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Last Updated: 08/15/19

NYU Melanoma SPORE

New York University School of Medicine

PRINCIPAL INVESTIGATORS:

Iman Osman, MD
Iman Osman, MD
Jeffrey S. Weber, MD, PhD
Jeffrey S. Weber, MD, PhD

PRINCIPAL INVESTIGATOR CONTACT INFORMATION

Iman Osman, MD
Associate Dean for Translational Research Support
Director, Interdisciplinary Melanoma Program
Professor, Departments of Dermatology, Medicine and Urology
NYU Langone Health
522 First Avenue, Smilow Room 405
New York, NY 10016
Phone: 212-263-9076
Fax: 212-263-9090
Email: Iman.Osman@nyulangone.org

Jeffrey S. Weber, MD, PhD
Deputy Director, Perlmutter Cancer Center
Professor of Medicine
NYU Langone Health
522 First Avenue, Smilow Room 1310
New York, NY 10016
Phone: 212-263-9333
Email: Jeffrey.Weber@nyulangone.org

OVERVIEW

New York University’s Specialized Program of Research Excellence (SPORE) in Melanoma aims to address the urgent need to develop and validate clinically useful, personalized biomarkers to optimally administer immune checkpoint inhibition therapies in the adjuvant setting. Our SPORE leverages our expertise in melanoma — specifically in developing immune checkpoint inhibitor (ICI) drugs, conducting clinical trials, and studying biomarkers to solve pressing needs in the melanoma field that can be extended to the increasing number of ICI-treated cancers.

Our SPORE includes four translational research projects:

  • Project 1: Defining predictive biomarkers in the blood and microbiome in stage-III/IV resected melanoma patients receiving immune checkpoint inhibition in the adjuvant setting
  • Project 2: Genomic profiling of the T-cell regulome in stage-III/IV resected melanoma patients treated with adjuvant immune checkpoint inhibition
  • Project 3: Predicting immune-related toxicity in stage-III/IV melanoma patients treated in the adjuvant setting with checkpoint inhibition
  • Project 4: Optimizing the clinical management of stage-II melanoma patients using miRNA

These projects are supported by three shared resources: the Admin Core, Core B — Biospecimen Procurement and Utilization, and Core C — Biostatistics and Bioinformatics. This SPORE also supports a Career Enhancement Program to recruit and mentor new investigators in translational melanoma research and a Developmental Research Program to support innovative translational concepts.

Project 1: Defining predictive biomarkers in the blood and microbiome in stage-III/IV resected melanoma patients receiving immune checkpoint inhibition in the adjuvant setting

Project Co-Leaders:
Jiyoung Ahn, PhD (Basic)
Jeffrey S. Weber, MD, PhD (Clinical)

We hypothesize that interplay between host immune responses and the gut microbiota affect the efficacy and toxicity of immune checkpoint inhibition (ICI) in melanoma patients. Increasing evidence suggests that gut microbiota play important roles in regulating the innate and adaptive immune response to cancer immunotherapy. We and others have provided compelling evidence that the gut microbiome is associated with the efficacy and the toxicity of immunotherapy. We also showed that novel baseline pre-treatment T-cell phenotypes and the levels and suppressive function of T regulatory cells in the peripheral blood were associated with increased relapse-free survival (RFS) after PD-1 blockade in melanoma. Moreover, we found that alterations in serum protein immune pathways were associated with decreased survival with PD-1 blockade, underlining the importance of host immune responses for immunotherapy outcomes. Nonetheless, no definitive, large scale human studies have identified the gut microbial taxa associated with the efficacy and/or toxicity of immunotherapy, nor investigated their relationships with host immune responses.

The goal of Project 1 is to identify microbial and host immune biomarkers that predict the efficacy and toxicity of ICI in a randomized phase-III adjuvant trial testing combination PD-1/CTLA-4 blockade versus PD-1 alone in patients with high-risk resected stage-IIIB/C and -IV melanoma. As part of a large, well-controlled randomized and blinded trial (n=2000; a subset of n=1500 available blood/stool samples), we will evaluate gut microbiota in stool and a series of innovative biomarkers in serum and peripheral blood immune cells and examine the utility of these biomarkers to predict clinical efficacy and toxicity from immunotherapy (Aims 1 and 2). Based on integration of these biomarkers, we will additionally define cohorts of patients who may derive differential benefit from combination versus single-agent checkpoint blockade (Aim 3). This study, based on a large clinical trial with standardized treatments and clinical outcome as well as toxicity assessments, will provide excellent power for biomarker identification with rigorous replications.

This research will improve patient care by defining predictive biomarkers and developing a predictive classifier — using easily obtainable stool, serum, and blood samples — that can facilitate personalized immunotherapy decisions. Finally, given the modifiable nature of gut bacteria, findings could lead to tailored microbe-targeted interventional approaches to improve the efficacy of, and attenuate the toxicity of, ICI.

Specific Aims:

  • Identify gut microbiota and their related gene functional pathways predicting clinical outcomes in melanoma patients treated in an adjuvant trial of anti-PD-1 or a combination of anti-CTLA-4/anti-PD-1.
  • Identify host factors in the serum and peripheral blood immune cells predicting clinical outcomes in melanoma patients treated in an adjuvant trial of anti-PD-1 or a combination of anti-CTLA-4/anti-PD-1.
  • Develop and validate a classifier based on baseline gut microbiota (Aim 1) and host serum and peripheral blood immune cell biomarkers (Aim 2) that can differentiate patients who benefit from anti-PD-1 or combination of anti-CTLA-4/anti-PD-1 in an adjuvant trial.

Project 2: Genomic profiling of the T cell regulome in stage III/IV resected melanoma patients treated with adjuvant immune checkpoint inhibition

Project Co-leaders:
Tomas Kirchhoff, PhD (Basic)
Jeffrey S. Weber, MD, PhD (Clinical)

Immune checkpoint inhibitor (ICI) adjuvant therapies — including ipilimumab (IPI; targets cytotoxic T lymphocyte-antigen 4) and nivolumab (NIVO; targets programmed death protein 1) — increase relapse-free survival (RFS) in melanoma patients. Nonetheless, 35-40% of these patients relapse within 24 months after completing ICI therapy, and no biomarkers — either alone or together — can predict RFS after ICI therapy and potentially identify novel targets for more effective adjuvant treatments. Efforts to identify biomarkers of ICI efficacy have centered mainly on the tumor microenvironment in the metastatic setting, leaving putative biomarkers of adjuvant ICI treatments largely unexplored. Because anti-tumor T-cell immunity is the primary target of ICI, the focus has been predominantly on tumor T-cell infiltration. Here we propose the novel hypothesis that underlying inherited factors that influence host immunity impact RFS after adjuvant ICI. Phenotypic variation in T-cell subsets, including CD8+ T cells, can be attributed to germline genetic variation. We recently showed that this inherited component maps to the non-coding regulatory genome, impacting transcriptional regulation of T-cell differentiation and function. Based on these data, we hypothesize that germline genetic variation in the T-cell-specific non-coding regulatory genome (regulome) controls circulating CD4+ and CD8+ T cells (the primary targets of NIVO and NIVO+IPI ICI), and that this genetic variability is associated with RFS after ICI treatment. We propose to discover inherited signatures of the CD4+- and CD8+- T-cell regulome that predict ICI relapse and RFS. Using samples from 600 melanoma patients treated in an adjuvant clinical trial of NIVO compared to NIVO+IPI, we will perform whole-genome (WGS) and whole-transcriptome sequence analyses of CD4+ and CD8+ T cells from peripheral blood collected before ICI treatment to identify non-coding transcriptome signatures that predict RFS after adjuvant ICI (Aim 1). We will also comprehensively assess open chromatin states in pre-treatment CD4+ and CD8+ T cells from the same 600 patients to identify epigenetic signatures controlled by inherited genetic variation and predict RFS after adjuvant ICI (Aim 2), and integrate these data with microbiome, immuno-phenotyping, and seromics profiles from Project 1 (Aim 3). Our preliminary data have revealed novel genomic imprints in the non-coding regulome that predict ICI response with high clinical accuracy, thus substantially supporting our hypotheses and study design. For the first time, we will elucidate the effect of inherited anti-tumor host immunity on ICI outcomes in the adjuvant setting. Besides having applicability to personalized prediction of ICI benefit, the integration of genomic information from all three aims of this project promises to reveal novel T-cell-specific transcriptional networks that potentially affect ICI resistance and might serve as targets for improved adjuvant ICI therapies in melanoma and other cancers.

Specific Aims:

  • Determine whether germline genetic regulation of CD8+ and CD4+ T-cell specific long non-coding RNAs (IncRNAs) is associated with RFS in 300 stage-IIIB/C/D/IV resected melanoma patients treated by NIVO or NIVO+IPI immune checkpoint inhibition.
  • Assess the impact of inherited CD8+ and CD4+ T-cell specific epigenetic regulome states on relapse-free survival (RFS) in 300 stage-IIIB/C/D/IV resected melanoma patients treated by NIVO or NIVO+IPI adjuvant therapy.
  • Investigate the interaction of germline immune cell genomics with components of the tumor microenvironment, microbiome, and baseline peripheral blood features from Project 1, in modulating RFS in 300 stage-IIIB/C/D/IV melanoma patients treated by adjuvant NIVO or NIVO+IPI.

Project 3: Predicting immune-related toxicity in stage-III/IV melanoma patients treated in the adjuvant setting with checkpoint inhibition

Project Co-leaders:
Michelle Krogsgaard, PhD (Basic)
Iman Osman, MD (Clinical)

Immune checkpoint inhibitors have transformed melanoma treatment, producing durable responses, prolonged survival, and clinical benefit in a significant proportion of patients. Moreover, they delay recurrence and extend survival in the adjuvant melanoma setting and have also shown efficacy in a range of different cancer types. However, immune checkpoint inhibition (ICI) therapy can also be accompanied by immune-related adverse events (irAEs) that impact multiple organs, cause significant morbidity, and require immunosuppression or discontinuation of ICI treatment. There is an urgent need to identify patients who will develop severe irAEs from ICI. This would enable us to optimize treatment selection and sequencing, justify preventive strategies to mitigate toxicity, and better manage toxicities. While there is intense interest in identifying markers to predict response to ICI, no pre-treatment biomarker tool can predict irAEs associated with ICI for any cancer type. The goal of our project is to develop a predictive tool that enables clinicians to minimize exposure of patients to severe toxicity, while maximizing clinical benefit from ICI.

We hypothesize that a subset of melanoma patients has a baseline, sub-clinical autoimmune susceptibility, characterized by specific pre-existing autoantibodies (autoAbs) that can predict and exacerbate the development of toxicity from ICI therapy. We have identified autoAb signatures in baseline (pre-treatment) sera that predict severe immune toxicity in melanoma patients treated with ICI (AUC >0.95). Using a humanized mouse model, we found that autoAbs from baseline sera of melanoma patients can exacerbate irAEs from ICI. In this project, we propose to refine and validate baseline autoAb biomarker signatures of ICI toxicity using sera (n=600) from two large adjuvant ICI clinical trials for resected stage-III/IV melanoma (Aim 1). To understand the relevance of specific autoAbs to common irAEs (e.g., colitis) and to investigate an autoimmune predisposition in some patients, we will compare irAE-associated autoAbs with those from inflammatory bowel disease patients and from normal donors. We will use our humanized FcgR mouse model to determine the cause-effect relationship between autoAbs and irAEs, with a focus on colitis, and for preclinical testing of prophylactic anti-TNF-α as a strategy to mitigate gastrointestinal (GI) toxicity from ICI (Aim 2). These findings will inform a biomarker-driven phase-II trial of prophylactic anti-TNF-a (infliximab) in patients receiving ICI therapy who are at high risk for developing severe diarrhea and colitis (Aim 3).

Our work will inform personalized melanoma treatment strategies by validating a robust pre-treatment biomarker to enable clinicians to optimize ICI regimens and minimize patient exposure to severe irAEs. We will both identify an autoimmune susceptibility to irAE development and establish whether prophylactic TNF-α blockade mitigates development of GI toxicity from ICI in patients identified as being at high risk of these irAEs.

Specific Aims:

  • Refine and clinically validate a signature of baseline autoAbs associated with the development of irAEs in randomized phase-III adjuvant trials of IPI, NIVO, and the IPI+NIVO combination.
  • Test the causal relationship between re-existing autoAbs and observed clinical toxicities from checkpoint inhibition and its possible prevention using a humanized FcgR mouse model.
  • Test the utility of prophylactic infliximab versus placebo for preventing diarrhea and colitis in patients determined to be at high risk of toxicity from IPI+NIVO using our validated autoAb signature.

Project 4: Optimizing the clinical management of Stage II melanoma patients using miRNA

Project Co-leaders:
Eva Hernando, PhD (Basic)
David Polsky, MD, PhD (Clinical)

Despite recent therapeutic advances, prognosis for metastatic melanoma remains poor. Patients with primary melanomas that are clinically and histologically similar at diagnosis often have vastly different outcomes: whereas some are cured after initial surgical resection, others develop loco-regional recurrence(s) and metastases, and eventually die. Such highly variable outcomes suggest underlying biological differences in tumors (cell-intrinsic) and/or the patients themselves (host-cell-extrinsic, e.g. immune response). Molecular alterations in tumors that can be robustly measured at diagnosis could be useful prognostic markers. Moreover, given that some of these markers may also drive disease progression, their study may yield novel insights into melanoma biology and generate new therapeutic targets. Recent trials have demonstrated that adjuvant treatments for advanced melanoma (stage III and IV) reduce rates of melanoma recurrence and metastasis. The success of adjuvant immune and small molecule inhibitor therapies has opened the possibility of extending their use to stage-II patients, for whom adjuvant therapy is yet not part of standard care. However, these therapies have a significant toxicity, monetary cost, and unclear long-term benefit. Companion assays that might accurately assign a patient’s risk of recurrence and even predict a patient’s benefit from adjuvant therapy — measured as increased relapse-free survival (RFS) — could transform clinical management, reduce unnecessary morbidity and toxicity, and dramatically improve patient outcomes. MicroRNAs (miRNAs) are promising biomarkers because of their stability in tissues and fluids, and their demonstrated roles in cancer biology, including in melanoma. We hypothesize that a set of candidate miRNAs can be integrated into a relapse-prediction model that can predict stage II patient outcomes and benefits from adjuvant therapy, and that some prognostic miRNAs functionally modulate melanoma progression.We identified a tumor tissue-based miRNA signature highly prognostic of outcome for stage II melanoma patients and used an independent cohort of patients to demonstrate its excellent discriminatory accuracy for identifying patients with short (<3 years) versus long (>3 years) RFS. Here we propose to transform melanoma clinical practice and research paradigms by: 1) using NanoString, a state-of-the-art technology currently employed in clinical labs, to develop a relapse-prediction model for stage II melanoma patients based on miRNA expression in tumor samples (Aim 1); 2) identifying clinically relevant miRNA-regulated mechanisms (e.g., cell proliferation, immune evasion) that drive metastatic spread of melanoma cells from the primary tumor (Aim 2); and 3) testing the clinical validity of the relapse-prediction model in a randomized, prospective trial, the gold standard for clinical validation of biomarkers (Aim 3). Successful completion of this project promises to demonstrate the potential of incorporating a novel relapse-prediction model into the management of stage-II melanoma patients and reveal candidate genes and pathways that contribute to melanoma progression and might emerge as new therapeutic targets.

Specific Aims:

  • Refine the miRNA signature as a central component of a relapse-prediction model for patients with resected stage-II melanoma.
  • Identify prognostic miRNAs that functionally modulate tumor progression and metastatic dissemination.
  • Clinically validate the relapse-prediction model and determine the effectiveness of adjuvant pembrolizumab in patients classified as high and low risk for relapse.

CORE A: Admin Core

Core Co-Directors:
Iman Osman, MD
Jeffrey S. Weber, MD, PhD

The Admin Core will execute the administrative needs of SPORE investigators and collaborators and optimize the resources and intellectual depth available to investigators at NYU Langone Health (NYULH) to achieve the translational research goals of NIH’s SPORE program. The Admin Core will provide strategic planning and evaluation of all SPORE activities, establish and maintain policies for prudent financial management, and initiate communication with outside collaborators. Additionally, the Admin Core will be responsible for regulatory compliance, resource sharing, material transfer agreements, and the organization of travel arrangements for all SPORE meetings and for sustaining communication and cooperation with the NYULH, PCC, and NCI/NIH administration, and overseeing the timely submission of all required progress reports. Facilitation of collaborations with programs outside of NYU — including active SPORE programs and industry partners — will fall under the Admin Core.

CORE B: Biospecimen Procurement and Utilization

Core Co-Directors:
Iman Osman, MD
George Jour, MD

The goal of the NYU Melanoma SPORE Core B (Biospecimen Procurement and Utilization Core) is to stimulate patient-centered melanoma translational research by providing all NYU Melanoma SPORE investigators with access to high-quality melanoma biospecimens linked to prospectively collected clinical and pathological data, and innovative services to further the development of clinically impactful prognostic and predictive biomarkers for the personalized management of resectable melanoma patients. Core B will process biospecimens, including performing nucleic acid extraction and T-cell isolation, and provide specialized, innovative pathology services to support the aims of full SPORE research projects, CEP projects, and DRP projects. Through a governance committee, Core B will also provide oversight of SPORE biospecimen use. Building on the NYU Melanoma Clinicopathological-Biospecimen Database and Repository’s infrastructure, biospecimen resources, and extensive support of NYU Melanoma Program studies internally and with other institutions, Core B will stimulate collaborations within the NYU Melanoma SPORE community as well as with outside collaborators, including other active Melanoma and Skin Cancer SPOREs.

CORE C: Biostatistics and Bioinformatics

Core Co-Directors:
Yongzhao Shao, PhD
Itai Yanai, PhD

The Biostatistics and Bioinformatics Core (Core C) of the NYU Melanoma SPORE will provide statistical and bioinformatics collaboration and consultation to all SPORE Research Projects and Cores. Consultation is available from the study design and planning stages through implementation, data management, statistical and bioinformatics analysis, and interpretation of results. Core C will provide support for all proposed laboratory studies and translational studies, including biomarker development based on samples from existing and new clinical trials to support the overarching mission and central scientific strategy of the NYU Melanoma SPORE. Furthermore, strategies for the systematic selection of samples from all the projects and the coordination of informatics support in Core C will permit the overall integration of results across projects to develop comprehensive models to predict treatment outcomes and toxicity. Core C will develop innovative statistical and bioinformatics methods, including scalable computation algorithms to identify and evaluate biomarkers in translational studies, and will make these newly developed algorithms publicly available to the larger cancer research community. In particular, Core C’s identification of biomarkers that may optimize the personalized management of advanced melanoma patients will enable the development of integrated, multivariable predictive models for treatment response and toxicity. This work, based on biomarkers discovered across SPORE Projects, will contribute to personalized melanoma management and amplify the translational impact of the NYU Melanoma SPORE.

DEVELOPMENTAL RESEARCH PROGRAM

Core Co-Directors:
Iannis Aifantis, PhD
Seth Orlow, MD, PhD

The overall goal of the NYU Melanoma SPORE Developmental Research Program (DRP) is to support pilot projects that take maximum advantage of new research opportunities in melanoma and aid in recruiting established cancer investigators at the level of Assistant Professor or higher to the translational study of melanoma. The DRP focuses on and will select innovative and promising translational research projects in melanoma and will monitor their progress to ensure that goals are achieved. The NYU Melanoma SPORE DRP will support projects for up to 2 years, enabling awardees to adequately explore the potential of novel topics in translational melanoma research. Focusing on innovation, the DRP will support the development of “high-risk, high-reward” investigations in melanoma and encourage proposals for novel approaches to screening, diagnosis, prognosis, prediction, and treatment of melanoma. The DRP is strongly committed to training women and underrepresented minority candidates at all levels for careers as independent investigators.

CAREER ENHANCEMENT PROGRAM

Core Co-Directors:
Seth Orlow, MD, PhD
Iannis Aifantis, PhD

The NYU Melanoma SPORE Career Enhancement Program (CEP) will prepare investigators for independent translational research careers to study melanoma. The CEP will select, support, and guide individuals focused on becoming leading translational researchers in melanoma. The NYU Melanoma SPORE CEP will support outstanding candidates for up to 2 full years by providing both financial assistance and academic guidance. This will enable awardees to establish successful investigations related to melanoma, and simultaneously provide a solid foundation to further develop full research projects within the SPORE. The CEP will nurture and grow the pipeline of talent in melanoma translational research by recruiting and supporting promising junior or rising faculty in addition to more established investigators with the potential to become accomplished independent investigators focused on melanoma translational research. The CEP is strongly committed to training women and underrepresented minority candidates at all levels for careers as independent investigators. The CEP is thematically aligned to the NYU Melanoma SPORE’s overarching mission to use personalized biomarkers to optimize clinical management of melanoma patients and is highly integrated with the programs and projects of the SPORE. This thematic integration will enable the CEP to maximize the progress of the awardees’ careers.