Brent Hanks

Overview:

We are interested in understanding the mechanisms that cancers have evolved to suppress the generation of tumor antigen-specific immune responses and how this knowledge can be exploited for the development of novel and more effective cancer immunotherapy strategies. This work involves the utilization of both autochthonous transgenic tumor model systems as well as clinical specimens to develop novel strategies to enhance the efficacy of immunotherapies while also developing predictive biomarkers to better guide the management of cancer patients with these agents. We strive to translate our understanding of the fundamental biochemical and metabolic pathways within the tumor microenvironment that are critical for driving immune evasion and resistance into early phase clinical trial testing.

Our work utilizes a variety of techniques and methodologies that span the breadth of basic biological research. This work integrates studies based on both 1) transgenic mouse tumor models that are monitored using bioluminescence and micro-CT imaging and 2) a variety of clinical specimens.

Our current areas of focus include:

  1. Investigating mechanisms of adaptive or acquired immunotherapy resistance in cancer
  2. Studying the relationship between EMT pathways and immunotherapy resistance.
  3. Elucidating mechanisms of dendritic cell tolerization in the tumor microenvironment and how these processes may contribute to immunotherapy resistance
  4. Development of novel pharmacologic and genetic strategies to overcome immunotherapy resistance
  5. Investigating mechanisms contributing to select immunotherapy-associated toxicities

Positions:

Associate Professor of Medicine

Medicine, Medical Oncology
School of Medicine

Assistant Professor of Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2004

Baylor College of Medicine

M.D. 2006

Baylor College of Medicine

Internship and Residency, Internal Medicine

Duke University School of Medicine

Fellowship, Hematology/Oncology

Duke University School of Medicine

Grants:

Therapeutic Targeting of the TGF-beta Signaling Axis to Modulate the Tumor Immune Microenvironment and Enhance Melanoma Immunotherapy

Administered By
Medicine, Medical Oncology
Awarded By
Melanoma Research Alliance
Role
Principal Investigator
Start Date
End Date

Role of Type III TGF-b Receptor in Mediating Immunosuppression During Breast Cancer Progression

Administered By
Medicine, Medical Oncology
Awarded By
Department of Defense
Role
Principal Investigator
Start Date
End Date

Investigating the Role of EMT-mediated Dendritic Cell Tolerization in Checkpoint Inhibitor Resistance

Administered By
Medicine, Medical Oncology
Awarded By
Damon Runyon Cancer Research Foundation
Role
Principal Investigator
Start Date
End Date

Investigating Oncogenic Signaling Pathways that Drive Wnt Ligand-mediated Immune Tolerance in Melanoma

Administered By
Medicine, Medical Oncology
Awarded By
Conquer Cancer Foundation
Role
Principal Investigator
Start Date
End Date

HSP70-TLR4-mediated MDSC Recruitment as an Adaptive Resistance

Administered By
Medicine, Medical Oncology
Awarded By
Merck Sharp & Dohme
Role
Principal Investigator
Start Date
End Date

Publications:

Editorial: Signaling pathways behind immune evasion and therapy resistance.

Authors
Martin-Orozco, E; Wang, L; Chatterjee, S; Hanks, BA
MLA Citation
Martin-Orozco, Elena, et al. “Editorial: Signaling pathways behind immune evasion and therapy resistance.Front Immunol, vol. 13, 2022, p. 1104167. Pubmed, doi:10.3389/fimmu.2022.1104167.
URI
https://scholars.duke.edu/individual/pub1560768
PMID
36569846
Source
pubmed
Published In
Frontiers in Immunology
Volume
13
Published Date
Start Page
1104167
DOI
10.3389/fimmu.2022.1104167

923P Molecular classification of cancers of unknown primary expands and refines treatment options

Authors
George, DJ; Moore, E; Blobe, GC; DeVito, N; Hanks, BA; Harrison, MR; Hoimes, CJ; Jia, J; Morse, M; Jayaprakasan, P; MacKelfresh, A; Mulder, H; Beauchamp, K; Michuda, J; Stumpe, MC; Perakslis, E; Taxter, T
MLA Citation
George, D. J., et al. “923P Molecular classification of cancers of unknown primary expands and refines treatment options.” Annals of Oncology, vol. 33, Elsevier BV, 2022, pp. S968–69. Crossref, doi:10.1016/j.annonc.2022.07.1048.
URI
https://scholars.duke.edu/individual/pub1559949
Source
crossref
Published In
Annals of Oncology
Volume
33
Published Date
Start Page
S968
End Page
S969
DOI
10.1016/j.annonc.2022.07.1048

Tumor-intrinsic NLRP3-HSP70-TLR4 axis drives premetastatic niche development and hyperprogression during anti-PD-1 immunotherapy.

The tumor-intrinsic NOD-, LRR- and pyrin domain-containing protein-3 (NLRP3) inflammasome-heat shock protein 70 (HSP70) signaling axis is triggered by CD8+ T cell cytotoxicity and contributes to the development of adaptive resistance to anti-programmed cell death protein 1 (PD-1) immunotherapy by recruiting granulocytic polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) into the tumor microenvironment. Here, we demonstrate that the tumor NLRP3-HSP70 axis also drives the accumulation of PMN-MDSCs into distant lung tissues in a manner that depends on lung epithelial cell Toll-like receptor 4 (TLR4) signaling, establishing a premetastatic niche that supports disease hyperprogression in response to anti-PD-1 immunotherapy. Lung epithelial HSP70-TLR4 signaling induces the downstream Wnt5a-dependent release of granulocyte colony-stimulating factor (G-CSF) and C-X-C motif chemokine ligand 5 (CXCL5), thus promoting myeloid granulopoiesis and recruitment of PMN-MDSCs into pulmonary tissues. Treatment with anti-PD-1 immunotherapy enhanced the activation of this pathway through immunologic pressure and drove disease progression in the setting of Nlrp3 amplification. Genetic and pharmacologic inhibition of NLRP3 and HSP70 blocked PMN-MDSC accumulation in the lung in response to anti-PD-1 therapy and suppressed metastatic progression in preclinical models of melanoma and breast cancer. Elevated baseline concentrations of plasma HSP70 and evidence of NLRP3 signaling activity in tumor tissue specimens correlated with the development of disease hyperprogression and inferior survival in patients with stage IV melanoma undergoing anti-PD-1 immunotherapy. Together, this work describes a pathogenic mechanism underlying the phenomenon of disease hyperprogression in melanoma and offers candidate targets and markers capable of improving the management of patients with melanoma.
Authors
Theivanthiran, B; Yarla, N; Haykal, T; Nguyen, Y-V; Cao, L; Ferreira, M; Holtzhausen, A; Al-Rohil, R; Salama, AKS; Beasley, GM; Plebanek, MP; DeVito, NC; Hanks, BA
MLA Citation
Theivanthiran, Balamayooran, et al. “Tumor-intrinsic NLRP3-HSP70-TLR4 axis drives premetastatic niche development and hyperprogression during anti-PD-1 immunotherapy.Sci Transl Med, vol. 14, no. 672, Nov. 2022, p. eabq7019. Pubmed, doi:10.1126/scitranslmed.abq7019.
URI
https://scholars.duke.edu/individual/pub1557466
PMID
36417489
Source
pubmed
Published In
Sci Transl Med
Volume
14
Published Date
Start Page
eabq7019
DOI
10.1126/scitranslmed.abq7019

Multicenter Experience with Neoadjuvant Therapy in Melanoma Highlights Heterogeneity in Contemporary Practice.

OBJECTIVE: To determine the feasibility and impact of neoadjuvant therapy (NT) in patients who present with advanced melanoma amenable to surgical resection. SUMMARY BACKGROUND DATA: Given current effective systemic therapy for melanoma, the use of NT is being explored in patients with advanced melanoma with disease amenable to surgical resection. METHODS: Prospective data from 3 institutions was obtained in patients with clinically evident Stage III/IV melanoma who underwent NT. The primary objective was to compare recurrence-free survival between patients who had pathologic complete response (pCR) to those with persistent disease. RESULTS: NT was offered to 45 patients, with 43 patients initiating various NT regimens including PD-1 antagonist (PD-1) therapy (N = 16), PD-1 plus ipilimumab (N = 10), BRAF/MEK inhibitor therapy (N = 14), a combination of those three (N = 1), and talimogene laherparepvec (TVEC) (N = 2). Thirty-two (74.1%) patients underwent surgery whereas 11 patients did not undergo surgery for these reasons: clinical CR (N = 7), progressive disease not amenable to resection (N = 3), and ongoing therapy (N = 1). 12 of 32 patients (37.5%) had pCR with these therapies: PD-1 (N = 4), PD-1 plus ipilimumab (N = 2), BRAF/MEK (N = 4), combination (N = 1), and TVEC (N = 1). At median follow-up of 16.4 months there was only 1 recurrence in the pCR group and patients with a pCR had significantly improved recurrence-free survival compared to patients without pCR (p = 0.004). CONCLUSIONS: Despite variability in NT regimens across institutions, NT for melanoma is feasible and associated with improved prognosis in patients who achieve a pCR. Maximizing rates of pCR could improve prognosis for patients with advanced melanoma.
Authors
Rhodin, KE; Gaughan, EM; Raman, V; Salama, AK; Hanks, BA; Shah, R; Tyler, DS; Slingluff, CL; Beasley, GM
MLA Citation
Rhodin, Kristen E., et al. “Multicenter Experience with Neoadjuvant Therapy in Melanoma Highlights Heterogeneity in Contemporary Practice.Ann Surg, July 2022. Pubmed, doi:10.1097/SLA.0000000000005459.
URI
https://scholars.duke.edu/individual/pub1526196
PMID
35797609
Source
pubmed
Published In
Ann Surg
Published Date
DOI
10.1097/SLA.0000000000005459

Complete Pathologic Response Predicts Disease-Free Survival for Melanoma Patients Undergoing Neoadjuvant Therapy

Authors
Rhodin, KE; Gaughan, EM; Raman, V; Salama, AK; Hanks, BA; Shah, R; Tyler, DS; Slingluff, CLJ; Beasley, GM
MLA Citation
Rhodin, Kristen E., et al. “Complete Pathologic Response Predicts Disease-Free Survival for Melanoma Patients Undergoing Neoadjuvant Therapy.” Journal of the American College of Surgeons, vol. 233, no. 5, 2021, pp. S246–S246.
URI
https://scholars.duke.edu/individual/pub1503193
Source
wos-lite
Published In
Journal of the American College of Surgeons
Volume
233
Published Date
Start Page
S246
End Page
S246

Research Areas:

Biomarkers, Pharmacological
Cell Line, Tumor
Chemokine CCL22
Combined Modality Therapy
Dendritic Cells
Disease-Free Survival
Down-Regulation
Female
Humans
Indoleamine-Pyrrole 2,3,-Dioxygenase
Lymphocyte Activation
Mammary Neoplasms, Experimental
Melanoma
Melanoma, Experimental
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Transgenic
Molecular Targeted Therapy
Neoplasm Staging
Neoplasm Transplantation
Neoplasms
Prognosis
Proteoglycans
Receptors, Transforming Growth Factor beta
Signal Transduction
Transforming Growth Factor beta
Tumor Escape
Tumor Microenvironment