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:

Therapeutic Targeting of the TGF-BSignaling Axis to Modulate the Tumor Immune Microenvironment and Enhance Melanoma Immu

Administered By
Medicine, Medical Oncology
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
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

Sanofi SAR439459

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

Publications:

Blood-based genomic profiling of cell-free DNA (cfDNA) to identify microsatellite instability (MSI-H), tumor mutational burden (TMB) and Wnt/B-Catenin pathway alterations in patients with gastrointestinal (GI) tract cancers.

Authors
Isaacs, J; Nixon, AB; Bolch, E; Quinn, K; Banks, K; Hanks, BA; Strickler, JH
MLA Citation
Isaacs, James, et al. “Blood-based genomic profiling of cell-free DNA (cfDNA) to identify microsatellite instability (MSI-H), tumor mutational burden (TMB) and Wnt/B-Catenin pathway alterations in patients with gastrointestinal (GI) tract cancers..” Journal of Clinical Oncology, vol. 37, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2019, pp. 3552–3552. Crossref, doi:10.1200/jco.2019.37.15_suppl.3552.
URI
https://scholars.duke.edu/individual/pub1414970
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
37
Published Date
Start Page
3552
End Page
3552
DOI
10.1200/jco.2019.37.15_suppl.3552

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

Targeting the TGF-β Signaling Pathway to Augment the Efficacy of Immunotherapy Checkpoint Inhibitors in Melanoma

Authors
URI
https://scholars.duke.edu/individual/pub1126745
Source
manual

Updates in adjuvant systemic therapy for melanoma.

There has been a rapid increase in adjuvant therapies approved for treatment following surgical resection of stages III/IV melanoma. We review current indications for adjuvant therapy, which currently includes a heterogenous group of stages III and IV patients with melanoma. We describe several pivotal clinical trials of systemic immune therapies, targeted immune therapies, and adjuvant vaccine strategies. Finally, we discuss the evidence for selecting the most appropriate treatment regimen(s) for the individual patient.
Authors
Kwak, M; Farrow, NE; Salama, AKS; Mosca, PJ; Hanks, BA; Slingluff, CL; Beasley, GM
MLA Citation
Kwak, Minyoung, et al. “Updates in adjuvant systemic therapy for melanoma..” J Surg Oncol, vol. 119, no. 2, Jan. 2019, pp. 222–31. Pubmed, doi:10.1002/jso.25298.
URI
https://scholars.duke.edu/individual/pub1358560
PMID
30481375
Source
pubmed
Published In
J Surg Oncol
Volume
119
Published Date
Start Page
222
End Page
231
DOI
10.1002/jso.25298

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