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:

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:

Three-year survival, correlates and salvage therapies in patients receiving first-line pembrolizumab for advanced Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive skin cancer associated with poor survival. Programmed cell death-1 (PD-1) pathway inhibitors have shown high rates of durable tumor regression compared with chemotherapy for MCC. The current study was undertaken to assess baseline and on-treatment factors associated with MCC regression and 3-year survival, and to explore the effects of salvage therapies in patients experiencing initial non-response or tumor progression after response or stable disease following first-line pembrolizumab therapy on Cancer Immunotherapy Trials Network-09/KEYNOTE-017. METHODS: In this multicenter phase II trial, 50 patients with advanced unresectable MCC received pembrolizumab 2 mg/kg every 3 weeks for ≤2 years. Patients were followed for a median of 31.8 months. RESULTS: Overall response rate to pembrolizumab was 58% (complete response 30%+partial response 28%; 95% CI 43.2 to 71.8). Among 29 responders, the median response duration was not reached (NR) at 3 years (range 1.0+ to 51.8+ months). Median progression-free survival (PFS) was 16.8 months (95% CI 4.6 to 43.4) and the 3-year PFS was 39.1%. Median OS was NR; the 3-year OS was 59.4% for all patients and 89.5% for responders. Baseline Eastern Cooperative Oncology Group performance status of 0, greater per cent tumor reduction, completion of 2 years of treatment and low neutrophil-to-lymphocyte ratio were associated with response and longer survival. Among patients with initial disease progression or those who developed progression after response or stable disease, some had extended survival with subsequent treatments including chemotherapies and immunotherapies. CONCLUSIONS: This study represents the longest available follow-up from any first-line anti-programmed death-(ligand) 1 (anti-PD-(L)1) therapy in MCC, confirming durable PFS and OS in a proportion of patients. After initial tumor progression or relapse following response, some patients receiving salvage therapies survived. Improving the management of anti-PD-(L)1-refractory MCC remains a challenge and a high priority. TRIAL REGISTRATION NUMBER: NCT02267603.
Authors
Nghiem, P; Bhatia, S; Lipson, EJ; Sharfman, WH; Kudchadkar, RR; Brohl, AS; Friedlander, PA; Daud, A; Kluger, HM; Reddy, SA; Boulmay, BC; Riker, A; Burgess, MA; Hanks, BA; Olencki, T; Kendra, K; Church, C; Akaike, T; Ramchurren, N; Shinohara, MM; Salim, B; Taube, JM; Jensen, E; Kalabis, M; Fling, SP; Homet Moreno, B; Sharon, E; Cheever, MA; Topalian, SL
MLA Citation
Nghiem, Paul, et al. “Three-year survival, correlates and salvage therapies in patients receiving first-line pembrolizumab for advanced Merkel cell carcinoma.J Immunother Cancer, vol. 9, no. 4, Apr. 2021. Pubmed, doi:10.1136/jitc-2021-002478.
URI
https://scholars.duke.edu/individual/pub1480910
PMID
33879601
Source
pubmed
Published In
Journal for Immunotherapy of Cancer
Volume
9
Published Date
DOI
10.1136/jitc-2021-002478

A case report of microsatellite instability (MSI)-high, HER2 amplified pancreatic adenocarcinoma with central nervous system metastasis.

Pancreatic adenocarcinoma commonly presents as metastatic disease and harbors a dire prognosis due to its aggressive behavior, propensity for resistance to therapies, and lack of targetable driver mutations. Additionally, despite advances in other cancers, immunotherapy has been ineffective in this disease thus far and treatment remains centered around cytotoxic chemotherapy. Here, we present a case of a patient with pancreatic adenocarcinoma harboring both high microsatellite instability (MSI-H) and HER2 amplification. After an initial response to standard-of-care chemotherapy with FOLFIRINOX followed by progression, she was treated with dual immune checkpoint blockade, which resulted in a period of disease control. This was complicated by the development of autoimmune hypophysitis and an incidental finding of brain metastasis on magnetic resonance imaging (MRI). Her extracranial disease progressed while receiving stereotactic radiosurgery, with findings of lymphangitic spread in her lungs, and her treatment was changed to gemcitabine/nab-paclitaxel with trastuzumab. This resulted in a degree of extracranial disease control, though she experienced progressive brain metastases despite radiation and therapeutic switch to lapatinib and trastuzumab. Ultimately, the patient developed leptomeningeal disease which was not controlled by intrathecal trastuzumab. Given the rarity of central nervous system metastasis, HER2 amplification, and MSI in pancreatic cancer, this patient's presentation represents a confluence of multiple unique features. This case highlights the clinical value of up-front next-generation sequencing in metastatic pancreatic cancer and the ability of pancreatic cancer with actionable molecular variants to develop atypical sites of disease and adaptive resistance.
MLA Citation
DeVito, Nicholas C., et al. “A case report of microsatellite instability (MSI)-high, HER2 amplified pancreatic adenocarcinoma with central nervous system metastasis.Ame Case Rep, vol. 5, 2021, p. 14. Pubmed, doi:10.21037/acr-20-154.
URI
https://scholars.duke.edu/individual/pub1481212
PMID
33912803
Source
pubmed
Published In
Ame Case Rep
Volume
5
Published Date
Start Page
14
DOI
10.21037/acr-20-154

The State of Melanoma: Emergent Challenges and Opportunities.

Five years ago, the Melanoma Research Foundation (MRF) conducted an assessment of the challenges and opportunities facing the melanoma research community and patients with melanoma. Since then, remarkable progress has been made on both the basic and clinical research fronts. However, the incidence, recurrence, and death rates for melanoma remain unacceptably high and significant challenges remain. Hence, the MRF Scientific Advisory Council and Breakthrough Consortium, a group that includes clinicians and scientists, reconvened to facilitate intensive discussions on thematic areas essential to melanoma researchers and patients alike, prevention, detection, diagnosis, metastatic dormancy and progression, response and resistance to targeted and immune-based therapy, and the clinical consequences of COVID-19 for patients with melanoma and providers. These extensive discussions helped to crystalize our understanding of the challenges and opportunities facing the broader melanoma community today. In this report, we discuss the progress made since the last MRF assessment, comment on what remains to be overcome, and offer recommendations for the best path forward.
Authors
Atkins, MB; Curiel-Lewandrowski, C; Fisher, DE; Swetter, SM; Tsao, H; Aguirre-Ghiso, JA; Soengas, MS; Weeraratna, AT; Flaherty, KT; Herlyn, M; Sosman, JA; Tawbi, HA; Pavlick, AC; Cassidy, PB; Chandra, S; Chapman, PB; Daud, A; Eroglu, Z; Ferris, LK; Fox, BA; Gershenwald, JE; Gibney, GT; Grossman, D; Hanks, BA; Hanniford, D; Hernando, E; Jeter, JM; Johnson, DB; Khleif, SN; Kirkwood, JM; Leachman, SA; Mays, D; Nelson, KC; Sondak, VK; Sullivan, RJ; Merlino, G; Melanoma Research Foundation,
MLA Citation
Atkins, Michael B., et al. “The State of Melanoma: Emergent Challenges and Opportunities.Clin Cancer Res, vol. 27, no. 10, May 2021, pp. 2678–97. Pubmed, doi:10.1158/1078-0432.CCR-20-4092.
URI
https://scholars.duke.edu/individual/pub1470645
PMID
33414132
Source
pubmed
Published In
Clinical Cancer Research
Volume
27
Published Date
Start Page
2678
End Page
2697
DOI
10.1158/1078-0432.CCR-20-4092

Pharmacological Wnt ligand inhibition overcomes key tumor-mediated resistance pathways to anti-PD-1 immunotherapy.

While immune checkpoint blockade is associated with prolonged responses in multiple cancers, most patients still do not benefit from this therapeutic strategy. The Wnt-β-catenin pathway is associated with diminished T cell infiltration; however, activating mutations are rare, implicating a role for autocrine/paracrine Wnt ligand-driven signaling in immune evasion. In this study, we show that proximal mediators of the Wnt signaling pathway are associated with anti-PD-1 resistance, and pharmacologic inhibition of Wnt ligand signaling supports anti-PD-1 efficacy by reversing dendritic cell tolerization and the recruitment of granulocytic myeloid-derived suppressor cells in autochthonous tumor models. We further demonstrate that the inhibition of Wnt signaling promotes the development of a tumor microenvironment that is more conducive to favorable responses to checkpoint blockade in cancer patients. These findings support a rationale for Wnt ligand-focused treatment approaches in future immunotherapy clinical trials and suggest a strategy for selecting those tumors more responsive to Wnt inhibition.
Authors
DeVito, NC; Sturdivant, M; Thievanthiran, B; Xiao, C; Plebanek, MP; Salama, AKS; Beasley, GM; Holtzhausen, A; Novotny-Diermayr, V; Strickler, JH; Hanks, BA
MLA Citation
DeVito, Nicholas C., et al. “Pharmacological Wnt ligand inhibition overcomes key tumor-mediated resistance pathways to anti-PD-1 immunotherapy.Cell Rep, vol. 35, no. 5, May 2021, p. 109071. Pubmed, doi:10.1016/j.celrep.2021.109071.
URI
https://scholars.duke.edu/individual/pub1470781
PMID
33951424
Source
pubmed
Published In
Cell Reports
Volume
35
Published Date
Start Page
109071
DOI
10.1016/j.celrep.2021.109071

Ipilimumab and Radiation in Patients with High-risk Resected or Regionally Advanced Melanoma.

PURPOSE: In this prospective trial, we sought to assess the feasibility of concurrent administration of ipilimumab and radiation as adjuvant, neoadjuvant, or definitive therapy in patients with regionally advanced melanoma. PATIENTS AND METHODS: Twenty-four patients in two cohorts were enrolled and received ipilimumab at 3 mg/kg every 3 weeks for four doses in conjunction with radiation; median dose was 4,000 cGy (interquartile range, 3,550-4,800 cGy). Patients in cohort 1 were treated adjuvantly; patients in cohort 2 were treated either neoadjuvantly or as definitive therapy. RESULTS: Adverse event profiles were consistent with those previously reported with checkpoint inhibition and radiation. For the neoadjuvant/definitive cohort, the objective response rate was 64% (80% confidence interval, 40%-83%), with 4 of 10 evaluable patients achieving a radiographic complete response. An additional 3 patients in this cohort had a partial response and went on to surgical resection. With 2 years of follow-up, the 6-, 12-, and 24-month relapse-free survival for the adjuvant cohort was 85%, 69%, and 62%, respectively. At 2 years, all patients in the neoadjuvant/definitive cohort and 10/13 patients in the adjuvant cohort were still alive. Correlative studies suggested that response in some patients were associated with specific CD4+ T-cell subsets. CONCLUSIONS: Overall, concurrent administration of ipilimumab and radiation was feasible, and resulted in a high response rate, converting some patients with unresectable disease into surgical candidates. Additional studies to investigate the combination of radiation and checkpoint inhibitor therapy are warranted.
Authors
Salama, AKS; Palta, M; Rushing, CN; Selim, MA; Linney, KN; Czito, BG; Yoo, DS; Hanks, BA; Beasley, GM; Mosca, PJ; Dumbauld, C; Steadman, KN; Yi, JS; Weinhold, KJ; Tyler, DS; Lee, WT; Brizel, DM
MLA Citation
Salama, April K. S., et al. “Ipilimumab and Radiation in Patients with High-risk Resected or Regionally Advanced Melanoma.Clin Cancer Res, vol. 27, no. 5, Mar. 2021, pp. 1287–95. Pubmed, doi:10.1158/1078-0432.CCR-20-2452.
URI
https://scholars.duke.edu/individual/pub1464016
PMID
33172894
Source
pubmed
Published In
Clinical Cancer Research
Volume
27
Published Date
Start Page
1287
End Page
1295
DOI
10.1158/1078-0432.CCR-20-2452

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