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-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

A Phase 1/1b first-in-human dose escalation and expansion study for theevaluation of safety, pharmacokinetics, pharmacodynamics and anti-tumor activity of SAR439459 administered intravenously as monotherapy and in combination with REGN2810 in adult

Administered By
Duke Cancer Institute
Awarded By
Sanofi US
Role
Principal Investigator
Start Date
End Date

Publications:

Role of Tumor-Mediated Dendritic Cell Tolerization in Immune Evasion.

The vast majority of cancer-related deaths are due to metastasis, a process that requires evasion of the host immune system. In addition, a significant percentage of cancer patients do not benefit from our current immunotherapy arsenal due to either primary or secondary immunotherapy resistance. Importantly, select subsets of dendritic cells (DCs) have been shown to be indispensable for generating responses to checkpoint inhibitor immunotherapy. These observations are consistent with the critical role of DCs in antigen cross-presentation and the generation of effective anti-tumor immunity. Therefore, the evolution of efficient tumor-extrinsic mechanisms to modulate DCs is expected to be a potent strategy to escape immunosurveillance and various immunotherapy strategies. Despite this critical role, little is known regarding the methods by which cancers subvert DC function. Herein, we focus on those select mechanisms utilized by developing cancers to co-opt and tolerize local DC populations. We discuss the reported mechanisms utilized by cancers to induce DC tolerization in the tumor microenvironment, describing various parallels between the evolution of these mechanisms and the process of mesenchymal transformation involved in tumorigenesis and metastasis, and we highlight strategies to reverse these mechanisms in order to enhance the efficacy of the currently available checkpoint inhibitor immunotherapies.
Authors
DeVito, NC; Plebanek, MP; Theivanthiran, B; Hanks, BA
MLA Citation
DeVito, Nicholas C., et al. “Role of Tumor-Mediated Dendritic Cell Tolerization in Immune Evasion.Front Immunol, vol. 10, 2019, p. 2876. Pubmed, doi:10.3389/fimmu.2019.02876.
URI
https://scholars.duke.edu/individual/pub1426782
PMID
31921140
Source
pubmed
Published In
Frontiers in Immunology
Volume
10
Published Date
Start Page
2876
DOI
10.3389/fimmu.2019.02876

Durable tumor regression and overall survival (OS) in patients with advanced Merkel cell carcinoma (aMCC) receiving pembrolizumab as first-line therapy.

Authors
Nghiem, P; Bhatia, S; Lipson, EJ; Sharfman, WH; Kudchadkar, RR; Friedlander, PA; Brohl, AS; Daud, A; Kluger, HM; Reddy, SA; Burgess, MA; Hanks, BA; Olencki, T; Boulmay, BC; Lundgren, LM; Ramchurren, N; Homet Moreno, B; Sharon, E; Cheever, MA; Topalian, SL
MLA Citation
Nghiem, Paul, et al. “Durable tumor regression and overall survival (OS) in patients with advanced Merkel cell carcinoma (aMCC) receiving pembrolizumab as first-line therapy.Journal of Clinical Oncology, vol. 36, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2018, pp. 9506–9506. Crossref, doi:10.1200/jco.2018.36.15_suppl.9506.
URI
https://scholars.duke.edu/individual/pub1441987
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
36
Published Date
Start Page
9506
End Page
9506
DOI
10.1200/jco.2018.36.15_suppl.9506

Pilot trial of an Indoleamine 2,3-dioxygenase-1 (IDO1) inhibitor plus a multipeptide melanoma vaccine in patients with advanced melanoma.

Authors
Slingluff, CL; Fling, S; Mauldin, IS; Ernstoff, MS; Hanks, BA; Delman, KA; Lawson, DH; Gastman, B; Kaiser, JC; Cheever, MA
MLA Citation
Slingluff, Craig L., et al. “Pilot trial of an Indoleamine 2,3-dioxygenase-1 (IDO1) inhibitor plus a multipeptide melanoma vaccine in patients with advanced melanoma.Journal of Clinical Oncology, vol. 36, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2018, pp. 3033–3033. Crossref, doi:10.1200/jco.2018.36.15_suppl.3033.
URI
https://scholars.duke.edu/individual/pub1441988
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
36
Published Date
Start Page
3033
End Page
3033
DOI
10.1200/jco.2018.36.15_suppl.3033

Role of dendritic cell metabolic reprogramming in tumor immune evasion.

The dendritic cell (DC) is recognized as a vital mediator of anti-tumor immunity. More recent studies have also demonstrated the important role of DCs in the generation of effective responses to checkpoint inhibitor immunotherapy. Metabolic programming of DCs dictates their functionality and can determine which DCs become immunostimulatory versus those that develop a tolerized phenotype capable of actively suppressing effector T-cell responses to cancers. As a result, there is great interest in understanding what mechanisms have evolved in cancers to alter these metabolic pathways, thereby allowing for their continued progression and metastasis. The therapeutic strategies developed to reverse these processes of DC tolerization in the tumor microenvironment represent promising candidates for future testing in combination immunotherapy clinical trials.
Authors
Plebanek, MP; Sturdivant, M; DeVito, NC; Hanks, BA
MLA Citation
Plebanek, Michael P., et al. “Role of dendritic cell metabolic reprogramming in tumor immune evasion.Int Immunol, vol. 32, no. 7, June 2020, pp. 485–91. Pubmed, doi:10.1093/intimm/dxaa036.
URI
https://scholars.duke.edu/individual/pub1442098
PMID
32449776
Source
pubmed
Published In
Int Immunol
Volume
32
Published Date
Start Page
485
End Page
491
DOI
10.1093/intimm/dxaa036

A tumor-intrinsic PD-L1/NLRP3 inflammasome signaling pathway drives resistance to anti-PD-1 immunotherapy.

An in-depth understanding of immune escape mechanisms in cancer is likely to lead to innovative advances in immunotherapeutic strategies. However, much remains unknown regarding these mechanisms and how they impact immunotherapy resistance. Using several preclinical tumor models as well as clinical specimens, we identified a mechanism whereby CD8+ T cell activation in response to programmed cell death 1 (PD-1) blockade induced a programmed death ligand 1/NOD-, LRR-, and pyrin domain-containing protein 3 (PD-L1/NLRP3) inflammasome signaling cascade that ultimately led to the recruitment of granulocytic myeloid-derived suppressor cells (PMN-MDSCs) into tumor tissues, thereby dampening the resulting antitumor immune response. The genetic and pharmacologic inhibition of NLRP3 suppressed PMN-MDSC tumor infiltration and significantly augmented the efficacy of anti-PD-1 antibody immunotherapy. This pathway therefore represents a tumor-intrinsic mechanism of adaptive resistance to anti-PD-1 checkpoint inhibitor immunotherapy and is a promising target for future translational research.
Authors
Theivanthiran, B; Evans, KS; DeVito, NC; Plebanek, M; Sturdivant, M; Wachsmuth, LP; Salama, AK; Kang, Y; Hsu, D; Balko, JM; Johnson, DB; Starr, M; Nixon, AB; Holtzhausen, A; Hanks, BA
MLA Citation
Theivanthiran, Balamayoora, et al. “A tumor-intrinsic PD-L1/NLRP3 inflammasome signaling pathway drives resistance to anti-PD-1 immunotherapy.J Clin Invest, vol. 130, no. 5, May 2020, pp. 2570–86. Pubmed, doi:10.1172/JCI133055.
URI
https://scholars.duke.edu/individual/pub1431106
PMID
32017708
Source
pubmed
Published In
J Clin Invest
Volume
130
Published Date
Start Page
2570
End Page
2586
DOI
10.1172/JCI133055

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