# Identifying mechanisms of response and resistance to immunotherapies in lung cancer

> **NIH NIH F99** · YALE UNIVERSITY · 2020 · $45,520

## Abstract

Project Summary
Lung cancer is the leading cause of cancer related deaths worldwide, demonstrating the pressing need for
effective and lasting treatments. Immune checkpoint inhibitors, which block negative regulators of T cell function,
have the potential to generate lasting responses in lung cancer patients. However, only a minority of patients
respond to these therapies and ~50% of patients whose tumors initially respond to therapy eventually
develop acquired resistance. Clinical studies have identified correlations between tumor non-synonymous
mutation burden and response to immune checkpoint inhibitors across multiple cancer types. However, most
existing pre-clinical mouse models of lung cancer do not recapitulate the complexity of mutational landscapes in
human cancers, and importantly, the tumors in these models do not respond to immune checkpoint inhibition.
Due in part to the lack of available models, mechanisms of primary and acquired resistance to immune
checkpoint inhibition in lung cancer are not fully understood and strategies to overcome resistance are
lacking. To address this challenge, we developed novel orthotopic mouse models of Kras mutant lung
adenocarcinoma that recapitulate features of human disease essential for studying tumor-immune interactions,
including the tumor mutational landscape as well as responsiveness and acquired resistance to immune
checkpoint inhibition. Using these novel models of murine lung cancer, my goal is to investigate mechanisms of
resistance to these new widely-used lung cancer therapies (F99 phase). I will test the overarching hypothesis
that diverse genetic alterations and transcriptional programs resulting in antigen presentation defects and
neoantigen loss are major mechanisms of acquired resistance to ICIs and that these drive the emergence of
tumor-cell extrinsic features of resistance in the tumor microenvironment. I will investigate the spectrum of
genetic and transcriptional drivers of acquired resistance, focusing on defects in antigen processing and
presentation (Aim 1.2.A). I will also investigate whether neoantigen loss can mediate acquired resistance in lung
cancer (Aim 1.2.B). As a post-doc (K00 phase), I plan to work on approaches to improve immunotherapies for
lung cancer to expand their benefits to a broader patient population than those who currently benefit, specifically
by investigating the efficacy of personalized neoantigen vaccines that induce tissue resident memory T cells
(Aim 2). The aims described here will identify drivers of resistance to checkpoint therapy and explore methods
to use neoantigen vaccines in patients that currently do not benefit from approved immunotherapies, yielding
strategies to expand immunotherapy benefits to a broader patient pool.

## Key facts

- **NIH application ID:** 10017940
- **Project number:** 5F99CA245819-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Camila Robles-Oteiza
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2019-09-13 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10017940

## Citation

> US National Institutes of Health, RePORTER application 10017940, Identifying mechanisms of response and resistance to immunotherapies in lung cancer (5F99CA245819-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10017940. Licensed CC0.

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