# Project 3

> **NIH NIH P50** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $268,195

## Abstract

PROJECT 3 SUMMARY
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 FcR 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- 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- (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- blockade mitigates
developmen...

## Key facts

- **NIH application ID:** 9980833
- **Project number:** 5P50CA225450-02
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** MICHELLE KROGSGAARD
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $268,195
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980833

## Citation

> US National Institutes of Health, RePORTER application 9980833, Project 3 (5P50CA225450-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9980833. Licensed CC0.

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