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Last Updated: 09/13/21

NYU Melanoma SPORE

New York University

Principal Investigator(s):

Iman Osman, MD
Iman Osman, MD

Jeffrey Weber, MD, PhD
Jeffrey Weber, MD, PhD

Principal Investigator(s) 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
(212) 263-9076

Jeffrey Weber, MD, PhD
Deputy Director, Perlmutter Cancer Center
Professor of Medicine
NYU Langone Health
522 First Avenue, Smilow Room 1310
New York, NY 10016
(212) 263-9333

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 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 A, 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 Co-Leader)
Jeffrey S. Weber, MD, PhD (Clinical Co-Leader)

We hypothesize that interplay between host immunity and gut microbiota affect the efficacy and toxicity of immune checkpoint inhibition (ICI) in melanoma patients. The gut microbiota play important roles in regulating innate and adaptive immune response to cancer immunotherapy. We and others have shown that the gut microbiome is associated with the efficacy and the toxicity of immunotherapy. We demonstrated 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. Alterations in serum protein immune pathways were associated with decreased survival with PD-1 blockade, indicating the impact of host immunity on immunotherapy outcomes. 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 immunity.

Project 1’s goal 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 resected stage-IIIB/C and -IV melanoma. Using 1500 available blood/stool samples from a large, well-controlled randomized and blinded trial, we will evaluate gut microbiota and innovative biomarkers in serum and peripheral blood and examine the utility of these biomarkers to predict clinical efficacy and toxicity from immunotherapy (Aims 1 and 2). By integrating these biomarkers, we will define cohorts of patients who may derive benefit from combination versus single-agent ICI (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.

This research will improve patient care by defining predictive biomarkers and developing a predictive classifier that can facilitate personalized immunotherapy. Given the modifiable nature of gut bacteria, findings could lead to tailored microbe-targeted intervention 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; targeting cytotoxic T lymphocyte-antigen 4) and nivolumab (NIVO; targeting programmed death protein 1) — increase relapse-free survival (RFS) in resected melanoma patients. Nonetheless, ~40% of these patients relapse within 24 months after completing ICI therapy. Currently, no biomarkers — either alone or together —reliably predict RFS after ICI therapy. ICI biomarker efforts have centered mainly on the tumor microenvironment in the metastatic setting, leaving putative surrogates of adjuvant ICI treatments largely unexplored. Because T-cell immunity is the primary focus of ICI, herein we propose the novel hypothesis that genomic control of host T-cell immunity impacts RFS after adjuvant ICI. We and others have shown that genetic control determined by the non-coding regulatory genome has an effect on phenotypic variation in T-cell subsets, including CD8+ T cells, impacting transcriptional regulation of T-cell differentiation and activity. Based on these data, we hypothesize that 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 imprint is associated with RFS after ICI treatment. We propose to develop genomic 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 sequencing (WGS) and whole-transcriptome sequencing (RNS-seq) analyses of CD4+ and CD8+ T cells from peripheral blood cells collected before ICI treatment to identify baseline 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 genetically controlled transcriptional regulatory networks that 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, substantially supporting our hypotheses and study design. For the first time, we will elucidate the effect of genomic control of anti-tumor baseline 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 has the potential 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 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 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 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 Co-Leader)
Iman Osman, MD (Clinical Co-Leader)

Immune checkpoint inhibition (ICI) therapy can 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 which patients will develop severe irAEs from ICI. This will enable optimized treatment selection, and justify preventive strategies to mitigate toxicity. 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. Here we propose to refine and validate baseline autoAb biomarker signatures of ICI toxicity using sera from two large adjuvant ICI clinical trials for resected stage-III/IV melanoma (Aim 1). To understand the relevance of specific autoAbs to common toxicities, in aim 2, we will use a humanized FcgR mouse model to determine the cause-effect relationship between autoAbs and irAEs, focusing on colitis, and 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 at high risk of developing severe diarrhea and colitis (Aim 3).

Project 4: Optimizing the Clinical Management of Stage II Melanoma Patients Using MIRNA

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

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 despite recent therapeutic advances. Such highly variable outcomes suggest underlying differences in tumor biology and/or patient host immune responses. 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 surgically resected advanced melanoma (stage III and IV) reduce rates of melanoma recurrence. 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 not yet part of standard care. However, these therapies have 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 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 melanoma. We hypothesize that a set of candidate miRNAs can be integrated into a relapse-prediction model that can accurately predict stage II patient outcomes and benefits from adjuvant therapy, and that some miRNAs that functionally modulate melanoma progression have prognostic utility. 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 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 biological mechanisms 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 prospective, randomized trial, the gold standard for clinical validation of biomarkers (Aim 3).

Administrative Core

Core 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 available 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. 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 progress reports. Facilitation of collaborations with programs outside of NYU will fall under the Admin Core.

Biospecimen Procurement and Utilization Core

Core Directors:
Iman Osman, MD
George Jour, MD

The goal of the NYU Melanoma SPORE Core B 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, and provide specialized, innovative pathology services to support the aims of full SPORE research projects, CEP 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.

Biostatistics and Bioinformatics Core

Core Directors:
Yongzhao Shao, PhD
Itai Yanai, PhD

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 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. Strategies for the systematic selection of samples from the projects and the coordination of informatics support, will permit the overall integration of results to develop comprehensive models to predict treatment outcomes and toxicity. Core C will develop innovative statistical and bioinformatics methods to identify and evaluate biomarkers in translational studies, and will make these newly developed algorithms publicly available to the larger cancer research community. Core C’s identification of biomarkers will enable the development of integrated, multivariable predictive models for treatment response and toxicity. This work will contribute to personalized melanoma management and amplify the translational impact of the NYU Melanoma SPORE.

Developmental Research Program

Program 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 to take advantage of new research opportunities in melanoma and aid in recruiting established cancer investigators at the Assistant Professor level or higher to the translational study of melanoma. The DRP focuses on selecting innovative and promising translational research projects in melanoma and will monitor their progress to ensure that goals are achieved. The DRP will support projects for up to 2 years, enabling awardees to adequately explore the potential of novel topics in translational melanoma research. 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 for careers as independent investigators.

Career Enhancement Program

Program 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 CEP will support outstanding candidates for up to 2 years by providing 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 and 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 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.

Institutional SPORE Website

https://med.nyu.edu/departments-institutes/perlmutter-cancer-center/cancer-research/melanoma-spore