Brent Hanks

Overview:

My lab is interested in elucidating the molecular and cellular mechanisms involved in tumor-mediated immune suppression and cancer immunotherapy resistance. Our overriding hypothesis is that tumor cells and/or their associated stromal elements elicit soluble factors that tolerize local dendritic cell populations and/or recruit other immunosuppressive cell populations to the tumor bed; thereby, interfering with the generation of an effective anti-tumor immune response. This work has both basic and translational significance in that it is capable of providing 1. novel pharmacological targets for enhancing anti-tumor immunity and 2.  much needed biomarkers for guiding the management of cancer patients with immunotherapies.  We perform these investigations utilizing both transgenic murine models as well as clinical specimens derived from cancer patients undergoing immunotherapy.  We focus these studies on melanoma, non-small cell lung cancer, pancreatic cancer, and colon cancer. 

We currently have the following ongoing projects in our lab:
1.  Investigating mechanisms by which developing cancers alter the metabolism of local dendritic cells thereby hijacking this antigen-presenting cell population to generate an immunotolerant tumor microenvironment. 
2.  Identifying soluble factors expressed by cancers which manipulate local dendritic cell function to drive regulatory T cell  differentiation within the tumor microenvironment as well as any potential oncogenic signaling pathways driving this process.
3.  Characterizing mechanisms of innate and adaptive resistance mechanisms to checkpoint inhibitor therapies.
4.  Examining the role of the tumor stroma in interfering with immunotherapy efficacy.
5.  Design and development of novel dendritic cell-based vaccine strategies

Positions:

Assistant 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:

Melanoma-mediated Dendritic Cell Tolerization and Immune Evasion

Administered By
Medicine, Medical Oncology
Awarded By
National Institutes of Health
Role
Co-Mentor
Start Date
End Date

Sanofi SAR439459

Administered By
Duke Cancer Institute
Role
Principal Investigator
Start Date
End Date

HSP70-TLR4-mediated MDSC Recruitment as an Adaptive Resistance

Administered By
Medicine, Medical Oncology
Role
Principal Investigator
Start Date
End Date

Investigating the Immunotherapeutic Properties of the DKK1 Antibody, DKN-01, in Pre-Clinical Models of Melanoma

Administered By
Medicine, Medical Oncology
Role
Principal Investigator
Start Date
End Date

Investigating the Impact of TPST-1120 PPAR ¿ Inhibition on Anti-PD-1 Antibody Immunotherapy Efficacy in Pre-Clinical Melanoma Models

Administered By
Medicine, Medical Oncology
Role
Principal Investigator
Start Date
End Date

Publications:

Durable Tumor Regression and Overall Survival in Patients With Advanced Merkel Cell Carcinoma Receiving Pembrolizumab as First-Line Therapy.

PURPOSE: Merkel cell carcinoma (MCC) is an aggressive skin cancer often caused by the Merkel cell polyomavirus. Clinical trials of programmed cell death-1 pathway inhibitors for advanced MCC (aMCC) demonstrate increased progression-free survival (PFS) compared with historical chemotherapy data. However, response durability and overall survival (OS) data are limited. PATIENTS AND METHODS: In this multicenter phase II trial (Cancer Immunotherapy Trials Network-09/Keynote-017), 50 adults naïve to systemic therapy for aMCC received pembrolizumab (2 mg/kg every 3 weeks) for up to 2 years. Radiographic responses were assessed centrally per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. RESULTS: Among 50 patients, the median age was 70.5 years, and 64% had Merkel cell polyomavirus-positive tumors. The objective response rate (ORR) to pembrolizumab was 56% (complete response [24%] plus partial response [32%]; 95% CI, 41.3% to 70.0%), with ORRs of 59% in virus-positive and 53% in virus-negative tumors. Median follow-up time was 14.9 months (range, 0.4 to 36.4+ months). Among 28 responders, median response duration was not reached (range, 5.9 to 34.5+ months). The 24-month PFS rate was 48.3%, and median PFS time was 16.8 months (95% CI, 4.6 months to not estimable). The 24-month OS rate was 68.7%, and median OS time was not reached. Although tumor viral status did not correlate with ORR, PFS, or OS, there was a trend toward improved PFS and OS in patients with programmed death ligand-1-positive tumors. Grade 3 or greater treatment-related adverse events occurred in 14 (28%) of 50 patients and led to treatment discontinuation in seven (14%) of 50 patients, including one treatment-related death. CONCLUSION: Here, we present the longest observation to date of patients with aMCC receiving first-line anti-programmed cell death-1 therapy. Pembrolizumab demonstrated durable tumor control, a generally manageable safety profile, and favorable OS compared with historical data from patients treated with first-line chemotherapy.
Authors
Nghiem, P; Bhatia, S; Lipson, EJ; Sharfman, WH; Kudchadkar, RR; Brohl, AS; Friedlander, PA; Daud, A; Kluger, HM; Reddy, SA; Boulmay, BC; Riker, AI; Burgess, MA; Hanks, BA; Olencki, T; Margolin, K; Lundgren, LM; Soni, A; Ramchurren, N; Church, C; Park, SY; Shinohara, MM; Salim, B; Taube, JM; Bird, SR; Ibrahim, N; Fling, SP; Homet Moreno, B; Sharon, E; Cheever, MA; Topalian, SL
MLA Citation
Nghiem, Paul, et al. “Durable Tumor Regression and Overall Survival in Patients With Advanced Merkel Cell Carcinoma Receiving Pembrolizumab as First-Line Therapy..” J Clin Oncol, vol. 37, no. 9, Mar. 2019, pp. 693–702. Pubmed, doi:10.1200/JCO.18.01896.
URI
https://scholars.duke.edu/individual/pub1369152
PMID
30726175
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
37
Published Date
Start Page
693
End Page
702
DOI
10.1200/JCO.18.01896

Combinatorial TGF-β signaling blockade and anti-CTLA-4 antibody immunotherapy in a murine BRAFV600E-PTEN-/- transgenic model of melanoma.

Authors
Hanks, BA; Holtzhausen, A; Evans, K; Heid, M; Blobe, GC
MLA Citation
Hanks, Brent Allen, et al. “Combinatorial TGF-β signaling blockade and anti-CTLA-4 antibody immunotherapy in a murine BRAFV600E-PTEN-/- transgenic model of melanoma..” Journal of Clinical Oncology, vol. 32, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2014, pp. 3011–3011. Crossref, doi:10.1200/jco.2014.32.15_suppl.3011.
URI
https://scholars.duke.edu/individual/pub1085235
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
32
Published Date
Start Page
3011
End Page
3011
DOI
10.1200/jco.2014.32.15_suppl.3011

The Influence of the Tumor Microenvironment on Checkpoint Inhibitor Efficacy: Lessons Learned from Targeting the TGF-β Signaling Pathway.

Authors
Hanks, BA
URI
https://scholars.duke.edu/individual/pub1126744
Source
manual

Phase 1/2 study of epacadostat in combination with ipilimumab in patients with unresectable or metastatic melanoma.

BACKGROUND: Epacadostat is a potent inhibitor of the immunosuppressive indoleamine 2,3-dioxygenase 1 (IDO1) enzyme. We present phase 1 results from a phase 1/2 clinical study of epacadostat in combination with ipilimumab, an anti-cytotoxic T-lymphocyte-associated protein 4 antibody, in advanced melanoma (NCT01604889). METHODS: Only the phase 1, open-label portion of the study was conducted, per the sponsor's decision to terminate the study early based on the changing melanoma treatment landscape favoring exploration of programmed cell death protein 1 (PD-1)/PD-ligand 1 inhibitor-based combination strategies. Such decision was not related to the safety of epacadostat plus ipilimumab. Patients received oral epacadostat (25, 50, 100, or 300 mg twice daily [BID]; 75 mg daily [50 mg AM, 25 mg PM]; or 50 mg BID intermittent [2 weeks on/1 week off]) plus intravenous ipilimumab 3 mg/kg every 3 weeks. RESULTS: Fifty patients received ≥1 dose of epacadostat. As of January 20, 2017, 2 patients completed treatment and 48 discontinued, primarily because of adverse events (AEs) and disease progression (n = 20 each). Dose-limiting toxicities occurred in 11 patients (n = 1 each with epacadostat 25 mg BID, 50 mg BID intermittent, 75 mg daily; n = 4 each with epacadostat 50 mg BID, 300 mg BID). The most common immune-related treatment-emergent AEs included rash (50%), alanine aminotransferase elevation (28%), pruritus (28%), aspartate aminotransferase elevation (24%), and hypothyroidism (10%). Among immunotherapy-naive patients (n = 39), the objective response rate was 26% by immune-related response criteria and 23% by Response Evaluation Criteria in Solid Tumors version 1.1. No objective response was seen in the 11 patients who received prior immunotherapy. Epacadostat exposure was dose proportional, with clinically significant IDO1 inhibition at doses ≥25 mg BID. CONCLUSIONS: When combined with ipilimumab, epacadostat ≤50 mg BID demonstrated clinical and pharmacologic activity and was generally well tolerated in patients with advanced melanoma. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01604889 . Registration date, May 9, 2012, retrospectively registered.
Authors
Gibney, GT; Hamid, O; Lutzky, J; Olszanski, AJ; Mitchell, TC; Gajewski, TF; Chmielowski, B; Hanks, BA; Zhao, Y; Newton, RC; Maleski, J; Leopold, L; Weber, JS
MLA Citation
Gibney, Geoffrey T., et al. “Phase 1/2 study of epacadostat in combination with ipilimumab in patients with unresectable or metastatic melanoma..” J Immunother Cancer, vol. 7, no. 1, Mar. 2019. Pubmed, doi:10.1186/s40425-019-0562-8.
URI
https://scholars.duke.edu/individual/pub1376264
PMID
30894212
Source
pubmed
Published In
Journal for Immunotherapy of Cancer
Volume
7
Published Date
Start Page
80
DOI
10.1186/s40425-019-0562-8

Early Carcinogenesis Involves the Establishment of Immune Privilege via Intrinsic and Extrinsic Regulation of Indoleamine 2,3-dioxygenase-1: Translational Implications in Cancer Immunotherapy.

Although prolonged genetic pressure has been conjectured to be necessary for the eventual development of tumor immune evasion mechanisms, recent work is demonstrating that early genetic mutations are capable of moonlighting as both intrinsic and extrinsic modulators of the tumor immune microenvironment. The indoleamine 2,3-dioxygenase-1 (IDO) immunoregulatory enzyme is emerging as a key player in tumor-mediated immune tolerance. While loss of the tumor suppressor, BIN-1, and the over-expression of cyclooxygenase-2 have been implicated in intrinsic regulation of IDO, recent findings have demonstrated the loss of TβRIII and the upregulation of Wnt5a by developing cancers to play a role in the extrinsic control of IDO activity by local dendritic cell populations residing within tumor and tumor-draining lymph node tissues. Together, these genetic changes are capable of modulating paracrine signaling pathways in the early stages of carcinogenesis to establish a site of immune privilege by promoting the differentiation and activation of local regulatory T cells. Additional investigation of these immune evasion pathways promises to provide opportunities for the development of novel strategies to synergistically enhance the efficacy of the evolving class of T cell-targeted "checkpoint" inhibitors.
Authors
Holtzhausen, A; Zhao, F; Evans, KS; Hanks, BA
URI
https://scholars.duke.edu/individual/pub1048604
PMID
25339948
Source
pubmed
Published In
Frontiers in Immunology
Volume
5
Published Date
Start Page
438
DOI
10.3389/fimmu.2014.00438

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