo-activation of psoralen directly in situ, from Cherenkov light generated by a clinical megavoltage treatment beam.

Authors
Yoon, SW; Tsvankin, V; Shrock, Z; Meng, B; Zhang, X; Dewhirst, M; Fecci, P; Adamson, J; Oldham, M
MLA Citation
Yoon, Suk W., et al. “Enhancing Radiation Therapy Through Cherenkov Light-Activated Phototherapy..” Int J Radiat Oncol Biol Phys, vol. 100, no. 3, Mar. 2018, pp. 794–801. Pubmed, doi:10.1016/j.ijrobp.2017.11.013.
Website
https://hdl.handle.net/10161/16475
PMID
29413289
Source
pubmed
Published In
Int J Radiat Oncol Biol Phys
Volume
100
Issue
3
Publish Date
2018
Start Page
794
End Page
801
DOI
10.1016/j.ijrobp.2017.11.013

Dendritic Cells Enhance Polyfunctionality of Adoptively Transferred T Cells That Target Cytomegalovirus in Glioblastoma.

Median survival for glioblastoma (GBM) remains <15 months. Human cytomegalovirus (CMV) antigens have been identified in GBM but not normal brain, providing an unparalleled opportunity to subvert CMV antigens as tumor-specific immunotherapy targets. A recent trial in recurrent GBM patients demonstrated the potential clinical benefit of adoptive T-cell therapy (ATCT) of CMV phosphoprotein 65 (pp65)-specific T cells. However, ex vivo analyses from this study found no change in the capacity of CMV pp65-specific T cells to gain multiple effector functions or polyfunctionality, which has been associated with superior antitumor efficacy. Previous studies have shown that dendritic cells (DC) could further enhance tumor-specific CD8+ T-cell polyfunctionality in vivo when administered as a vaccine. Therefore, we hypothesized that vaccination with CMV pp65 RNA-loaded DCs would enhance the frequency of polyfunctional CMV pp65-specific CD8+ T cells after ATCT. Here, we report prospective results of a pilot trial in which 22 patients with newly diagnosed GBM were initially enrolled, of which 17 patients were randomized to receive CMV pp65-specific T cells with CMV-DC vaccination (CMV-ATCT-DC) or saline (CMV-ATCT-saline). Patients who received CMV-ATCT-DC vaccination experienced a significant increase in the overall frequencies of IFNγ+, TNFα+, and CCL3+ polyfunctional, CMV-specific CD8+ T cells. These increases in polyfunctional CMV-specific CD8+ T cells correlated (R = 0.7371, P = 0.0369) with overall survival, although we cannot conclude this was causally related. Our data implicate polyfunctional T-cell responses as a potential biomarker for effective antitumor immunotherapy and support a formal assessment of this combination approach in a larger randomized study.Significance: A randomized pilot trial in patients with GBM implicates polyfunctional T-cell responses as a biomarker for effective antitumor immunotherapy. Cancer Res; 78(1); 256-64. ©2017 AACR.

Authors
Reap, EA; Suryadevara, CM; Batich, KA; Sanchez-Perez, L; Archer, GE; Schmittling, RJ; Norberg, PK; Herndon, JE; Healy, P; Congdon, KL; Gedeon, PC; Campbell, OC; Swartz, AM; Riccione, KA; Yi, JS; Hossain-Ibrahim, MK; Saraswathula, A; Nair, SK; Dunn-Pirio, AM; Broome, TM; Weinhold, KJ; Desjardins, A; Vlahovic, G; McLendon, RE; Friedman, AH; Friedman, HS; Bigner, DD; Fecci, PE; Mitchell, DA; Sampson, JH
MLA Citation
Reap, Elizabeth A., et al. “Dendritic Cells Enhance Polyfunctionality of Adoptively Transferred T Cells That Target Cytomegalovirus in Glioblastoma..” Cancer Res, vol. 78, no. 1, Jan. 2018, pp. 256–64. Pubmed, doi:10.1158/0008-5472.CAN-17-0469.
PMID
29093005
Source
pubmed
Published In
Cancer Res
Volume
78
Issue
1
Publish Date
2018
Start Page
256
End Page
264
DOI
10.1158/0008-5472.CAN-17-0469

Flow Cytometric Identification of Tumor-Infiltrating Lymphocytes from Glioblastoma.

We describe an isolation method of tumor-infiltrating lymphocytes (TILs) from glioblastoma tumors for the purpose of analysis by flow cytometry. This protocol is unique from many others in that the use of a selective lymphocyte isolation procedure, such as a Ficoll or Percoll gradient, is not used. We find that staining of TILs and analysis by flow cytometry is not affected by the presence of heterogeneous populations, while other selective isolation procedures can significantly decrease lymphocyte yield from already rare populations.

Authors
Woroniecka, K; Chongsathidkiet, P; Elsamadicy, A; Farber, H; Cui, X; Fecci, PE
MLA Citation
Woroniecka, Karolina, et al. “Flow Cytometric Identification of Tumor-Infiltrating Lymphocytes from Glioblastoma..” Methods Mol Biol, vol. 1741, 2018, pp. 221–26. Pubmed, doi:10.1007/978-1-4939-7659-1_18.
PMID
29392704
Source
pubmed
Published In
Methods Mol Biol
Volume
1741
Publish Date
2018
Start Page
221
End Page
226
DOI
10.1007/978-1-4939-7659-1_18

Temozolomide lymphodepletion enhances CAR abundance and correlates with antitumor efficacy against established glioblastoma.

Adoptive transfer of T cells expressing chimeric antigen receptors (CARs) is an effective immunotherapy for B-cell malignancies but has failed in some solid tumors clinically. Intracerebral tumors may pose challenges that are even more significant. In order to devise a treatment strategy for patients with glioblastoma (GBM), we evaluated CARs as a monotherapy in a murine model of GBM. CARs exhibited poor expansion and survival in circulation and failed to treat syngeneic and orthotopic gliomas. We hypothesized that CAR engraftment would benefit from host lymphodepletion prior to immunotherapy and that this might be achievable by using temozolomide (TMZ), which is standard treatment for these patients and has lymphopenia as its major side effect. We modelled standard of care temozolomide (TMZSD) and dose-intensified TMZ (TMZDI) in our murine model. Both regimens are clinically approved and provide similar efficacy. Only TMZDI pretreatment prompted dramatic CAR proliferation and enhanced persistence in circulation compared to treatment with CARs alone or TMZSD + CARs. Bioluminescent imaging revealed that TMZDI + CARs induced complete regression of 21-day established brain tumors, which correlated with CAR abundance in circulation. Accordingly, TMZDI + CARs significantly prolonged survival and led to long-term survivors. These findings are highly consequential, as it suggests that GBM patients may require TMZDI as first line chemotherapy prior to systemic CAR infusion to promote CAR engraftment and antitumor efficacy. On this basis, we have initiated a phase I trial in patients with newly diagnosed GBM incorporating TMZDI as a preconditioning regimen prior to CAR immunotherapy (NCT02664363).

Authors
Suryadevara, CM; Desai, R; Abel, ML; Riccione, KA; Batich, KA; Shen, SH; Chongsathidkiet, P; Gedeon, PC; Elsamadicy, AA; Snyder, DJ; Herndon, JE; Healy, P; Archer, GE; Choi, BD; Fecci, PE; Sampson, JH; Sanchez-Perez, L
MLA Citation
Suryadevara, Carter M., et al. “Temozolomide lymphodepletion enhances CAR abundance and correlates with antitumor efficacy against established glioblastoma..” Oncoimmunology, vol. 7, no. 6, 2018. Pubmed, doi:10.1080/2162402X.2018.1434464.
PMID
29872570
Source
pubmed
Published In
Oncoimmunology
Volume
7
Issue
6
Publish Date
2018
Start Page
e1434464
DOI
10.1080/2162402X.2018.1434464

Atypical teratoid rhabdoid tumor in a 65-year-old man presenting with disseminated leptomeningeal disease: A case report and review of the literature.

Central nervous system atypical teratoid rhabdoid tumors are very rare aggressive tumor of childhood, primarily occurring at age of less than 3 years old. The prognosis of these tumors is very poor, with a reported median survival of 6-12 months in most cases. Treatment typically consists of aggressive chemotherapy and radiotherapy. We present the case of a 65-year-old man who presented with progressive encephalopathy and change in personality over 3 months period. The patient had further accelerated decline over 3 weeks. The diagnosis of atypical teratoid rhabdoid tumor initially remained elusive despite very extensive workup, but was eventually confirmed via open brain biopsy. To the best of our knowledge, this is the oldest reported case of atypical teratoid rhabdoid tumor in the literature. We further extend the spectrum of this rare disease.

Authors
Babi, M-A; Fecci, P; Luedke, M; Pineda, O; O'Keefe, YA
MLA Citation
Babi, Marc-Alain, et al. “Atypical teratoid rhabdoid tumor in a 65-year-old man presenting with disseminated leptomeningeal disease: A case report and review of the literature..” Sage Open Med Case Rep, vol. 6, 2018. Pubmed, doi:10.1177/2050313X18775298.
PMID
29785266
Source
pubmed
Published In
Sage Open Medical Case Reports
Volume
6
Publish Date
2018
Start Page
2050313X18775298
DOI
10.1177/2050313X18775298

CD27 stimulation unveils the efficacy of linked class I/II peptide vaccines in poorly immunogenic tumors by orchestrating a coordinated CD4/CD8 T cell response.

Despite their promise, tumor-specific peptide vaccines have limited efficacy. CD27 is a costimulatory molecule expressed on CD4+ and CD8+ T cells that is important in immune activation. Here we determine if a novel CD27 agonist antibody (αhCD27) can enhance the antitumor T cell response and efficacy of peptide vaccines. We evaluated the effects of αhCD27 on the immunogenicity and antitumor efficacy of whole protein, class I-restricted, and class II-restricted peptide vaccines using a transgenic mouse expressing human CD27. We found that αhCD27 preferentially enhances the CD8+ T cell response in the setting of vaccines comprised of linked class I and II ovalbumin epitopes (SIINFEKL and TEWTSSNVMEERKIKV, respectively) compared to a peptide vaccine comprised solely of SIINFEKL, resulting in the antitumor efficacy of adjuvant αhCD27 against intracranial B16.OVA tumors when combined with vaccines containing linked class I/II ovalbumin epitopes. Indeed, we demonstrate that this efficacy is both CD8- and CD4-dependent and αhCD27 activity on ovalbumin-specific CD4+ T cells is necessary for its adjuvant effect. Importantly for clinical translation, a linked universal CD4+ helper epitope (tetanus P30) was sufficient to instill the efficacy of SIINFEKL peptide combined with αhCD27, eliminating the need for a tumor-specific class II-restricted peptide. This approach unveiled the efficacy of a class I-restricted peptide vaccine derived from the tumor-associated Trp2 antigen in mice bearing intracranial B16 tumors. CD27 agonist antibodies combined with peptide vaccines containing linked tumor-specific CD8+ epitopes and tumor-specific or universal CD4+ epitopes enhance the efficacy of active cancer immunotherapy.

Authors
Riccione, KA; He, L-Z; Fecci, PE; Norberg, PK; Suryadevara, CM; Swartz, A; Healy, P; Reap, E; Keler, T; Li, Q-J; Congdon, KL; Sanchez-Perez, L; Sampson, JH
MLA Citation
Riccione, Katherine A., et al. “CD27 stimulation unveils the efficacy of linked class I/II peptide vaccines in poorly immunogenic tumors by orchestrating a coordinated CD4/CD8 T cell response..” Oncoimmunology, vol. 7, no. 12, 2018. Pubmed, doi:10.1080/2162402X.2018.1502904.
PMID
30524899
Source
pubmed
Published In
Oncoimmunology
Volume
7
Issue
12
Publish Date
2018
Start Page
e1502904
DOI
10.1080/2162402X.2018.1502904

ANTITUMOR EFFICACY OF ANTI-PDL1 IN ACTH-SECRETING PITUITARY ADENOMAS: AN IMMUNOTHERAPEUTIC APPROACH FOR CUSHING'S DISEASE

Authors
Elsamadicy, AA; Farber, SH; Chongsathidkiet, P; Kemeny, H; Woroniecka, K; Cui, X; Dunn, I; Fecci, P
MLA Citation
Elsamadicy, Aladine A., et al. “ANTITUMOR EFFICACY OF ANTI-PDL1 IN ACTH-SECRETING PITUITARY ADENOMAS: AN IMMUNOTHERAPEUTIC APPROACH FOR CUSHING'S DISEASE.” Neuro Oncology, vol. 19, OXFORD UNIV PRESS INC, 2017, pp. 264–65.
Source
wos
Published In
Neuro Oncology
Volume
19
Publish Date
2017
Start Page
264
End Page
265

Biopsy of enlarging lesions after stereotactic radiosurgery for brain metastases frequently reveals radiation necrosis.

Background: Stereotactic radiosurgery (SRS) offers excellent local control for brain metastases (BM) with low rates of toxicity. Radiation necrosis (RN) may occur after treatment and is challenging to distinguish from local recurrence (LR). We evaluated enlarging brain lesions following SRS that were subsequently biopsied to differentiate RN versus LR. Methods: This study reviewed patients receiving SRS for BM between 2008 and 2012 who underwent a biopsy for suspicion of RN versus LR on MRI. Data collection included demographics, radiation parameters, imaging findings, and post-biopsy pathology. Kaplan-Meier methods determined overall survival. Fisher's exact test assessed for association between lesion biopsy result and variables of interest. Results: Thirty-four patients with 35 biopsied BM were included. Lesions were biopsied a median of 8.8 months after SRS. Most patients had primary lung cancer (11; 31.4%). Eleven (31.4%) biopsies were positive for LR and 24 (68.6%) showed RN only. Median overall survival was longer for patients with RN (31.0 mo) than for patients with LR (14.5 mo; P = 0.135). Time from SRS to biopsy was significantly different between RN and LR groups; 10 lesions (52.5%) biopsied ≤9 months after SRS showed LR, whereas 1 lesion (6.3%) biopsied >9 months after SRS showed LR (P = 0.004). For 16 (65.7%) lesions, management was changed or directed by the biopsy results. Conclusions: Stereotactic biopsy for accessible enlarging lesions after SRS appears diagnostically valuable in patients with few lesions and changes clinical management. RN should be suspected in patients with an enlarging lesion more than 9 months post-SRS.

Authors
Narloch, JL; Farber, SH; Sammons, S; McSherry, F; Herndon, JE; Hoang, JK; Yin, F-F; Sampson, JH; Fecci, PE; Blackwell, KL; Kirkpatrick, JP; Kim, GJ
MLA Citation
Narloch, Jessica L., et al. “Biopsy of enlarging lesions after stereotactic radiosurgery for brain metastases frequently reveals radiation necrosis..” Neuro Oncol, vol. 19, no. 10, Oct. 2017, pp. 1391–97. Pubmed, doi:10.1093/neuonc/nox090.
PMID
28472527
Source
pubmed
Published In
Neuro Oncol
Volume
19
Issue
10
Publish Date
2017
Start Page
1391
End Page
1397
DOI
10.1093/neuonc/nox090

Single fraction stereotactic radiosurgery for multiple brain metastases.

Introduction: Due to the neurocognitive side effects of whole brain radiation therapy (WBRT), stereotactic radiosurgery (SRS) is being used with increasing frequency. The use of SRS is expanding for patients with multiple (>4) brain metastases (BM). This study summarizes our institutional experience with single-fraction, linear-accelerator-based SRS for multiple BM. Methods and materials: All patients who were treated between January 1, 2013, and September 30, 2015, with single-fraction SRS for ≥4 BM were included in this institutional review board-approved, retrospective, single-institution study. Patients were treated with linear accelerator-based image guided SRS. Results: A total of 59 patients with ≥4 BM were treated with single-fraction SRS. The median follow-up was 15.2 months, and the median overall survival for the entire cohort was 5.8 months. The median number of treated lesions per patient was 5 (range, 4-23). Per patient, the median planning target volume (PTV) was 4.8 cc (range, 0.7-28.8 cc). The prescribed dose across all 380 BM for the 59 patients ranged from 7 to 20 Gy. The median of the mean dose to the total PTV was 19.5 Gy. Although the number of treated lesions (4-5 vs ≥6) did not influence survival, better survival was noted for a total PTV <10 cc versus ≥10 cc (7.1 vs 4.2 months, respectively; P = .0001). A mean dose of ≥19 Gy to the entire PTV was also associated with increased survival (6.6 vs 5.0 months, respectively; P = .0172). Patients receiving a dose of >12 Gy to ≥10 cc of normal brain had worse survival (5.1 vs 8.6 months, respectively; P = .0028). Conclusion: In single-fraction SRS for patients with multiple BM, smaller total tumor volume, higher total dose, and lower volume of normal brain receiving >12 Gy were associated with increased survival. These data suggest that using SRS for the treatment of multiple BM is efficacious and that outcomes may be affected more by total tumor volume than by the number of lesions.

Authors
Limon, D; McSherry, F; Herndon, J; Sampson, J; Fecci, P; Adamson, J; Wang, Z; Yin, F-F; Floyd, S; Kirkpatrick, J; Kim, GJ
MLA Citation
Limon, Dror, et al. “Single fraction stereotactic radiosurgery for multiple brain metastases..” Adv Radiat Oncol, vol. 2, no. 4, Oct. 2017, pp. 555–63. Pubmed, doi:10.1016/j.adro.2017.09.002.
Website
http://hdl.handle.net/10161/15933
PMID
29204522
Source
pubmed
Published In
Advances in Radiation Oncology
Volume
2
Issue
4
Publish Date
2017
Start Page
555
End Page
563
DOI
10.1016/j.adro.2017.09.002

Enhancing Radiation Therapy Through Cherenkov Light-Activated Phototherapy from Clinical Megavoltage Treatment Beams

Authors
Oldham, M; Yoon, SW; Adamson, J; Shrock, Z; Tsvankin, V; Fecci, P; Dewhirst, MW
MLA Citation
Oldham, M., et al. “Enhancing Radiation Therapy Through Cherenkov Light-Activated Phototherapy from Clinical Megavoltage Treatment Beams.” International Journal of Radiation Oncology*Biology*Physics, vol. 99, no. 2, Elsevier BV, 2017, pp. S229–30. Crossref, doi:10.1016/j.ijrobp.2017.06.564.
Source
crossref
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
99
Issue
2
Publish Date
2017
Start Page
S229
End Page
S230
DOI
10.1016/j.ijrobp.2017.06.564

Leptomeningeal disease: current diagnostic and therapeutic strategies.

Leptomeningeal disease has become increasingly prevalent as novel therapeutic interventions extend the survival of cancer patients. Although a majority of leptomeningeal spread occurs secondary to breast cancer, lung cancer, and melanoma, a wide variety of malignancies have been reported as primary sources. Symptoms on presentation are equally diverse, often involving a combination of neurological deficits with the possibility of obstructive hydrocephalus. Diagnosis is definitively made via cerebrospinal fluid cytology for malignant cells, but neuro-imaging with high quality T1-weighted magnetic resonance imaging can aid diagnosis and localization. While leptomeningeal disease is still a terminal, late-stage complication, a variety of treatment modalities, such as intrathecal chemotherapeutics and radiation therapy, have improved median survival from 4-6 weeks to 3-6 months. Positive prognosticative factors for survival include younger age, high performance scores, and controlled systemic disease. In looking to the future, diagnostics that improve early detection and chemotherapeutics tailored to the primary malignancy will likely be the most significant advances in improving survival.

Authors
Nayar, G; Ejikeme, T; Chongsathidkiet, P; Elsamadicy, AA; Blackwell, KL; Clarke, JM; Lad, SP; Fecci, PE
MLA Citation
Nayar, Gautam, et al. “Leptomeningeal disease: current diagnostic and therapeutic strategies..” Oncotarget, vol. 8, no. 42, Sept. 2017, pp. 73312–28. Pubmed, doi:10.18632/oncotarget.20272.
PMID
29069871
Source
pubmed
Published In
Oncotarget
Volume
8
Issue
42
Publish Date
2017
Start Page
73312
End Page
73328
DOI
10.18632/oncotarget.20272

372 Evolving Patterns in Clinical Utilization of Stereotactic Laser Ablation (SLA): An Analysis of the Multi-center Prospective Registry LAANTERN

Authors
Chen, CC; Rennert, R; Khan, U; Tatter, SB; Field, M; Toyota, B; Fecci, PE; Judy, KD; Mohammadi, AM; Landazuri, P; Sloan, AE; Leuthardt, EC
MLA Citation
Chen, Clark C., et al. “372 Evolving Patterns in Clinical Utilization of Stereotactic Laser Ablation (SLA): An Analysis of the Multi-center Prospective Registry LAANTERN.” Neurosurgery, vol. 64, no. CN_suppl_1, Oxford University Press (OUP), 2017, pp. 287–88. Crossref, doi:10.1093/neuros/nyx417.372.
Source
crossref
Published In
Neurosurgery
Volume
64
Issue
CN_suppl_1
Publish Date
2017
Start Page
287
End Page
288
DOI
10.1093/neuros/nyx417.372

223 Procedural Safety of Stereotactic Laser Ablation (SLA) and Associated Hospital Stay: Outcome from the First Hundred Patient from LAANTERN Prospective Registry

Authors
Chen, CC; Rennert, R; Khan, U; Tatter, SB; Field, M; Toyota, B; Fecci, PE; Judy, KD; Mohammadi, AM; Landazuri, P; Sloan, AE; Leuthardt, EC
MLA Citation
Chen, Clark C., et al. “223 Procedural Safety of Stereotactic Laser Ablation (SLA) and Associated Hospital Stay: Outcome from the First Hundred Patient from LAANTERN Prospective Registry.” Neurosurgery, vol. 64, no. CN_suppl_1, Oxford University Press (OUP), 2017, pp. 261–261. Crossref, doi:10.1093/neuros/nyx417.223.
Source
crossref
Published In
Neurosurgery
Volume
64
Issue
CN_suppl_1
Publish Date
2017
Start Page
261
End Page
261
DOI
10.1093/neuros/nyx417.223

A Novel Method to Enhance Standard of Care Radiation Therapy: Cherenkov Light Activated Psoralen (CLAP)

Authors
Yoon, S; Tsvankin, V; Shrock, Z; Meng, B; Dewhirst, M; Fecci, P; Adamson, J; Oldham, M
MLA Citation
Yoon, S., et al. “A Novel Method to Enhance Standard of Care Radiation Therapy: Cherenkov Light Activated Psoralen (CLAP).” Medical Physics, vol. 44, no. 6, WILEY, 2017, pp. 2995–96.
Source
wos
Published In
Medical Physics
Volume
44
Issue
6
Publish Date
2017
Start Page
2995
End Page
2996

Number of tumor-infiltrating lymphocytes in breast cancer brain metastases compared to matched breast primaries.

Authors
Narloch, J; Luedke, C; Broadwater, G; Priedigkeit, N; Hall, A; Hyslop, T; Sammons, SL; Huggins-Puhalla, SL; Leone, JP; Ramirez, J; Kirkpatrick, JP; Ewend, MG; Fecci, PE; Brufsky, A; Lee, AV; Anders, CK; Blackwell, KL
MLA Citation
Narloch, Jessie, et al. “Number of tumor-infiltrating lymphocytes in breast cancer brain metastases compared to matched breast primaries..” Journal of Clinical Oncology, vol. 35, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2017, pp. 2049–2049. Crossref, doi:10.1200/jco.2017.35.15_suppl.2049.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
35
Issue
15_suppl
Publish Date
2017
Start Page
2049
End Page
2049
DOI
10.1200/jco.2017.35.15_suppl.2049

Host Lymphopenia Enhances the Abundance, Activation Status, and Antitumor Efficacy of Tumor-specific T Cells Delivered Directly into the Brain

Authors
Suryadevara, C; Chongsathidkiet, P; Desai, R; Abel, M; Elsamadicy, A; Woroniecka, K; Snyder, D; Li, Q-J; Fecci, P; Sanchez-Perez, L; Sampson, J
MLA Citation
Suryadevara, Carter, et al. “Host Lymphopenia Enhances the Abundance, Activation Status, and Antitumor Efficacy of Tumor-specific T Cells Delivered Directly into the Brain.” Journal of Neurosurgery, vol. 126, no. 4, AMER ASSOC NEUROLOGICAL SURGEONS, 2017, pp. A1443–A1443.
Source
wos
Published In
Journal of Neurosurgery
Volume
126
Issue
4
Publish Date
2017
Start Page
A1443
End Page
A1443

Downregulation of sphingosine-1-phosphate receptor type 1 mediates T-cell sequestration in bone marrow amidst glioblastoma

Authors
Chongsathidkiet, P; Farber, S; Woroniecka, K; Elsamadicy, A; Cui, X; Fecci, P
MLA Citation
Chongsathidkiet, Pakawat, et al. “Downregulation of sphingosine-1-phosphate receptor type 1 mediates T-cell sequestration in bone marrow amidst glioblastoma.” Journal of Neurosurgery, vol. 126, no. 4, AMER ASSOC NEUROLOGICAL SURGEONS, 2017, pp. A1442–A1442.
Source
wos
Published In
Journal of Neurosurgery
Volume
126
Issue
4
Publish Date
2017
Start Page
A1442
End Page
A1442

Prospect of rindopepimut in the treatment of glioblastoma.

INTRODUCTION: Rindopepimut (CDX-110) is a peptide vaccine that targets epidermal growth factor receptor variant III (EGFRvIII), a tumor-specific epitope expressed in the most common and lethal primary malignant neoplasm of the brain - glioblastoma (GBM). Areas covered: The EGFRvIII mutation introduces an 801 base pair in-frame deletion of the extracellular domain of the transmembrane tyrosine kinase, resulting in constitutive kinase activity, amplification of cell growth, and inhibition of apoptosis. Rindopepimut contains a 14mer amino acid peptide spanning the EGFRvIII mutation site that is conjugated to keyhole limpet hemocyanin (KLH). The EGFRvIII neoantigen is exclusively present on GBM cells, providing rindopepimut tumor-specific activity. The authors review rindopepimut's clinical efficacy, administration, safety, and prospects in the treatment of GBM. Expert opinion: Rindopepimut showed clinical benefit and significant efficacy in phase II clinical trials, including as part of a multi-immunotherapy approach. A phase III clinical trial was terminated early, however, as it was deemed likely the study would fail to meet its primary endpoint. Longer term and sub-group analyses will be necessary to better understand rindopepimut's future role in GBM therapy.

Authors
Elsamadicy, AA; Chongsathidkiet, P; Desai, R; Woroniecka, K; Farber, SH; Fecci, PE; Sampson, JH
MLA Citation
Elsamadicy, Aladine A., et al. “Prospect of rindopepimut in the treatment of glioblastoma..” Expert Opin Biol Ther, vol. 17, no. 4, Apr. 2017, pp. 507–13. Pubmed, doi:10.1080/14712598.2017.1299705.
PMID
28274144
Source
pubmed
Published In
Expert Opin Biol Ther
Volume
17
Issue
4
Publish Date
2017
Start Page
507
End Page
513
DOI
10.1080/14712598.2017.1299705

Immune Constitution of Patients with Brain Tumors

© 2017 Elsevier Inc. All rights reserved. Immune deficiencies in patients with glioblastoma (GBM) are not a new discovery. Researchers have been perplexed and challenged by impairments to immunity in the context of GBM dating back to the 1970s. As immunotherapy has become both more studied and more developed, increasing evidence has highlighted factors ranging from lymphopenia to innate and cellular immune dysfunction. Much work has been done to uncover a variety of tumor-inducible mechanisms for limiting the antitumor immune response. In this chapter, we will explore the evolution of our understanding of these immune-restricting mechanisms, as well as strategies for their reversal.

Authors
Berry-Candelario, J; Farber, SH; Fecci, PE
MLA Citation
Berry-Candelario, J., et al. “Immune Constitution of Patients with Brain Tumors.” Translational Immunotherapy of Brain Tumors, 2017, pp. 13–32. Scopus, doi:10.1016/B978-0-12-802420-1.00002-8.
Source
scopus
Publish Date
2017
Start Page
13
End Page
32
DOI
10.1016/B978-0-12-802420-1.00002-8

The Safety of available immunotherapy for the treatment of glioblastoma.

INTRODUCTION: Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Current standard of care involves maximal surgical resection combined with adjuvant chemoradiation. Growing support exists for a role of immunotherapy in treating these tumors with the goal of targeted cytotoxicity. Here we review data on the safety for current immunotherapies being tested in GBM. Areas covered: Safety data from published clinical trials, including ongoing clinical trials were reviewed. Immunotherapeutic classes currently under investigation in GBM include various vaccination strategies, adoptive T cell immunotherapy, immune checkpoint blockade, monoclonal antibodies, and cytokine therapies. Trials include children, adolescents, and adults with either primary or recurrent GBM. Expert opinion: Based on the reviewed clinical trials, the current immunotherapies targeting GBM are safe and well-tolerated with minimal toxicities which should be noted. However, the gains in patient survival have been modest. A safe and well-tolerated combinatory immunotherapeutic approach may be essential for optimal efficacy towards GBM.

Authors
Farber, SH; Elsamadicy, AA; Atik, AF; Suryadevara, CM; Chongsathidkiet, P; Fecci, PE; Sampson, JH
MLA Citation
Farber, S. Harrison, et al. “The Safety of available immunotherapy for the treatment of glioblastoma..” Expert Opin Drug Saf, vol. 16, no. 3, Mar. 2017, pp. 277–87. Pubmed, doi:10.1080/14740338.2017.1273898.
PMID
27989218
Source
pubmed
Published In
Expert Opin Drug Saf
Volume
16
Issue
3
Publish Date
2017
Start Page
277
End Page
287
DOI
10.1080/14740338.2017.1273898

Abstract P5-08-12: HER2 status remains the primary predictor of improved survival in patients with BCBM over the past 2 decades (1996-2015)

Authors
Narloch, JL; Harnden, K; Broadwater, G; Peterson, B; Hyslop, T; Kirkpatrick, J; Fecci, P; Kim, G; Blackwell, KL
MLA Citation
Narloch, J. L., et al. “Abstract P5-08-12: HER2 status remains the primary predictor of improved survival in patients with BCBM over the past 2 decades (1996-2015).” Poster Session Abstracts, American Association for Cancer Research, 2017. Crossref, doi:10.1158/1538-7445.sabcs16-p5-08-12.
Source
crossref
Published In
Poster Session Abstracts
Publish Date
2017
DOI
10.1158/1538-7445.sabcs16-p5-08-12

Increased expression of programmed death ligand 1 (PD-L1) in human pituitary tumors.

PURPOSE: Subsets of pituitary tumors exhibit an aggressive clinical courses and recur despite surgery, radiation, and chemotherapy. Because modulation of the immune response through inhibition of T-cell checkpoints has led to durable clinical responses in multiple malignancies, we explored whether pituitary adenomas express immune-related biomarkers that could suggest suitability for immunotherapy. Specifically, programmed death ligand 1 (PD-L1) has emerged as a potential biomarker whose expression may portend more favorable responses to immune checkpoint blockade therapies. We thus investigated the expression of PD-L1 in pituitary adenomas. METHODS: PD-L1 RNA and protein expression were evaluated in 48 pituitary tumors, including functioning and non-functioning adenomas as well as atypical and recurrent tumors. Tumor infiltrating lymphocyte populations were also assessed by immunohistochemistry. RESULTS: Pituitary tumors express variable levels of PD-L1 transcript and protein. PD-L1 RNA and protein expression were significantly increased in functioning (growth hormone and prolactin-expressing) pituitary adenomas compared to non-functioning (null cell and silent gonadotroph) adenomas. Moreover, primary pituitary adenomas harbored higher levels of PD-L1 mRNA compared to recurrent tumors. Tumor infiltrating lymphocytes were observed in all pituitary tumors and were positively correlated with increased PD-L1 expression, particularly in the functional subtypes. CONCLUSIONS: Human pituitary adenomas harbor PD-L1 across subtypes, with significantly higher expression in functioning adenomas compared to non-functioning adenomas. This expression is accompanied by the presence of tumor infiltrating lymphocytes. These findings suggest the existence of an immune response to pituitary tumors and raise the possibility of considering checkpoint blockade immunotherapy in cases refractory to conventional management.

Authors
Mei, Y; Bi, WL; Greenwald, NF; Du, Z; Agar, NYR; Kaiser, UB; Woodmansee, WW; Reardon, DA; Freeman, GJ; Fecci, PE; Laws, ER; Santagata, S; Dunn, GP; Dunn, IF
MLA Citation
Mei, Yu, et al. “Increased expression of programmed death ligand 1 (PD-L1) in human pituitary tumors..” Oncotarget, vol. 7, no. 47, Nov. 2016, pp. 76565–76. Pubmed, doi:10.18632/oncotarget.12088.
PMID
27655724
Source
pubmed
Published In
Oncotarget
Volume
7
Issue
47
Publish Date
2016
Start Page
76565
End Page
76576
DOI
10.18632/oncotarget.12088

LYMPHOPENIA ENHANCES THE EFFICACY OF CAR T CELLS DELIVERED LOCO-REGIONALLY IN THE BRAIN FOR THE TREATMENT OF GLIOBLASTOMA

Authors
Suryadevara, CM; Desai, R; Snyder, DJ; Li, Q-J; Fecci, PE; Sanchez-Perez, L; Sampson, JH
MLA Citation
Suryadevara, Carter M., et al. “LYMPHOPENIA ENHANCES THE EFFICACY OF CAR T CELLS DELIVERED LOCO-REGIONALLY IN THE BRAIN FOR THE TREATMENT OF GLIOBLASTOMA.” Neuro Oncology, vol. 18, OXFORD UNIV PRESS INC, 2016, pp. 96–96.
Source
wos
Published In
Neuro Oncology
Volume
18
Publish Date
2016
Start Page
96
End Page
96

CAR T CELLS INDUCE COMPLETE REGRESSION OF MURINE GLIOBLASTOMA AFTER PRECONDITIONING HOSTS WITH TEMOZOLOMIDE

Authors
Suryadevara, CM; Chongsathidkiet, P; Riccione, K; Gedeon, PC; Desai, R; Choi, BD; Snyder, DJ; Li, Q-J; Fecci, PE; Sanchez-Perez, L; Sampson, JH
MLA Citation
Suryadevara, Carter M., et al. “CAR T CELLS INDUCE COMPLETE REGRESSION OF MURINE GLIOBLASTOMA AFTER PRECONDITIONING HOSTS WITH TEMOZOLOMIDE.” Neuro Oncology, vol. 18, OXFORD UNIV PRESS INC, 2016, pp. 94–95.
Source
wos
Published In
Neuro Oncology
Volume
18
Publish Date
2016
Start Page
94
End Page
95

DOWNREGULATION OF SPHINGOSINE-1-PHOSPHATE RECEPTOR TYPE 1 MEDIATES BONE MARROW T-CELL SEQUESTRATION IN PATIENTS AND MICE WITH GLIOBLASTOMA

Authors
Chongsathidkiet, P; Farber, SH; Woroniecka, K; Elsamadicy, AA; Cui, X; Fecci, P
MLA Citation
Chongsathidkiet, Pakawat, et al. “DOWNREGULATION OF SPHINGOSINE-1-PHOSPHATE RECEPTOR TYPE 1 MEDIATES BONE MARROW T-CELL SEQUESTRATION IN PATIENTS AND MICE WITH GLIOBLASTOMA.” Neuro Oncology, vol. 18, OXFORD UNIV PRESS INC, 2016, pp. 88–88.
Source
wos
Published In
Neuro Oncology
Volume
18
Publish Date
2016
Start Page
88
End Page
88

EXPRESSION OF PDL-1 ON PITUITARY ADENOMAS: A ROLE FOR IMMUNOTHERAPY

Authors
Elsamadicy, AA; Farber, SH; Chongsathidkiet, P; Woroniecka, K; Cui, X; Fecci, P
MLA Citation
Elsamadicy, Aladine A., et al. “EXPRESSION OF PDL-1 ON PITUITARY ADENOMAS: A ROLE FOR IMMUNOTHERAPY.” Neuro Oncology, vol. 18, OXFORD UNIV PRESS INC, 2016, pp. 87–87.
Source
wos
Published In
Neuro Oncology
Volume
18
Publish Date
2016
Start Page
87
End Page
87

T CELL EXHAUSTION IN PATIENTS AND MICE WITH GBM

Authors
Woroniecka, K; Farber, SH; Chongsathidkiet, P; Elsamadicy, AA; Cui, X; Fecci, P
MLA Citation
Woroniecka, Karolina, et al. “T CELL EXHAUSTION IN PATIENTS AND MICE WITH GBM.” Neuro Oncology, vol. 18, OXFORD UNIV PRESS INC, 2016, pp. 93–93.
Source
wos
Published In
Neuro Oncology
Volume
18
Publish Date
2016
Start Page
93
End Page
93

Single-Fraction Radiosurgery for 4 or More Brain Metastases.

Authors
Limon, D; Kim, GJ; McSherry, F; Herndon, J; Fecci, PE; Adamson, J; Sampson, JH; Floyd, SR; Wang, Z; Vlahovic, G; Yin, FF; Kirkpatrick, JP
MLA Citation
Limon, D., et al. “Single-Fraction Radiosurgery for 4 or More Brain Metastases..” International Journal of Radiation Oncology, Biology, Physics, vol. 96, no. 2S, Oct. 2016, pp. E84–85. Epmc, doi:10.1016/j.ijrobp.2016.06.804.
PMID
27675479
Source
epmc
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
96
Issue
2S
Publish Date
2016
Start Page
E84
End Page
E85
DOI
10.1016/j.ijrobp.2016.06.804

369 Chimeric Antigen Receptors Deficient in Lck Signaling Require 4-1BB Costimulation to Expand in Vivo, Resist Regulatory T-Cell Suppression, and Treat Solid Tumors in Immune-Intact Hosts.

Authors
Suryadevara, CM; Desai, R; Farber, SH; Gedeon, PC; Swartz, A; Snyder, D; Herndon, J; Healy, P; Choi, BD; Fecci, PE; Sanchez-Perez, L; Sampson, JH
MLA Citation
Suryadevara, C. M., et al. “369 Chimeric Antigen Receptors Deficient in Lck Signaling Require 4-1BB Costimulation to Expand in Vivo, Resist Regulatory T-Cell Suppression, and Treat Solid Tumors in Immune-Intact Hosts..” Neurosurgery, vol. 63, no. CN_suppl_1, Aug. 2016, pp. 209–10. Pubmed, doi:10.1227/01.neu.0000489857.70440.98.
PMID
28175613
Source
pubmed
Published In
Neurosurgery
Volume
63
Issue
CN_suppl_1
Publish Date
2016
Start Page
209
End Page
210
DOI
10.1227/01.neu.0000489857.70440.98

369 Chimeric Antigen Receptors Deficient in Lck Signaling Require 4-1BB Costimulation to Expand in Vivo, Resist Regulatory T-Cell Suppression, and Treat Solid Tumors in Immune-Intact Hosts.

INTRODUCTION: Adoptive transfer of T cells expressing chimeric antigen receptors (CARs) is an effective immunotherapy for hematological cancers but requires a rethinking for clinical efficacy against solid tumors, where CARs have largely failed. Lymphodepletive preconditioning regimens can enhance CAR activity in vivo by promoting T-cell expansion and depleting immunoinhibitory cells that counteract cellular immunity. These nonspecific regimens, however, can be exceedingly toxic and contribute to poor quality of life. Novel strategies are needed to bypass the intratumoral inhibition of CARs. CD4+FoxP3+ regulatory T cells (Tregs) play a critical role in treatment failure, and, importantly, CARs have been shown to inadvertently potentiate Tregs by providing a local source of interleukin-2 (IL-2) for Treg consumption. We explored whether specific disruption of this axis would confer efficacy against solid tumors. METHODS: We developed second (CD28z) and third (CD28-4-1BBz) generation CARs targeting the tumor-specific mutation, EGFRvIII. To eliminate secretion of IL-2, 2 amino acid substitutions were introduced in the PYAP Lck binding motif of the CD28 domain (xCD28) of CAR transgenes. We evaluated these modified second- and third-generation CARs against established B16 melanomas expressing EGFRvIII. RESULTS: Second-generation CD28z CARs fail to expand in vivo. Addition of 4-1BB in third-generation CARs improves expansion, but this modification alone was insufficient for CD28-4-1BBz CARs to treat tumors without prior host lymphodepletion. CARs deficient in Lck signaling, however, significantly retarded tumor growth in immune-intact mice without prior lymphodepletion, and this was dependent on inclusion of 4-1BB in CAR design. To determine if deficient Lck signaling altered CAR vulnerability to Tregs, we lymphodepleted mice and transferred CARs ± Tregs. Cotransfer was sufficient to abrogate the efficacy of CD28-4-1BBz CARs, whereas the efficacy of xCD28-4-1BBz CARs remained unperturbed. CONCLUSION: xCD28-4-1BBz CARs may be an effective immunotherapy for solid tumors infiltrated with Treg and may mitigate the need for toxic lymphodepletive preconditioning.

Authors
Suryadevara, CM; Desai, R; Farber, SH; Gedeon, PC; Swartz, A; Snyder, D; Herndon, J; Healy, P; Choi, BD; Fecci, PE; Sanchez-Perez, L; Sampson, JH
MLA Citation
Suryadevara, Carter M., et al. “369 Chimeric Antigen Receptors Deficient in Lck Signaling Require 4-1BB Costimulation to Expand in Vivo, Resist Regulatory T-Cell Suppression, and Treat Solid Tumors in Immune-Intact Hosts..” Neurosurgery, vol. 63 Suppl 1, Aug. 2016, pp. 209–10. Pubmed, doi:10.1227/01.neu.0000489857.70440.98.
PMID
27399566
Source
pubmed
Published In
Neurosurgery
Volume
63 Suppl 1
Publish Date
2016
Start Page
209
End Page
210
DOI
10.1227/01.neu.0000489857.70440.98

Embracing rejection: Immunologic trends in brain metastasis.

Brain metastases represent the most common type of brain tumor. These tumors offer a dismal prognosis and significantly impact quality of life for patients. Their capacity for central nervous system (CNS) invasion is dependent upon induced disruptions to the blood-brain barrier (BBB), alterations to the brain microenvironment, and mechanisms for escaping CNS immunosurveillance. In the emerging era of immunotherapy, understanding how metastases are influenced by the immunologic peculiarities of the CNS will be crucial to forging therapeutic advances. In this review, the immunology of brain metastasis is explored.

Authors
Farber, SH; Tsvankin, V; Narloch, JL; Kim, GJ; Salama, AKS; Vlahovic, G; Blackwell, KL; Kirkpatrick, JP; Fecci, PE
MLA Citation
Farber, S. Harrison, et al. “Embracing rejection: Immunologic trends in brain metastasis..” Oncoimmunology, vol. 5, no. 7, July 2016. Pubmed, doi:10.1080/2162402X.2016.1172153.
PMID
27622023
Source
pubmed
Published In
Oncoimmunology
Volume
5
Issue
7
Publish Date
2016
Start Page
e1172153
DOI
10.1080/2162402X.2016.1172153

Immunotherapy for gliomas

Authors
Fecci, PE; Riccione, K; Dunn, GP; Reap, E; Vlahovic, G; Congdon, K; Sampson, JH
MLA Citation
Fecci, P. E., et al. “Immunotherapy for gliomas.” The Duke Glioma Handbook: Pathology, Diagnosis, and Management, 2016, pp. 91–120. Scopus, doi:10.1017/CBO9781107588721.006.
Source
scopus
Publish Date
2016
Start Page
91
End Page
120
DOI
10.1017/CBO9781107588721.006

STK11/LKB1 Deficiency Promotes Neutrophil Recruitment and Proinflammatory Cytokine Production to Suppress T-cell Activity in the Lung Tumor Microenvironment.

STK11/LKB1 is among the most commonly inactivated tumor suppressors in non-small cell lung cancer (NSCLC), especially in tumors harboring KRAS mutations. Many oncogenes promote immune escape, undermining the effectiveness of immunotherapies, but it is unclear whether the inactivation of tumor suppressor genes, such as STK11/LKB1, exerts similar effects. In this study, we investigated the consequences of STK11/LKB1 loss on the immune microenvironment in a mouse model of KRAS-driven NSCLC. Genetic ablation of STK11/LKB1 resulted in accumulation of neutrophils with T-cell-suppressive effects, along with a corresponding increase in the expression of T-cell exhaustion markers and tumor-promoting cytokines. The number of tumor-infiltrating lymphocytes was also reduced in LKB1-deficient mouse and human tumors. Furthermore, STK11/LKB1-inactivating mutations were associated with reduced expression of PD-1 ligand PD-L1 in mouse and patient tumors as well as in tumor-derived cell lines. Consistent with these results, PD-1-targeting antibodies were ineffective against Lkb1-deficient tumors. In contrast, treating Lkb1-deficient mice with an IL6-neutralizing antibody or a neutrophil-depleting antibody yielded therapeutic benefits associated with reduced neutrophil accumulation and proinflammatory cytokine expression. Our findings illustrate how tumor suppressor mutations can modulate the immune milieu of the tumor microenvironment, and they offer specific implications for addressing STK11/LKB1-mutated tumors with PD-1-targeting antibody therapies.

Authors
Koyama, S; Akbay, EA; Li, YY; Aref, AR; Skoulidis, F; Herter-Sprie, GS; Buczkowski, KA; Liu, Y; Awad, MM; Denning, WL; Diao, L; Wang, J; Parra-Cuentas, ER; Wistuba, II; Soucheray, M; Thai, T; Asahina, H; Kitajima, S; Altabef, A; Cavanaugh, JD; Rhee, K; Gao, P; Zhang, H; Fecci, PE; Shimamura, T; Hellmann, MD; Heymach, JV; Hodi, FS; Freeman, GJ; Barbie, DA; Dranoff, G; Hammerman, PS; Wong, K-K
MLA Citation
Koyama, Shohei, et al. “STK11/LKB1 Deficiency Promotes Neutrophil Recruitment and Proinflammatory Cytokine Production to Suppress T-cell Activity in the Lung Tumor Microenvironment..” Cancer Res, vol. 76, no. 5, Mar. 2016, pp. 999–1008. Pubmed, doi:10.1158/0008-5472.CAN-15-1439.
PMID
26833127
Source
pubmed
Published In
Cancer Res
Volume
76
Issue
5
Publish Date
2016
Start Page
999
End Page
1008
DOI
10.1158/0008-5472.CAN-15-1439

Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints.

Despite compelling antitumour activity of antibodies targeting the programmed death 1 (PD-1): programmed death ligand 1 (PD-L1) immune checkpoint in lung cancer, resistance to these therapies has increasingly been observed. In this study, to elucidate mechanisms of adaptive resistance, we analyse the tumour immune microenvironment in the context of anti-PD-1 therapy in two fully immunocompetent mouse models of lung adenocarcinoma. In tumours progressing following response to anti-PD-1 therapy, we observe upregulation of alternative immune checkpoints, notably T-cell immunoglobulin mucin-3 (TIM-3), in PD-1 antibody bound T cells and demonstrate a survival advantage with addition of a TIM-3 blocking antibody following failure of PD-1 blockade. Two patients who developed adaptive resistance to anti-PD-1 treatment also show a similar TIM-3 upregulation in blocking antibody-bound T cells at treatment failure. These data suggest that upregulation of TIM-3 and other immune checkpoints may be targetable biomarkers associated with adaptive resistance to PD-1 blockade.

Authors
Koyama, S; Akbay, EA; Li, YY; Herter-Sprie, GS; Buczkowski, KA; Richards, WG; Gandhi, L; Redig, AJ; Rodig, SJ; Asahina, H; Jones, RE; Kulkarni, MM; Kuraguchi, M; Palakurthi, S; Fecci, PE; Johnson, BE; Janne, PA; Engelman, JA; Gangadharan, SP; Costa, DB; Freeman, GJ; Bueno, R; Hodi, FS; Dranoff, G; Wong, K-K; Hammerman, PS
MLA Citation
Koyama, Shohei, et al. “Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints..” Nat Commun, vol. 7, Feb. 2016. Pubmed, doi:10.1038/ncomms10501.
PMID
26883990
Source
pubmed
Published In
Nature Communications
Volume
7
Publish Date
2016
Start Page
10501
DOI
10.1038/ncomms10501

X-Ray Psoralen Activated Cancer Therapy (X-PACT).

This work investigates X-PACT (X-ray Psoralen Activated Cancer Therapy): a new approach for the treatment of solid cancer. X-PACT utilizes psoralen, a potent anti-cancer therapeutic with current application to proliferative disease and extracorporeal photopheresis (ECP) of cutaneous T Cell Lymphoma. An immunogenic role for light-activated psoralen has been reported, contributing to long-term clinical responses. Psoralen therapies have to-date been limited to superficial or extracorporeal scenarios due to the requirement for psoralen activation by UVA light, which has limited penetration in tissue. X-PACT solves this challenge by activating psoralen with UV light emitted from novel non-tethered phosphors (co-incubated with psoralen) that absorb x-rays and re-radiate (phosphoresce) at UV wavelengths. The efficacy of X-PACT was evaluated in both in-vitro and in-vivo settings. In-vitro studies utilized breast (4T1), glioma (CT2A) and sarcoma (KP-B) cell lines. Cells were exposed to X-PACT treatments where the concentrations of drug (psoralen and phosphor) and radiation parameters (energy, dose, and dose rate) were varied. Efficacy was evaluated primarily using flow cell cytometry in combination with complimentary assays, and the in-vivo mouse study. In an in-vitro study, we show that X-PACT induces significant tumor cell apoptosis and cytotoxicity, unlike psoralen or phosphor alone (p<0.0001). We also show that apoptosis increases as doses of phosphor, psoralen, or radiation increase. Finally, in an in-vivo pilot study of BALBc mice with syngeneic 4T1 tumors, we show that the rate of tumor growth is slower with X-PACT than with saline or AMT + X-ray (p<0.0001). Overall these studies demonstrate a potential therapeutic effect for X-PACT, and provide a foundation and rationale for future studies. In summary, X-PACT represents a novel treatment approach in which well-tolerated low doses of x-ray radiation are delivered to a specific tumor site to generate UVA light which in-turn unleashes both short- and potentially long-term antitumor activity of photo-active therapeutics like psoralen.

Authors
Oldham, M; Yoon, P; Fathi, Z; Beyer, WF; Adamson, J; Liu, L; Alcorta, D; Xia, W; Osada, T; Liu, C; Yang, XY; Dodd, RD; Herndon, JE; Meng, B; Kirsch, DG; Lyerly, HK; Dewhirst, MW; Fecci, P; Walder, H; Spector, NL
MLA Citation
Oldham, Mark, et al. “X-Ray Psoralen Activated Cancer Therapy (X-PACT)..” Plos One, vol. 11, no. 9, 2016. Pubmed, doi:10.1371/journal.pone.0162078.
Website
http://hdl.handle.net/10161/13034
PMID
27583569
Source
pubmed
Published In
Plos One
Volume
11
Issue
9
Publish Date
2016
Start Page
e0162078
DOI
10.1371/journal.pone.0162078

Pathologic Evaluation of Radiographically Enlarging Lesions After Stereotactic Radiosurgery for Brain Metastases

Authors
Kim, GJ; Barkdoll, T; Sampson, JH; Wang, Z; Hoang, J; Fecci, PE; Yin, FF; Kirkpatrick, JP
MLA Citation
Kim, G. J., et al. “Pathologic Evaluation of Radiographically Enlarging Lesions After Stereotactic Radiosurgery for Brain Metastases.” International Journal of Radiation Oncology*Biology*Physics, vol. 93, no. 3, Elsevier BV, 2015, pp. E93–E93. Crossref, doi:10.1016/j.ijrobp.2015.07.784.
Source
crossref
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
93
Issue
3
Publish Date
2015
Start Page
E93
End Page
E93
DOI
10.1016/j.ijrobp.2015.07.784

Editorial: Not everything that matters can be measured and not everything that can be measured matters.

Authors
Choi, BD; Fecci, PE; Sampson, JH
MLA Citation
Choi, Bryan D., et al. “Editorial: Not everything that matters can be measured and not everything that can be measured matters..” J Neurosurg, vol. 123, no. 3, Sept. 2015, pp. 543–44. Pubmed, doi:10.3171/2015.2.JNS142977.
PMID
26115465
Source
pubmed
Published In
J Neurosurg
Volume
123
Issue
3
Publish Date
2015
Start Page
543
End Page
544
DOI
10.3171/2015.2.JNS142977

Programmed death ligand 1 (PD-L1) as an immunotherapy target in patients with glioblastoma.

Authors
Vlahovic, G; Fecci, PE; Reardon, D; Sampson, JH
MLA Citation
Vlahovic, Gordana, et al. “Programmed death ligand 1 (PD-L1) as an immunotherapy target in patients with glioblastoma..” Neuro Oncol, vol. 17, no. 8, Aug. 2015, pp. 1043–45. Pubmed, doi:10.1093/neuonc/nov071.
PMID
25964311
Source
pubmed
Published In
Neuro Oncol
Volume
17
Issue
8
Publish Date
2015
Start Page
1043
End Page
1045
DOI
10.1093/neuonc/nov071

Peptide vaccines for the treatment of glioblastoma.

Glioblastoma multiforme (GBM) is an extremely malignant brain tumor for which current therapies do little to remedy. Despite aggressive treatment with surgery, radiation therapy, and chemotherapy, tumors inevitably recur as a direct consequence of the infiltrative nature of GBM. The poor prognosis of patients with GBM underscores the clear and urgent need for more precise and potent therapies. Immunotherapy is emerging as a promising means to treat GBM based on the immune system's capacity to mediate tumor-specific cytotoxicity. In this review, we will discuss the use of peptide vaccines for the treatment of GBM. The simplicity of peptide vaccines and their ability to elicit tumor antigen-specific immune responses make them an invaluable tool for the study of brain tumor immunotherapy.

Authors
Swartz, AM; Batich, KA; Fecci, PE; Sampson, JH
MLA Citation
Swartz, Adam M., et al. “Peptide vaccines for the treatment of glioblastoma..” J Neurooncol, vol. 123, no. 3, July 2015, pp. 433–40. Pubmed, doi:10.1007/s11060-014-1676-y.
PMID
25491947
Source
pubmed
Published In
J Neurooncol
Volume
123
Issue
3
Publish Date
2015
Start Page
433
End Page
440
DOI
10.1007/s11060-014-1676-y

Editorial: Turning fluorescence into black and white.

Authors
Fecci, PE; Babu, R; Adamson, DC; Sampson, JH
MLA Citation
Fecci, Peter E., et al. “Editorial: Turning fluorescence into black and white..” J Neurosurg, vol. 122, no. 6, June 2015, pp. 1356–58. Pubmed, doi:10.3171/2014.10.JNS141788.
PMID
25839932
Source
pubmed
Published In
J Neurosurg
Volume
122
Issue
6
Publish Date
2015
Start Page
1356
End Page
1358
DOI
10.3171/2014.10.JNS141788

Are BiTEs the "missing link" in cancer therapy?

Conventional treatment for cancer routinely includes surgical resection and some combination of chemotherapy and radiation. These approaches are frequently accompanied by unintended and highly toxic collateral damage to healthy tissues, which are offset by only marginal prognostic improvements in patients with advanced cancers. This unfortunate balance has driven the development of novel therapies that aim to target tumors both safely and efficiently. Over the past decade, mounting evidence has supported the therapeutic utility of T-cell-centered cancer immunotherapy, which, in its various iterations, has been shown capable of eliciting highly precise and robust antitumor responses both in animal models and human trials. The identification of tumor-specific targets has further fueled a growing interest in T-cell therapies given their potential to circumvent the non-specific nature of traditional treatments. Of the several strategies geared toward achieving T-cell recognition of tumor, bispecific antibodies (bsAbs) represent a novel class of biologics that have garnered enthusiasm in recent years due to their versatility, specificity, safety, cost, and ease of production. Bispecific T-cell Engagers (BiTEs) are a subclass of bsAbs that are specific for CD3 on one arm and a tumor antigen on the second. As such, BiTEs function by recruiting and activating polyclonal populations of T-cells at tumor sites, and do so without the need for co-stimulation or conventional MHC recognition. Blinatumomab, a well-characterized BiTE, has emerged as a promising recombinant bscCD19×CD3 construct that has demonstrated remarkable antitumor activity in patients with B-cell malignancies. This clinical success has resulted in the rapid extension of BiTE technology against a greater repertoire of tumor antigens and the recent US Food and Drug Administration's (FDA) accelerated approval of blinatumomab for the treatment of a rare form of acute lymphoblastic leukemia (ALL). In this review, we dissect the role of T-cell therapeutics in the new era of cancer immunotherapy, appraise the value of CAR T-cells in the context of solid tumors, and discuss why the BiTE platform may rescue several of the apparent deficits and shortcomings of competing immunotherapies to support its widespread clinical application.

Authors
Suryadevara, CM; Gedeon, PC; Sanchez-Perez, L; Verla, T; Alvarez-Breckenridge, C; Choi, BD; Fecci, PE; Sampson, JH
MLA Citation
Suryadevara, Carter M., et al. “Are BiTEs the "missing link" in cancer therapy?.” Oncoimmunology, vol. 4, no. 6, June 2015. Pubmed, doi:10.1080/2162402X.2015.1008339.
PMID
26155413
Source
pubmed
Published In
Oncoimmunology
Volume
4
Issue
6
Publish Date
2015
Start Page
e1008339
DOI
10.1080/2162402X.2015.1008339

Immunotherapy for malignant glioma.

Malignant gliomas (MG) are the most common type of primary malignant brain tumor. Most patients diagnosed with glioblastoma (GBM), the most common and malignant glial tumor, die within 12-15 months. Moreover, conventional treatment, which includes surgery followed by radiation and chemotherapy, can be highly toxic by causing nonspecific damage to healthy brain and other tissues. The shortcomings of standard-of-care have thus created a stimulus for the development of novel therapies that can target central nervous system (CNS)-based tumors specifically and efficiently, while minimizing off-target collateral damage to normal brain. Immunotherapy represents an investigational avenue with the promise of meeting this need, already having demonstrated its potential against B-cell malignancy and solid tumors in clinical trials. T-cell engineering with tumor-specific chimeric antigen receptors (CARs) is one proven approach that aims to redirect autologous patient T-cells to sites of tumor. This platform has evolved dramatically over the past two decades to include an improved construct design, and these modern CARs have only recently been translated into the clinic for brain tumors. We review here emerging immunotherapeutic platforms for the treatment of MG, focusing on the development and application of a CAR-based strategy against GBM.

Authors
Suryadevara, CM; Verla, T; Sanchez-Perez, L; Reap, EA; Choi, BD; Fecci, PE; Sampson, JH
MLA Citation
Suryadevara, Carter M., et al. “Immunotherapy for malignant glioma..” Surg Neurol Int, vol. 6, no. Suppl 1, 2015, pp. S68–77. Pubmed, doi:10.4103/2152-7806.151341.
PMID
25722935
Source
pubmed
Published In
Surgical Neurology International
Volume
6
Issue
Suppl 1
Publish Date
2015
Start Page
S68
End Page
S77
DOI
10.4103/2152-7806.151341

Immunotherapy for primary brain tumors: no longer a matter of privilege.

Immunotherapy for cancer continues to gain both momentum and legitimacy as a rational mode of therapy and a vital treatment component in the emerging era of personalized medicine. Gliomas, and their most malignant form, glioblastoma, remain as a particularly devastating solid tumor for which standard treatment options proffer only modest efficacy and target specificity. Immunotherapy would seem a well-suited choice to address such deficiencies given both the modest inherent immunogenicity of gliomas and the strong desire for treatment specificity within the confines of the toxicity-averse normal brain. This review highlights the caveats and challenges to immunotherapy for primary brain tumors, as well as reviewing modalities that are currently used or are undergoing active investigation. Tumor immunosuppressive countermeasures, peculiarities of central nervous system immune access, and opportunities for rational treatment design are discussed.

Authors
Fecci, PE; Heimberger, AB; Sampson, JH
MLA Citation
Fecci, Peter E., et al. “Immunotherapy for primary brain tumors: no longer a matter of privilege..” Clin Cancer Res, vol. 20, no. 22, Nov. 2014, pp. 5620–29. Pubmed, doi:10.1158/1078-0432.CCR-14-0832.
PMID
25398845
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
20
Issue
22
Publish Date
2014
Start Page
5620
End Page
5629
DOI
10.1158/1078-0432.CCR-14-0832

Reversal of warfarin associated coagulopathy with 4-factor prothrombin complex concentrate in traumatic brain injury and intracranial hemorrhage.

Warfarin-associated intracranial hemorrhage is associated with a high mortality rate. Ongoing coagulopathy increases the likelihood of hematoma expansion and can result in catastrophic hemorrhage if surgery is performed without reversal. The current standard of care for emergency reversal of warfarin is with fresh frozen plasma (FFP). In April 2013, the USA Food and Drug Administration approved a new reversal agent, 4-factor prothrombin complex concentrate (PCC), which has the potential to more rapidly correct coagulopathy. We sought to determine the feasibility and outcomes of using PCC for neurosurgical patients. A prospective, observational study of all patients undergoing coagulopathy reversal for intracranial hemorrhage from April 2013 to December 2013 at a single, tertiary care center was undertaken. Thirty three patients underwent emergent reversal of coagulopathy using either FFP or PCC at the discretion of the treating physician. Intracranial hemorrhage included subdural hematoma, intraparenchymal hematoma, and subarachnoid hemorrhage. FFP was used in 28 patients and PCC was used in five patients. International normalized ratio at presentation was similar between groups (FFP 2.9, PCC 3.1, p=0.89). The time to reversal was significantly shorter in the PCC group (FFP 256 minutes, PCC 65 minutes, p<0.05). When operations were performed, the time delay to perform operations was also significantly shorter in the PCC group (FFP 307 minutes, PCC 159 minutes, p<0.05). In this preliminary experience, PCC appears to provide a rapid reversal of coagulopathy. Normalization of coagulation parameters may prevent further intracranial hematoma expansion and facilitate rapid surgical evacuation, thereby improving neurological outcomes.

Authors
Yanamadala, V; Walcott, BP; Fecci, PE; Rozman, P; Kumar, JI; Nahed, BV; Swearingen, B
MLA Citation
Yanamadala, Vijay, et al. “Reversal of warfarin associated coagulopathy with 4-factor prothrombin complex concentrate in traumatic brain injury and intracranial hemorrhage..” J Clin Neurosci, vol. 21, no. 11, Nov. 2014, pp. 1881–84. Pubmed, doi:10.1016/j.jocn.2014.05.001.
PMID
24953825
Source
pubmed
Published In
J Clin Neurosci
Volume
21
Issue
11
Publish Date
2014
Start Page
1881
End Page
1884
DOI
10.1016/j.jocn.2014.05.001

Antibody-based immunotherapy for malignant glioma.

Conventional therapy for malignant glioma (MG) fails to specifically eliminate tumor cells, resulting in toxicity that limits therapeutic efficacy. In contrast, antibody-based immunotherapy uses the immune system to eliminate tumor cells with exquisite specificity. Increased understanding of the pathobiology of MG and the profound immunosuppression present among patients with MG has revealed several biologic targets amenable to antibody-based immunotherapy. Novel antibody engineering techniques allow for the production of fully human antibodies or antibody fragments with vastly reduced antigen-binding dissociation constants, increasing safety when used clinically as therapeutics. In this report, we summarize the use of antibody-based immunotherapy for MG. Approaches currently under investigation include the use of antibodies or antibody fragments to: (1) redirect immune effector cells to target tumor mutations, (2) inhibit immunosuppressive signals and thereby stimulate an immunological response against tumor cells, and (3) provide costimulatory signals to evoke immunologic targeting of tumor cells. These approaches demonstrate highly compelling safety and efficacy for the treatment of MG, providing a viable adjunct to current standard-of-care therapy for MG.

Authors
Gedeon, PC; Riccione, KA; Fecci, PE; Sampson, JH
MLA Citation
Gedeon, Patrick C., et al. “Antibody-based immunotherapy for malignant glioma..” Semin Oncol, vol. 41, no. 4, Aug. 2014, pp. 496–510. Pubmed, doi:10.1053/j.seminoncol.2014.06.004.
PMID
25173142
Source
pubmed
Published In
Semin Oncol
Volume
41
Issue
4
Publish Date
2014
Start Page
496
End Page
510
DOI
10.1053/j.seminoncol.2014.06.004

Immunovirotherapy for the treatment of glioblastoma.

We have recently described a new murine model of glioblastoma, generated by the implantation of syngeneic glioblastoma stem cells into immunocompetent mice, that recapitulates the salient histopathological and immunological features of the human disease. We employed this model to demonstrate the multifaceted activity of an oncolytic herpes simplex virus genetically modified to express interleukin-12, G47∆-IL12.

Authors
Cheema, TA; Fecci, PE; Ning, J; Rabkin, SD
MLA Citation
Cheema, Tooba A., et al. “Immunovirotherapy for the treatment of glioblastoma..” Oncoimmunology, vol. 3, no. 1, Jan. 2014. Pubmed, doi:10.4161/onci.27218.
PMID
24575383
Source
pubmed
Published In
Oncoimmunology
Volume
3
Issue
1
Publish Date
2014
Start Page
e27218
DOI
10.4161/onci.27218

Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors.

UNLABELLED: The success in lung cancer therapy with programmed death (PD)-1 blockade suggests that immune escape mechanisms contribute to lung tumor pathogenesis. We identified a correlation between EGF receptor (EGFR) pathway activation and a signature of immunosuppression manifested by upregulation of PD-1, PD-L1, CTL antigen-4 (CTLA-4), and multiple tumor-promoting inflammatory cytokines. We observed decreased CTLs and increased markers of T-cell exhaustion in mouse models of EGFR-driven lung cancer. PD-1 antibody blockade improved the survival of mice with EGFR-driven adenocarcinomas by enhancing effector T-cell function and lowering the levels of tumor-promoting cytokines. Expression of mutant EGFR in bronchial epithelial cells induced PD-L1, and PD-L1 expression was reduced by EGFR inhibitors in non-small cell lung cancer cell lines with activated EGFR. These data suggest that oncogenic EGFR signaling remodels the tumor microenvironment to trigger immune escape and mechanistically link treatment response to PD-1 inhibition. SIGNIFICANCE: We show that autochthonous EGFR-driven lung tumors inhibit antitumor immunity by activating the PD-1/PD-L1 pathway to suppress T-cell function and increase levels of proinflammatory cytokines. These findings indicate that EGFR functions as an oncogene through non-cell-autonomous mechanisms and raise the possibility that other oncogenes may drive immune escape.

Authors
Akbay, EA; Koyama, S; Carretero, J; Altabef, A; Tchaicha, JH; Christensen, CL; Mikse, OR; Cherniack, AD; Beauchamp, EM; Pugh, TJ; Wilkerson, MD; Fecci, PE; Butaney, M; Reibel, JB; Soucheray, M; Cohoon, TJ; Janne, PA; Meyerson, M; Hayes, DN; Shapiro, GI; Shimamura, T; Sholl, LM; Rodig, SJ; Freeman, GJ; Hammerman, PS; Dranoff, G; Wong, K-K
MLA Citation
Akbay, Esra A., et al. “Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors..” Cancer Discov, vol. 3, no. 12, Dec. 2013, pp. 1355–63. Pubmed, doi:10.1158/2159-8290.CD-13-0310.
PMID
24078774
Source
pubmed
Published In
Cancer Discov
Volume
3
Issue
12
Publish Date
2013
Start Page
1355
End Page
1363
DOI
10.1158/2159-8290.CD-13-0310

Lost And Found: Therapeutic Implications Of Bone Marrow As Harbor For Missing T-Cells In Glioma

Authors
Fecci, PE; Koyama, S; Chen, C; Cheema, T; Dranoff, G; Martuza, R; Curry, W
MLA Citation
Fecci, Peter Edward, et al. “Lost And Found: Therapeutic Implications Of Bone Marrow As Harbor For Missing T-Cells In Glioma.” Journal of Neurosurgery, vol. 119, no. 2, AMER ASSOC NEUROLOGICAL SURGEONS, 2013, pp. A564–A564.
Source
wos
Published In
Journal of Neurosurgery
Volume
119
Issue
2
Publish Date
2013
Start Page
A564
End Page
A564

198 Of Mice and Men

Authors
Fecci, P; Chen, C; Koyama, S; Dranoff, G; Martuza, RL; Curry, WT
MLA Citation
Fecci, Peter, et al. “198 Of Mice and Men.” Neurosurgery, vol. 60, Oxford University Press (OUP), 2013, pp. 185–86. Crossref, doi:10.1227/01.neu.0000432788.37762.98.
Source
crossref
Published In
Neurosurgery
Volume
60
Publish Date
2013
Start Page
185
End Page
186
DOI
10.1227/01.neu.0000432788.37762.98

Multifaceted oncolytic virus therapy for glioblastoma in an immunocompetent cancer stem cell model.

Glioblastoma (World Health Organization grade IV) is an aggressive adult brain tumor that is inevitably fatal despite surgery, radiation, and chemotherapy. Treatment failures are attributed to combinations of cellular heterogeneity, including a subpopulation of often-resistant cancer stem cells, aberrant vasculature, and noteworthy immune suppression. Current preclinical models and treatment strategies do not incorporate or address all these features satisfactorily. Herein, we describe a murine glioblastoma stem cell (GSC) model that recapitulates tumor heterogeneity, invasiveness, vascularity, and immunosuppressive microenvironment in syngeneic immunocompetent mice and should prove useful for a range of therapeutic studies. Using this model, we tested a genetically engineered oncolytic herpes simplex virus that is armed with an immunomodulatory cytokine, interleukin 12 (G47-mIL12). G47Δ-mIL12 infects and replicates similarly to its unarmed oncolytic herpes simplex virus counterpart in mouse 005 GSCs in vitro, whereas in vivo, it significantly enhances survival in syngeneic mice bearing intracerebral 005 tumors. Mechanistically, G47-mIL12 targets not only GSCs but also increases IFN-γ release, inhibits angiogenesis, and reduces the number of regulatory T cells in the tumor. The increased efficacy is dependent upon T cells, but not natural killer cells. Taken together, our findings demonstrate that G47Δ-mIL12 provides a multifaceted approach to targeting GSCs, tumor microenvironment, and the immune system, with resultant therapeutic benefit in a stringent glioblastoma model.

Authors
Cheema, TA; Wakimoto, H; Fecci, PE; Ning, J; Kuroda, T; Jeyaretna, DS; Martuza, RL; Rabkin, SD
MLA Citation
Cheema, Tooba A., et al. “Multifaceted oncolytic virus therapy for glioblastoma in an immunocompetent cancer stem cell model..” Proc Natl Acad Sci U S A, vol. 110, no. 29, July 2013, pp. 12006–11. Pubmed, doi:10.1073/pnas.1307935110.
PMID
23754388
Source
pubmed
Published In
Proc Natl Acad Sci U S A
Volume
110
Issue
29
Publish Date
2013
Start Page
12006
End Page
12011
DOI
10.1073/pnas.1307935110

An update on vaccine therapy and other immunotherapeutic approaches for glioblastoma.

Outcome for glioblastoma (GBM), the most common primary CNS malignancy, remains poor. The overall survival benefit recently achieved with immunotherapeutics for melanoma and prostate cancer support evaluation of immunotherapies for other challenging cancers, including GBM. Much historical dogma depicting the CNS as immunoprivileged has been replaced by data demonstrating CNS immunocompetence and active interaction with the peripheral immune system. Several glioma antigens have been identified for potential immunotherapeutic exploitation. Active immunotherapy studies for GBM, supported by preclinical data, have focused on tumor lysate and synthetic antigen vaccination strategies. Results to date confirm consistent safety, including a lack of autoimmune reactivity; however, modest efficacy and variable immunogenicity have been observed. These findings underscore the need to optimize vaccination variables and to address challenges posed by systemic and local immunosuppression inherent to GBM tumors. Additional immunotherapy strategies are also in development for GBM. Future studies may consider combinatorial immunotherapy strategies with complimentary actions.

Authors
Reardon, DA; Wucherpfennig, KW; Freeman, G; Wu, CJ; Chiocca, EA; Wen, PY; Curry, WT; Mitchell, DA; Fecci, PE; Sampson, JH; Dranoff, G
MLA Citation
Reardon, David A., et al. “An update on vaccine therapy and other immunotherapeutic approaches for glioblastoma..” Expert Rev Vaccines, vol. 12, no. 6, June 2013, pp. 597–615. Pubmed, doi:10.1586/erv.13.41.
PMID
23750791
Source
pubmed
Published In
Expert Rev Vaccines
Volume
12
Issue
6
Publish Date
2013
Start Page
597
End Page
615
DOI
10.1586/erv.13.41

Regulatory T cells move in when gliomas say "I Do".

Indoleamine 2,3-dioxygenase (IDO) is an enzyme with known immunosuppressive and tolerogenic effects in cancer. Mounting evidence has associated IDO expression with the induction of regulatory T cells (Treg) and malignant progression. IDO inhibition may therefore provide a promising therapeutic approach for glioblastoma, where the need for novel treatment is great.

Authors
Choi, BD; Fecci, PE; Sampson, JH
MLA Citation
Choi, Bryan D., et al. “Regulatory T cells move in when gliomas say "I Do"..” Clin Cancer Res, vol. 18, no. 22, Nov. 2012, pp. 6086–88. Pubmed, doi:10.1158/1078-0432.CCR-12-2801.
PMID
23052252
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
18
Issue
22
Publish Date
2012
Start Page
6086
End Page
6088
DOI
10.1158/1078-0432.CCR-12-2801

Cancer immunoediting in malignant glioma.

Significant work from many laboratories over the last decade in the study of cancer immunology has resulted in the development of the cancer immunoediting hypothesis. This contemporary framework of the naturally arising immune system-tumor interaction is thought to comprise 3 phases: elimination, wherein immunity subserves an extrinsic tumor suppressor function and destroys nascent tumor cells; equilibrium, wherein tumor cells are constrained in a period of latency under immune control; and escape, wherein tumor cells outpace immunity and progress clinically. In this review, we address in detail the relevance of the cancer immunoediting concept to neurosurgeons and neuro-oncologists treating and studying malignant glioma by exploring the de novo immune response to these tumors, how these tumors may persist in vivo, the mechanisms by which these cells may escape/attenuate immunity, and ultimately how this concept may influence our immunotherapeutic approaches.

Authors
Dunn, GP; Fecci, PE; Curry, WT
MLA Citation
Dunn, Gavin P., et al. “Cancer immunoediting in malignant glioma..” Neurosurgery, vol. 71, no. 2, Aug. 2012, pp. 201–22. Pubmed, doi:10.1227/NEU.0b013e31824f840d.
PMID
22353795
Source
pubmed
Published In
Neurosurgery
Volume
71
Issue
2
Publish Date
2012
Start Page
201
End Page
222
DOI
10.1227/NEU.0b013e31824f840d

Sequential immunotherapy by vaccination with GM-CSF-expressing glioma cells and CTLA-4 blockade effectively treats established murine intracranial tumors.

Malignant glioma is an incurable disease with a relatively short median survival. Several clinical trials have demonstrated that immunotherapy with vaccination is a safe and possibly effective way of prolonging survival. Antibody-based blockade of cytotoxic T-lymphocyte antigen 4 (CTLA-4) ligation on T lymphocytes is associated with enhanced antitumor immunity in animal models of cancer and in patients with advanced melanoma. We hypothesized that sequential therapy with granulocyte-macrophage-colony-stimulating factor (GM-CSF)-expressing whole-glioma-cell vaccination and CTLA-4 blockade is an effective strategy for treating established intracranial gliomas. GL261 glioma cells were injected into the right frontal lobes of syngeneic C57/BL6 mice. At days 3, 6, and 9 after tumor implantation, mice were treated with subcutaneous injection of irradiated GM-CSF-expressing GL261 cells. Mice were also treated with intraperitoneal injection of anti-CTLA-4 monoclonal antibodies (mAbs), either at days 3, 6, and 9 or days 12, 15, and 18. Animals were followed for survival. Splenocytes were harvested at day 22 for use in enzyme-linked immunosorbent spot assays. Early treatment of established intracranial gliomas with high-dose CTLA-4 blockade was associated with increased survival in GL261-bearing mice. Later treatment with anti-CTLA-4 monoclonal antibodies did not significantly improve survival compared with control-treated mice. Early vaccination followed by subsequent CTLA-4 blockade was associated with significantly improved survival versus either treatment alone and intensified tumor-specific immunity as measured by interferon-γ enzyme-linked immunosorbent spot assay. Sequential immunotherapy with GM-CSF-expressing irradiated glioma cells and CTLA-4 blockade synergistically prolongs survival in mice bearing established intracranial gliomas.

Authors
Agarwalla, P; Barnard, Z; Fecci, P; Dranoff, G; Curry, WT
MLA Citation
Agarwalla, Pankaj, et al. “Sequential immunotherapy by vaccination with GM-CSF-expressing glioma cells and CTLA-4 blockade effectively treats established murine intracranial tumors..” J Immunother, vol. 35, no. 5, June 2012, pp. 385–89. Pubmed, doi:10.1097/CJI.0b013e3182562d59.
PMID
22576343
Source
pubmed
Published In
J Immunother
Volume
35
Issue
5
Publish Date
2012
Start Page
385
End Page
389
DOI
10.1097/CJI.0b013e3182562d59

Licorice-associated reversible cerebral vasoconstriction with PRES.

Authors
Chatterjee, N; Domoto-Reilly, K; Fecci, PE; Schwamm, LH; Singhal, AB
MLA Citation
Chatterjee, N., et al. “Licorice-associated reversible cerebral vasoconstriction with PRES..” Neurology, vol. 75, no. 21, Nov. 2010, pp. 1939–41. Pubmed, doi:10.1212/WNL.0b013e3181feb299.
PMID
21098410
Source
pubmed
Published In
Neurology
Volume
75
Issue
21
Publish Date
2010
Start Page
1939
End Page
1941
DOI
10.1212/WNL.0b013e3181feb299

CTLA-4 BLOCKADE AUGMENTS VACCINE-INDUCED ANTITUMOR IMMUNITY AGAINST INTRACRANIAL GLIOMA

Authors
Curry, WT; Barnard, ZR; Agarwalla, PK; Fecci, P; Dranoff, G
MLA Citation
Curry, William T., et al. “CTLA-4 BLOCKADE AUGMENTS VACCINE-INDUCED ANTITUMOR IMMUNITY AGAINST INTRACRANIAL GLIOMA.” Neuro Oncology, vol. 11, no. 5, DUKE UNIV PRESS, 2009, pp. 618–618.
Source
wos
Published In
Neuro Oncology
Volume
11
Issue
5
Publish Date
2009
Start Page
618
End Page
618

Molecular strategies for the treatment of malignant glioma--genes, viruses, and vaccines.

The standard treatment paradigm of surgery, radiation, and chemotherapy for malignant gliomas has only a modest effect on survival. It is well emphasized in the literature that despite aggressive multimodal therapy, most patients survive approximately 1 year after diagnosis, and less than 10% survive beyond 2 years. This dismal prognosis provides the impetus for ongoing investigations in search of improved therapeutics. Standard multimodal therapy has largely reached a plateau in terms of effectiveness, and there is now a growing body of literature on novel molecular approaches for the treatment of malignant gliomas. Gene therapy, oncolytic virotherapy, and immunotherapy are the major investigational approaches that have demonstrated promise in preclinical and early clinical studies. These new molecular technologies each have distinct advantages and limitations, and none has yet demonstrated a significant survival benefit in a phase II or III clinical trial. Molecular approaches may not lead to the discovery of a "magic bullet" for these aggressive tumors, but they may ultimately prove synergistic with more conventional approaches and lead to a broadening of the multimodal approach that is the current standard of care. This review will discuss the scientific background, therapeutic potential, and clinical limitations of these novel strategies with a focus on those that have made it to clinical trials.

Authors
Selznick, LA; Shamji, MF; Fecci, P; Gromeier, M; Friedman, AH; Sampson, J
MLA Citation
Selznick, Lee A., et al. “Molecular strategies for the treatment of malignant glioma--genes, viruses, and vaccines..” Neurosurg Rev, vol. 31, no. 2, Apr. 2008, pp. 141–55. Pubmed, doi:10.1007/s10143-008-0121-0.
PMID
18259789
Source
pubmed
Published In
Neurosurgical Review
Volume
31
Issue
2
Publish Date
2008
Start Page
141
End Page
155
DOI
10.1007/s10143-008-0121-0

Immunotherapy of malignant brain tumors.

Despite aggressive multi-modality therapy including surgery, radiation, and chemotherapy, the prognosis for patients with malignant primary brain tumors remains very poor. Moreover, the non-specific nature of conventional therapy for brain tumors often results in incapacitating damage to surrounding normal brain and systemic tissues. Thus, there is an urgent need for the development of therapeutic strategies that precisely target tumor cells while minimizing collateral damage to neighboring eloquent cerebral cortex. The rationale for using the immune system to target brain tumors is based on the premise that the inherent specificity of immunologic reactivity could meet the clear need for more specific and precise therapy. The success of this modality is dependent on our ability to understand the mechanisms of immune regulation within the central nervous system (CNS), as well as counter the broad defects in host cell-mediated immunity that malignant gliomas are known to elicit. Recent advances in our understanding of tumor-induced and host-mediated immunosuppressive mechanisms, the development of effective strategies to combat these suppressive effects, and a better understanding of how to deliver immunologic effector molecules more efficiently to CNS tumors have all facilitated significant progress toward the realization of true clinical benefit from immunotherapeutic treatment of malignant gliomas.

Authors
Mitchell, DA; Fecci, PE; Sampson, JH
MLA Citation
Mitchell, Duane A., et al. “Immunotherapy of malignant brain tumors..” Immunol Rev, vol. 222, Apr. 2008, pp. 70–100. Pubmed, doi:10.1111/j.1600-065X.2008.00603.x.
PMID
18363995
Source
pubmed
Published In
Immunol Rev
Volume
222
Publish Date
2008
Start Page
70
End Page
100
DOI
10.1111/j.1600-065X.2008.00603.x

Systemic CTLA-4 blockade ameliorates glioma-induced changes to the CD4+ T cell compartment without affecting regulatory T-cell function.

PURPOSE: Patients with malignant glioma suffer global compromise of their cellular immunity, characterized by dramatic reductions in CD4(+) T cell numbers and function. We have previously shown that increased regulatory T cell (T(reg)) fractions in these patients explain T-cell functional deficits. Our murine glioma model recapitulates these findings. Here, we investigate the effects of systemic CTLA-4 blockade in this model. EXPERIMENTAL DESIGN: A monoclonal antibody (9H10) to CTLA-4 was employed against well-established glioma. Survival and risks for experimental allergic encephalomyelitis were assessed, as were CD4(+) T cell numbers and function in the peripheral blood, spleen, and cervical lymph nodes. The specific capacities for anti-CTLA-4 to modify the functions of regulatory versus CD4(+)CD25(-) responder T cells were evaluated. RESULTS: CTLA-4 blockade confers long-term survival in 80% of treated mice, without eliciting experimental allergic encephalomyelitis. Changes to the CD4 compartment were reversed, as anti-CTLA-4 reestablishes normal CD4 counts and abrogates increases in CD4(+)CD25(+)Foxp3(+)GITR(+) regulatory T cell fraction observed in tumor-bearing mice. CD4(+) T-cell proliferative capacity is restored and the cervical lymph node antitumor response is enhanced. Treatment benefits are bestowed exclusively on the CD4(+)CD25(-) T cell population and not T(regs), as CD4(+)CD25(-) T cells from treated mice show improved proliferative responses and resistance to T(reg)-mediated suppression, whereas T(regs) from the same mice remain anergic and exhibit no restriction of their suppressive capacity. CONCLUSIONS: CTLA-4 blockade is a rational means of reversing glioma-induced changes to the CD4 compartment and enhancing antitumor immunity. These benefits were attained through the conferment of resistance to T(reg)-mediated suppression, and not through direct effects on T(regs).

Authors
Fecci, PE; Ochiai, H; Mitchell, DA; Grossi, PM; Sweeney, AE; Archer, GE; Cummings, T; Allison, JP; Bigner, DD; Sampson, JH
MLA Citation
Fecci, Peter E., et al. “Systemic CTLA-4 blockade ameliorates glioma-induced changes to the CD4+ T cell compartment without affecting regulatory T-cell function..” Clin Cancer Res, vol. 13, no. 7, Apr. 2007, pp. 2158–67. Pubmed, doi:10.1158/1078-0432.CCR-06-2070.
PMID
17404100
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
13
Issue
7
Publish Date
2007
Start Page
2158
End Page
2167
DOI
10.1158/1078-0432.CCR-06-2070

Profiling of CD4+, CD8+, and CD4+CD25+CD45RO+FoxP3+ T cells in patients with malignant glioma reveals differential expression of the immunologic transcriptome compared with T cells from healthy volunteers.

PURPOSE: Analyses of T-cell mRNA expression profiles in glioblastoma multiforme has not been previously reported but may help to define and characterize the immunosuppressed phenotype in patients with this type of cancer. EXPERIMENTAL DESIGN: We did microarray studies that have shown significant and fundamental differences in the expression profiles of CD4(+) and CD8(+) T cells and immunosuppressive CD4(+)CD25(+)CD45RO(+)FoxP3(+) regulatory T cells (T(reg)) from normal healthy volunteers compared with patients with newly diagnosed glioblastoma multiforme. For these investigations, we isolated total RNA from enriched CD4(+) and CD8(+) T cell or T(reg) cell populations from age-matched individuals and did microarray analyses. RESULTS: ANOVA and principal components analysis show that the various T cell compartments exhibit consistently similar mRNA expression profiles among individuals within either healthy or brain tumor groups but reflect significant differences between these groups. Compared with healthy volunteers, CD4(+) and CD8(+) T cells from patients with glioblastoma multiforme display coordinate down-regulation of genes involved in T cell receptor ligation, activation, and intracellular signaling. In contrast, T(regs) from patients with glioblastoma multiforme exhibit increased levels of transcripts involved in inhibiting host immunity. CONCLUSION: Our findings support the notion that key differences between expression profiles in T-cell populations from patients with glioblastoma multiforme results from differential expression of the immunologic transcriptome, such that a limited number of genes are principally important in producing the dysregulated T-cell phenotype.

Authors
Learn, CA; Fecci, PE; Schmittling, RJ; Xie, W; Karikari, I; Mitchell, DA; Archer, GE; Wei, Z; Dressman, H; Sampson, JH
MLA Citation
Learn, Chris A., et al. “Profiling of CD4+, CD8+, and CD4+CD25+CD45RO+FoxP3+ T cells in patients with malignant glioma reveals differential expression of the immunologic transcriptome compared with T cells from healthy volunteers..” Clin Cancer Res, vol. 12, no. 24, Dec. 2006, pp. 7306–15. Pubmed, doi:10.1158/1078-0432.CCR-06-1727.
PMID
17189402
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
12
Issue
24
Publish Date
2006
Start Page
7306
End Page
7315
DOI
10.1158/1078-0432.CCR-06-1727

Systemic anti-CD25 monoclonal antibody administration safely enhances immunity in murine glioma without eliminating regulatory T cells.

PURPOSE: Elevated proportions of regulatory T cells (T(reg)) are present in patients with a variety of cancers, including malignant glioma, yet recapitulative murine models are wanting. We therefore examined T(regs) in mice bearing malignant glioma and evaluated anti-CD25 as an immunotherapeutic adjunct. EXPERIMENTAL DESIGN: CD4+CD25+Foxp3+GITR+ T(regs) were quantified in the peripheral blood, spleens, cervical lymph nodes, and bone marrow of mice bearing malignant glioma. The capacities for systemic anti-CD25 therapy to deplete T(regs), enhance lymphocyte function, and generate antiglioma CTL responses were assessed. Lastly, survival and experimental allergic encephalitis risks were evaluated when anti-CD25 was combined with a dendritic cell-based immunization targeting shared tumor and central nervous system antigens. RESULTS: Similar to patients with malignant glioma, glioma-bearing mice show a CD4 lymphopenia. Additionally, CD4+CD25+Foxp3+GITR+ T(regs) represent an increased fraction of the remaining peripheral blood CD4+ T cells, despite themselves being reduced in number. Similar trends are observed in cervical lymph node and spleen, but not in bone marrow. Systemic anti-CD25 administration hinders detection of CD25+ cells but fails to completely eliminate T(regs), reducing their number only moderately, yet eliminating their suppressive function. This elimination of T(reg) function permits enhanced lymphocyte proliferative and IFN-gamma responses and up to 80% specific lysis of glioma cell targets in vitro. When combined with dendritic cell immunization, anti-CD25 elicits tumor rejection in 100% of challenged mice without precipitating experimental allergic encephalitis. CONCLUSIONS: Systemic anti-CD25 administration does not entirely eliminate T(regs) but does prevent T(reg) function. This leads to safe enhancement of tumor immunity in a murine glioma model that recapitulates the tumor-induced changes to the CD4 and T(reg) compartments seen in patients with malignant glioma.

Authors
Fecci, PE; Sweeney, AE; Grossi, PM; Nair, SK; Learn, CA; Mitchell, DA; Cui, X; Cummings, TJ; Bigner, DD; Gilboa, E; Sampson, JH
MLA Citation
Fecci, Peter E., et al. “Systemic anti-CD25 monoclonal antibody administration safely enhances immunity in murine glioma without eliminating regulatory T cells..” Clin Cancer Res, vol. 12, no. 14 Pt 1, July 2006, pp. 4294–305. Pubmed, doi:10.1158/1078-0432.CCR-06-0053.
PMID
16857805
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
12
Issue
14 Pt 1
Publish Date
2006
Start Page
4294
End Page
4305
DOI
10.1158/1078-0432.CCR-06-0053

Radiotherapy with regulatory T-cell depletion is synergistic for treatment of experimental model of malignant glioma

Authors
Unger, JM; Fecci, P; Ochiai, H; Mitchell, DA; Schmittling, R; Chewning, TA; Sampson, JH
MLA Citation
Unger, J. M., et al. “Radiotherapy with regulatory T-cell depletion is synergistic for treatment of experimental model of malignant glioma.” Journal of Neurosurgery, vol. 104, no. 4, AMER ASSOC NEUROLOGICAL SURGEONS, 2006, pp. A637–38.
Source
wos
Published In
Journal of Neurosurgery
Volume
104
Issue
4
Publish Date
2006
Start Page
A637
End Page
A638

Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma.

Immunosuppression is frequently associated with malignancy and is particularly severe in patients with malignant glioma. Anergy and counterproductive shifts toward T(H)2 cytokine production are long-recognized T-cell defects in these patients whose etiology has remained elusive for >30 years. We show here that absolute counts of both CD4(+) T cells and CD4(+)CD25(+)FOXP3(+)CD45RO(+) T cells (T(regs)) are greatly diminished in patients with malignant glioma, but T(regs) frequently represent an increased fraction of the remaining CD4 compartment. This increased T(reg) fraction, despite reduced counts, correlates with and is sufficient to elicit the characteristic manifestations of impaired patient T-cell responsiveness in vitro. Furthermore, T(reg) removal eradicates T-cell proliferative defects and reverses T(H)2 cytokine shifts, allowing T cells from patients with malignant glioma to function in vitro at levels equivalent to those of normal, healthy controls. Such restored immune function may give license to physiologic antiglioma activity, as in vivo, T(reg) depletion proves permissive for spontaneous tumor rejection in a murine model of established intracranial glioma. These findings dramatically alter our understanding of depressed cellular immune function in patients with malignant glioma and advance a role for T(regs) in facilitating tumor immune evasion in the central nervous system.

Authors
Fecci, PE; Mitchell, DA; Whitesides, JF; Xie, W; Friedman, AH; Archer, GE; Herndon, JE; Bigner, DD; Dranoff, G; Sampson, JH
MLA Citation
Fecci, Peter E., et al. “Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma..” Cancer Res, vol. 66, no. 6, Mar. 2006, pp. 3294–302. Pubmed, doi:10.1158/0008-5472.CAN-05-3773.
PMID
16540683
Source
pubmed
Published In
Cancer Research
Volume
66
Issue
6
Publish Date
2006
Start Page
3294
End Page
3302
DOI
10.1158/0008-5472.CAN-05-3773

Expression profiling of CD4+ and CD8+ T cells in malignant glioma.

Authors
Learn, CA; Schmittling, RJ; Fecci, PE; Mitchell, DA; Archer, GE; Sampson, JH
MLA Citation
Learn, C. A., et al. “Expression profiling of CD4+ and CD8+ T cells in malignant glioma..” Clinical Cancer Research, vol. 11, no. 24, AMER ASSOC CANCER RESEARCH, 2005, pp. 8999S-8999S.
Source
wos
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
11
Issue
24
Publish Date
2005
Start Page
8999S
End Page
8999S

The history, evolution, and clinical use of dendritic cell-based immunization strategies in the therapy of brain tumors.

Despite advancements in therapeutic regimens, the prognosis remains poor for patients with malignant gliomas. Specificity has been an elusive goal for current modalities, but immunotherapy has emerged as a potential means of designing more tumor-specific treatments. Dendritic cells (DC) are the specialized antigen presenting cells of the immune system and have served now as a platform for therapeutic immunizations against such cancers as lymphoma, multiple myeloma, melanoma, prostate cancer, renal cell carcinoma, non-small cell lung carcinoma, colon cancer, and even malignant gliomas. DC-based immunizations offer a number of advantages over traditional immunotherapeutic approaches to brain tumors, approaches that have proved promising despite concerns over central nervous system immune privilege and glioma-mediated immunosuppression. The future success of clinical trials will depend on the optimization and standardizing of procedures for DC generation, loading, and administration.

Authors
Fecci, PE; Mitchell, DA; Archer, GE; Morse, MA; Lyerly, HK; Bigner, DD; Sampson, JH
MLA Citation
Fecci, Peter E., et al. “The history, evolution, and clinical use of dendritic cell-based immunization strategies in the therapy of brain tumors..” J Neurooncol, vol. 64, no. 1–2, Aug. 2003, pp. 161–76.
PMID
12952297
Source
pubmed
Published In
Journal of Neuro Oncology
Volume
64
Issue
1-2
Publish Date
2003
Start Page
161
End Page
176

Adoptive immunotherapy for malignant glioma.

Despite remarkable advancements in imaging modalities and treatment options available to patients diagnosed with malignant brain tumors, the prognosis for those with high-grade lesions remains poor. The imprecise mechanisms of currently available treatments to manage these tumors do not spare damage to the normal surrounding brain and often result in major cognitive and motor deficits. Immunotherapy holds the promise of offering a potent, yet targeted, treatment to patients with brain tumors, with the potential to eradicate the malignant tumor cells without damaging normal tissues. The T cells of the immune system are uniquely capable of recognizing the altered protein expression patterns within tumor cells and mediating their destruction through a variety of effector mechanisms. Adoptive T-cell therapy is an attempt to harness and amplify the tumor-eradicating capacity of a patients' own T cells and then return these effectors to the patient in such a state that they effectively eliminate residual tumor. Although this approach is not new to the field of tumor immunology, new advancements in our understanding of T-cell activation and function and breakthroughs in tumor antigen discovery hold great promise for the translation of this modality into a clinical success.

Authors
Mitchell, DA; Fecci, PE; Sampson, JH
MLA Citation
Mitchell, Duane A., et al. “Adoptive immunotherapy for malignant glioma..” Cancer J, vol. 9, no. 3, May 2003, pp. 157–66.
PMID
12952301
Source
pubmed
Published In
Cancer Journal (Sudbury, Mass.)
Volume
9
Issue
3
Publish Date
2003
Start Page
157
End Page
166

Clinical immunotherapy for brain tumors.

As an immunization platform for brain tumors, dendritic cells supply an impressive host of advantages. On the simplest level, they provide the safety and tumor-specificity so wanted by current therapeutic options. Yet, in addition, as the fundamental antigen-presenting cell, they circumvent many of the immunologic challenges that gliomas and the CNS proffer and that other immunotherapeutic modes fail to overcome. Directions to take now include the identification of new tumor-specific and tumor-associated antigens; the determination of the optimal dendritic cell subtype, generation, loading method, maturation state, dose, and route of delivery for immunizations; the further characterization of dendritic cells and their activities; and, potentially, the discovery of ways to pulse dendritic cells efficiently in vivo. Preclinical studies continue to play an important role in refining this form of active immunotherapy.

Authors
Fecci, PE; Sampson, JH
MLA Citation
Fecci, Peter E., and John H. Sampson. “Clinical immunotherapy for brain tumors..” Neuroimaging Clin N Am, vol. 12, no. 4, Nov. 2002, pp. 641–64.
PMID
12687917
Source
pubmed
Published In
Neuroimaging Clinics of North America
Volume
12
Issue
4
Publish Date
2002
Start Page
641
End Page
664

Viruses in the treatment of brain tumors.

The grave outlook for malignant glioma patients in spite of improvements to current modalities has ushered in new approaches to therapy. Viruses have emerged on the scene and gained attention for their ability to play essentially two roles: first, as vectors for therapeutic gene delivery and second, as engineered infectious agents capable of selectively lysing tumor cells. To date, clinical brain tumor trials using viruses for gene delivery have employed retroviral or adenoviral vectors to introduce ganciclovir susceptibility to tumors in the form of the HSV1-TK gene. Clinical oncolytic studies, on the other hand, have evaluated a conditionally replicating HSV as an antineoplastic agent. Despite some promise afforded by these trials, further studies are warranted; the investigation of additional viruses to play these roles is inevitable and is now precedented.

Authors
Fecci, PE; Gromeier, M; Sampson, JH
MLA Citation
Fecci, Peter E., et al. “Viruses in the treatment of brain tumors..” Neuroimaging Clin N Am, vol. 12, no. 4, Nov. 2002, pp. 553–70.
PMID
12687911
Source
pubmed
Published In
Neuroimaging Clinics of North America
Volume
12
Issue
4
Publish Date
2002
Start Page
553
End Page
570
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Research Areas:

  • Blood-Brain Barrier
  • Brain metastasis
  • Cancer
  • Immunotherapy
  • Immunotherapy, Active
  • T cells
  • T cells--Effect of drugs on
  • T cells--Receptors