Immune-Related Adverse Events in Melanoma Patients Receiving Adjuvant Immune Checkpoint Inhibitor Therapy

PROJECT SUMMARY: Immune checkpoint inhibitors (ICIs) have transformed the treatment of melanoma, significantly

enhancing overall survival. The exponential increase in their use after being approved for melanoma in the adjuvant setting

is significantly changing the lanscape of cancer survivorship. Inspite of the survival benefits, the use of ICI can be limited by off-target inflammatory responses and autoimmunity in various organs. The clinical phenotypes of the acute immune

toxicities have been clearly documented in trials. Yet, their potential long-term adverse effects, and their impact quality of

life (QOL) are still undetermined. The overall goal of the proposed study is to understand the full impact of adjuvant ICI

therapy, including its potential toxicity/symptom burden and its immune correlates in melanoma patients receiving regular clinical care. We hypothesize that: adverse events and sustained inflammation induced by adjuvant ICIs increase symptom burden and negatively impact function and QOL in a subset of melanoma patients receiving therapy, and that elevated

expression of pro-inflammatory cytokines and T-cell signatures during therapy correlate with the toxicity and symptom

burden. We will test this hypothesis in a prospective cohort of 240 melanoma patients from the initiation of adjuvant ICI

therapy through 2-years of follow-up. We will determine the incidence, clinical phenotypes, timing, and severity of irAEs,

and will longitudinally assess patients reported outcomes through 2-years of follow-up. We will use validated instruments and ecological momentary assessments technology to assess adverse events and symptom burden in real time via patient- initiated reports. Lastly, we will characterize patient immune signatures (immune cell phenotypes and inflammatory

cytokines) from baseline through 2-years of follow-up and evaluate their association with irAEs and symptom burden. CAREER DEVELOPMENT PLAN: The primary objective of this application is to support Dr. Abdelwahab’s career development into an independent immuno-epidemiologist with a focus on autoimmunity arising in the context of cancer or

its therapy. Dr. Abdelwahab proposed training in four areas 1) immunology, 2) epidemiology and biostatistics, 3) health services and outcomes research, and 4) scientific writing and oral presentations. Dr. Abdelwahab has assembled an outstanding mentorship team led by Dr. Cassian Yee, Professor in Melanoma Medical Oncology and Director of Solid

Tumor Cell Therapy in the Center for Cancer Immunology Research, and Dr. Annemieke Kavelaars, Professor in Symptom Research at MD Anderson Cancer Center (MDACC) as co-primary mentors. This is complemented by mentoring advisory committee members including Dr. Adi Diab, Associate Professor in Melanoma Medical Oncology with expertise in tumor

immunology and immunotherapy, Dr. Suarez-Almazor, Professor of Rheumatology and Clinical Immunology, Dr. Susan

Peterson, Professor in Behavioral Science and Director of the Assessment, Intervention and Measurement Facility, and Dr.

Sanjay Shete, Chief of Behavioral and Social Statistics. MDACC, a leading center in cutting edge of cancer research, care, and prevention, is an excellent training environment for Dr. Abdelwahab.