# Towards Precision Immuno-Oncology: Unraveling the Genomic Determinants and Mechanisms Underlying Immunotherapy Efficacy and Resistance

> **NIH NIH R35** · CLEVELAND CLINIC LERNER COM-CWRU · 2021 · $865,728

## Abstract

PROJECT SUMMARY/ABSTRACT
Title: Towards Precision Immuno-Oncology: Unraveling the Genomic Determinants and Mechanisms
Underlying Immunotherapy Efficacy and Resistance
 Immunotherapy has shown considerable promise for improving outcomes for cancer patients.
Treatment of patients with antibodies against CTLA4, PD-1, or PD-L1 can result in dramatic responses and
durable tumor control in some patients. However, most patients do not benefit and ICB treatment can cause
severe side effects. Therefore, it is of paramount importance in the field to understand the mechanisms
underlying sensitivity and resistance to ICB and other immunotherapies. The long-term goal of our research
program is to unravel the molecular mechanisms underlying sensitivity and resistance to immunotherapies
such as ICB and to work towards a better understanding of how to use immunotherapy in a precise and
individualized manner. We propose to investigate how tumor and patient genetics/genomics affect tumor
immune phenotypes and influence the response and resistance to immunotherapies. Over the next 7 years,
our efforts will be focused on addressing three important questions with clear mechanistic and translational
relevance. First, we will undertake a comprehensive analysis of how the diversity of mutational landscapes
and densities, and DNA damage repair (DDR) deficiencies affect immunotherapy response in cancers treated
with ICB (anti-PD1 or anti-CTLA4). This is aimed at developing and credentialing a precise model for ICB
sensitivity and resistance to allow the design of rationale therapeutic combinations and personalization of ICB
treatment. Second, we will use pre-clinical models and patient samples to evaluate how driver mutations in
critical DDR mutations influence tumor immunity, ICB response, and acquired resistance. Third, we will
characterize how the patient germline genotype (HLA), together with somatic mutation profiles of tumors,
influence response to ICB.

## Key facts

- **NIH application ID:** 10264128
- **Project number:** 5R35CA232097-05
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Timothy An-thy Chan
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $865,728
- **Award type:** 5
- **Project period:** 2020-05-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10264128

## Citation

> US National Institutes of Health, RePORTER application 10264128, Towards Precision Immuno-Oncology: Unraveling the Genomic Determinants and Mechanisms Underlying Immunotherapy Efficacy and Resistance (5R35CA232097-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10264128. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*