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:

Clinical Trials with Biologic Primary Endpoints in Immuno-oncology: Concepts and Usage.

Clinical trials that have a pharmacokinetic or a pharmacodynamic immunologic mechanism of action-based primary outcome could substantially improve the validity and efficiency of early development of immuno-oncology agents. Here, we outline different trial design options in this area, review examples from the literature and their unique immunologic aspects, and highlight how these trials have been underutilized. We illustrate how new technologies and translationally focused approaches can be successfully used to develop different classes of immunotherapeutic agents.
Authors
Isaacs, J; Tan, AC; Hanks, BA; Wang, X; Owzar, K; Herndon, JE; Antonia, SJ; Piantadosi, S; Khasraw, M
MLA Citation
Isaacs, James, et al. “Clinical Trials with Biologic Primary Endpoints in Immuno-oncology: Concepts and Usage.Clin Cancer Res, July 2021. Pubmed, doi:10.1158/1078-0432.CCR-21-1593.
URI
https://scholars.duke.edu/individual/pub1489704
PMID
34312214
Source
pubmed
Published In
Clinical Cancer Research
Published Date
DOI
10.1158/1078-0432.CCR-21-1593

Immune Checkpoint Combinations with Inflammatory Pathway Modulators

Immune checkpoint inhibition of program death protein-1 (PD-1) and its ligands PD-L1 and PD-L2 is an established therapeutic modality in melanoma, non-small cell lung cancer, renal cell carcinoma, and other tumor types. Unfortunately, 60 to 80% of all patients experience disease progression and become refractory to immune checkpoint therapies. Broadly, mechanisms of immune checkpoint inhibitor resistance can be categorized as presence of oncogenic driver mutations, severe T cell exhaustion, neoantigen burden, epigenetic alterations, or mutations involved in critical pathways including PTEN, JAK, or Wnt signaling. The dysregulation of inflammatory signaling pathways (namely, genes involved in angiogenesis, chemotaxis, matrix remodeling, wound healing, and mesenchymal transition) is of critical importance to response to immune checkpoint therapies. Inflammatory cytokine signaling pathways exert downstream effects on immunosuppressive elements such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) which inhibit the function of effector T cells, NK cells, and dendritic cells, promoting immune tolerance and tumor growth. We herein review three targets for inflammatory pathway modulation: indoleamine 2,3-dioxygenase (IDO), transforming growth factor β (TGFβ), and adenosine. Targeting these pathways may address the unmet need to develop novel therapeutic approaches to increase response rates to immune checkpoint inhibitors and improve clinical outcomes.
MLA Citation
DeVito, N., et al. “Immune Checkpoint Combinations with Inflammatory Pathway Modulators.” Current Cancer Research, 2018, pp. 219–41. Scopus, doi:10.1007/978-3-319-63757-0_8.
URI
https://scholars.duke.edu/individual/pub1494214
Source
scopus
Published Date
Start Page
219
End Page
241
DOI
10.1007/978-3-319-63757-0_8

Inhibition of estrogen signaling in myeloid cells increases tumor immunity in melanoma.

Immune checkpoint inhibitors (ICB) have significantly prolonged patient survival across multiple tumor types, particularly in melanoma. Interestingly, gender specific differences in response to ICB have been observed with males getting more benefit than females, although the mechanism(s) underlying this difference are unknown. Mining published transcriptomic datasets, we determined that response to ICBs is influenced by the functionality of intratumoral macrophages. This puts into context our observation that estrogens (E2) working through the estrogen receptor (ERα) stimulate melanoma growth in murine models by skewing macrophage polarization towards an immune-suppressive state that promotes CD8+ T cell dysfunction/exhaustion and ICB resistance. This activity was not evident in mice harboring a macrophage specific depletion of ERα confirming a direct role for estrogen signaling within myeloid cells in establishing an immunosuppressed state. Inhibition of ERα using fulvestrant, a selective estrogen receptor downregulator (SERD) decreases tumor growth, stimulates adaptive immunity and increases the antitumor efficacy of ICBs. Further, a gene signature that reads on ER activity in macrophages predicted survival in ICB treated melanoma patients. These results highlight the importance of E2/ER as a regulator of intratumoral macrophage polarization; an activity that can be therapeutically targeted to reverse immune suppression and increase ICB efficacy.
Authors
Chakraborty, B; Byemerwa, J; Shepherd, JH; Haines, CN; Baldi, R; Gong, W; Liu, W; Mukherjee, D; Artham, S; Lim, F; Bae, Y; Brueckner, O; Heetderks, K; Wardell, SE; Hanks, BA; Perou, CM; Chang, C-Y; McDonnell, DP
MLA Citation
Chakraborty, Binita, et al. “Inhibition of estrogen signaling in myeloid cells increases tumor immunity in melanoma.J Clin Invest, Oct. 2021. Pubmed, doi:10.1172/JCI151347.
URI
https://scholars.duke.edu/individual/pub1498834
PMID
34637400
Source
pubmed
Published In
J Clin Invest
Published Date
DOI
10.1172/JCI151347

Overcoming Immunotherapy Resistance by Targeting the Tumor-Intrinsic NLRP3-HSP70 Signaling Axis.

The tumor-intrinsic NOD-like receptor family, pyrin-domain-containing-3 (NLRP3) inflammasome, plays an important role in regulating immunosuppressive myeloid cell populations in the tumor microenvironment (TME). While prior studies have described the activation of this inflammasome in driving pro-tumorigenic mechanisms, emerging data is now revealing the tumor NLRP3 inflammasome and the downstream release of heat shock protein-70 (HSP70) to regulate anti-tumor immunity and contribute to the development of adaptive resistance to anti-PD-1 immunotherapy. Genetic alterations that influence the activity of the NLRP3 signaling axis are likely to impact T cell-mediated tumor cell killing and may indicate which tumors rely on this pathway for immune escape. These studies suggest that the NLRP3 inflammasome and its secreted product, HSP70, represent promising pharmacologic targets for manipulating innate immune cell populations in the TME while enhancing responses to anti-PD-1 immunotherapy. Additional studies are needed to better understand tumor-specific regulatory mechanisms of NLRP3 to enable the development of tumor-selective pharmacologic strategies capable of augmenting responses to checkpoint inhibitor immunotherapy while minimizing unwanted off-target effects. The execution of upcoming clinical trials investigating this strategy to overcome anti-PD-1 resistance promises to provide novel insight into the role of this pathway in immuno-oncology.
Authors
Theivanthiran, B; Haykal, T; Cao, L; Holtzhausen, A; Plebanek, M; DeVito, NC; Hanks, BA
MLA Citation
Theivanthiran, Balamayooran, et al. “Overcoming Immunotherapy Resistance by Targeting the Tumor-Intrinsic NLRP3-HSP70 Signaling Axis.Cancers (Basel), vol. 13, no. 19, Sept. 2021. Pubmed, doi:10.3390/cancers13194753.
URI
https://scholars.duke.edu/individual/pub1497259
PMID
34638239
Source
pubmed
Published In
Cancers
Volume
13
Published Date
DOI
10.3390/cancers13194753

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

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