# (PQ8) Predicting immune-related toxicity in the adjuvant melanoma setting with checkpoint inhibition

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2021 · $495,996

## Abstract

PROJECT SUMMARY
Immune checkpoint inhibitors (ICI), e.g., anti-CTLA-4 (ipilimumab) or anti-PD-1 (nivolumab, pembrolizumab),
have transformed the therapeutic landscape for advanced melanoma, enhancing anti-tumor activity and
producing durable clinical benefit in a subset of patients. ICIs have been shown to be effective in the adjuvant
setting for melanoma, and for treatment of many other cancers (e.g., bladder, lung, renal cell). However,
immune-related adverse events (irAEs) are a critical obstacle to realizing the full potential of ICI: a substantial
proportion of ICI-treated patients develop severe immune toxicities involving multiple organs, causing
significant morbidity and requiring systemic treatment or therapy discontinuation. In pilot testing, we used a
human proteome array with ~20,000 full-length human proteins to analyze antibody levels in sera from 67
melanoma patients who received anti-CTLA-4 or anti-PD-1. Our results identified distinct pre-treatment serum
autoantibodies (autoAbs) associated with development of severe irAEs. Using a humanized FcgR mouse
model, we generated preliminary data to suggest that pre-treatment patient sera IgG may exacerbate
development of irAEs. Finally, using a novel mass spectrometry approach we demonstrated an association
between specific serum proteins from ICI-treated melanoma patients and treatment efficacy. Our central
hypothesis is that a subset of melanoma patients has a baseline autoimmune susceptibility, characterized by a
repertoire of specific preexisting autoAbs and serum proteins that predicts and exacerbates development of ICI
toxicity. Our proposal is in direct response to RFA-CA-17-017 - PQ8: “What are the predictive biomarkers
for the onset of immune-related adverse events associated with checkpoint inhibition, and are they
related to markers for efficacy?” We will utilize a large cohort of pre-treatment sera from the CheckMate-238
phase 3 trial of adjuvant anti-CTLA-4 vs. anti-PD-1 in resected Stage III/IV melanoma to assess the
relationship between autoAbs and serum proteins and development of irAEs and recurrence-free survival
(efficacy). We will use our mouse model to test the cause-effect relationship between pre-existing immune
responses and toxicities from ICI to select the autoAbs most likely to be biomarkers for irAEs. The translational
impact of our work is that detection of baseline toxicity-associated autoAbs could identify melanoma patients
likely to develop severe irAEs from treatment, guiding therapy selection and sequencing or toxicity
management. Our work with autoAbs and serum proteomics may define new targets which impact the onset of
irAEs and provide insight into new strategies to mitigate toxicity without compromising the anti-tumor immune
response.

## Key facts

- **NIH application ID:** 10241380
- **Project number:** 5R01CA231295-04
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Iman Osman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $495,996
- **Award type:** 5
- **Project period:** 2018-09-14 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241380

## Citation

> US National Institutes of Health, RePORTER application 10241380, (PQ8) Predicting immune-related toxicity in the adjuvant melanoma setting with checkpoint inhibition (5R01CA231295-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10241380. Licensed CC0.

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