The National Cancer Center Institute (NCI) has awarded NYU Langone Health a 5-year, $11 million grant to develop better tools to predict which patients with advanced melanoma will benefit from immune checkpoint inhibitors. The Ronald O. Perelman Department of Dermatology and Perlmutter Cancer Center are using the grant for four distinct and promising projects.

The grant is NYU Langone’s first to be funded by the NCI’s P50 Specialized Programs of Research Excellence (SPORE). The programs promote interdisciplinary investigations to help move findings quickly from laboratory to patient care.

Urgent Need for Biomarkers

“In my 30-year career as a surgical oncologist at NYU Langone, I have seen many attempts to develop treatments for patients with advanced melanoma,” notes Richard L. Shapiro, MD, professor in the Department of Surgery and director of surgical oncology operations at NYU Langone’s Perlmutter Cancer Center. “It’s only since 2010, with the introduction of immunotherapies, that the landscape of what happens to a patient with advanced melanoma has radically changed.”

Only 40 to 50 percent of patients successfully respond to immunotherapy, and a significant percentage experience immune-related toxicity, underscoring the urgent need to define biomarkers to help physicians tailor care. The goal is to predict a patient’s response to a treatment and their risk of immune-related side effects.

The SPORE program is investigating “checkpoints”—the sensors on immune cells that cancer cells hijack to turn off immune responses. Checkpoint inhibitors are one type of immunotherapy that counter this effect. But doctors need more detailed guidance on how to use them on surgically treated patients at higher risk of relapse, as well as patients with metastatic disease. Identifying biomarkers that can predict benefit or toxicity is critical and timely, and promises to have broad applicability.

The Path to Biomarker Development

NYU Langone investigators are using a phased approach to develop new biomarkers. The four SPORE projects—each led by a clinician and a basic scientist—span the biomarker development path from target identification and clinical relevance to assay and clinical validation and, ultimately, clinical utility with testing in an investigator-initiated clinical trial.

The multidisciplinary team is led by co-principal investigators Iman Osman, MD, the Rudolph L. Baer Professor in the Ronald O. Perelman Department of Dermatology, professor in the Departments of Medicine and Urology, and associate dean for translational research support; and Jeffrey S. Weber, MD, PhD, the Laura and Isaac Perlmutter Professor of Oncology in the Department of Medicine and deputy director of Perlmutter Cancer Center, as well as co-director of its Melanoma Research Program, overseeing work in experimental therapeutics.

Working Together for a New Prediction Model

Project 1 explores the role of the microbiome in immunotherapy response. It is co-led by Dr. Weber and Jiyoung Ahn, PhD, associate professor in the Departments of Population Health and Medicine, a member of the Division of Environmental Medicine, and associate director of population sciences and director of the Epidemiology Program at Perlmutter Cancer Center.

Dr. Ahn, whose research explores how the gut microbiome influences the development of gastrointestinal cancers, proposed a study of stool samples from participants in a randomized phase 3 adjuvant trial. The trial tests combination PD-1/CTLA-4 blockade versus PD-1 alone in patients with high-risk, resected stage IIIB/C and IV melanoma. The bacteria in the patients’ stool samples are analyzed to identify different species that are more likely to be associated with a positive response to immunotherapy or more likely to lead to toxicity.

Dr. Weber is assessing a series of serum and peripheral blood biomarkers whose association with clinical outcome and toxicity will be determined. The goal is to use the combined biomarkers to develop a risk prediction model that can guide physicians’ decisions regarding immunotherapy treatment.

“The melanoma SPORE grant brings investigators with various expertise working together, which is very attractive,” says Dr. Ahn, who investigates the causes and progression of cancer in human populations. “This is a great opportunity for clinical trialists, geneticists, and basic scientists to collaborate, with the potential to achieve something bigger than is possible with an individual grant.”

Homing In on Immunotherapy Resistance

Project 2 aims to identify biomarkers that predict relapse-free survival after immunotherapy. It is co-led by Tomas Kirchhoff, PhD, associate professor of population health and medicine, and Dr. Weber. This project focuses on patients with stage III/IV resected melanoma tumors treated with immunotherapy in the adjuvant setting. It proposes to identify novel T cell–specific transcriptional networks that potentially affect resistance to immune checkpoint inhibitors. The networks may serve as targets for improved adjuvant immunotherapies for melanoma and other cancers.

The team hypothesizes that underlying inherited factors that influence host immunity affect relapse-free survival after adjuvant immunotherapy. The findings from this project could enable clinicians to predict which patients might benefit from immunotherapy. The idea is to integrate genomic information, as well as so-called epigenetic information, from the DNA that is not coding.

Avoiding Immune-Related Toxicity

Project 3 addresses a pressing need to identify immunotherapy patients at risk of developing immune-related adverse events such as diarrhea and colitis. Co-led by Michelle Krogsgaard, PhD, associate professor in the Department of Pathology, and Dr. Osman, this project focuses on developing a predictive tool that enables clinicians to minimize exposure of patients with resected stage III/IV melanoma to severe toxicity while maximizing clinical benefit from immune checkpoint inhibitors. The researchers plan to identify autoimmune susceptibility to developing immune-related adverse events. They also hope to establish whether prophylactic infliximab mitigates development of gastrointestinal toxicity from immunotherapy in patients identified as being at high risk of developing those adverse events.

Project 4 explores the role of microRNAs in relapse following immunotherapy in patients with stage II melanoma. It is co-led by David Polsky, MD, PhD, the Alfred W. Kopf, MD, Professor of Dermatologic Oncology and director of the Pigmented Lesion Service in the Ronald O. Perelman Department of Dermatology and professor of pathology; and Eva M. Hernando-Monge, PhD, associate professor and vice chair for science in the Department of Pathology. This project aims to use microRNAs to optimize the clinical management of patients with stage II melanoma.

A preliminary study by Dr. Hernando-Monge measured expression levels of microRNAs in patients who had long-term survival or died after resection of their tumors. She and her colleagues generated microRNA “signatures” that accurately identify which patients are at high risk of relapse and death. To refine the microRNA signature, the SPORE project is analyzing a new cohort of patients enrolled at NYU Langone who are more representative of the intended use population.

“Patients with stage II melanoma have a 25 percent risk of death over the long term, and it is important for us to try and move adjuvant therapy to these patients,” Dr. Polsky says. “We think that our work can help identify which patients really need immunotherapy and spare patients the risk of the toxicity if they don’t need it.”

A Team Effort

The SPORE grant is the culmination of nearly two decades of work developing a melanoma biospecimen repository by the Interdisciplinary Melanoma Cooperative Group (IMCG), a multidisciplinary, translational melanoma research program. Established by Dr. Osman in 2002, IMCG includes 24 investigators representing 10 departments at NYU Langone and has enrolled close to 5,000 patients. The blood, tissue specimens, and clinical information the program has collected provide an unparalleled resource to study how to improve melanoma treatment. Expertise in pathology and biostatistics is crucial.

“NYU Langone has been recognized as a referral center for skin cancer since the 19th century,” Dr. Osman says. “There is a legacy we are building on.”

In addition to the project co-leaders, team members who were instrumental during the grant’s development were Dr. Shapiro and Anna C. Pavlick, DO, who recruited patients and obtained the large amount of biological material required for the grant; biostatistician Judith D. Goldberg, PhD, professor of population health and medicine (Project 1); Hua (Judy) Zhong, PhD, associate professor of population health and medicine (Project 3); Yongzhao Shao, PhD, professor of population health and medicine (Project 4); and bioinformatician Itai Yanai, PhD, professor in the Department of Biochemistry and Molecular Pharmacology and director of the Institute for Computational Medicine (Project 2).

“The SPORE grant is a team effort of many investigators over the years and is built on a broad patient base and the matching expertise of clinicians at NYU Langone,” Dr. Weber adds.

Disclosures: Jeffrey S. Weber, MD, PhD, consulted for Bristol-Myers Squibb and Merck, and accepted travel reimbursement from both. He was named on a PD-1 biomarker for outcome by Biodesix and named on an ipilimumab biomarker for outcome by Moffitt Cancer Center.