# Project 2: Targeting Neoantigens for Lung Cancer Immunotherapy

> **NIH NIH P50** · FRED HUTCHINSON CANCER CENTER · 2021 · $83,022

## Abstract

Project Summary/Abstract – Project 2
Immunotherapy with immune checkpoint inhibitors (ICI) is revolutionizing the treatment of many cancers,
including non-small cell lung cancer (NSCLC) where a small subset of patients with metastatic disease have
significant responses. The antitumor activity of ICI is thought in part to be mediated by CD4+ and CD8+ T cells
that recognize neoantigens, which are peptides derived from mutations in expressed genes in tumor cells and
presented by class I or II MHC molecules. Thus, the failure of most patients to respond to ICI may result from
an insufficient pre-existing tumor-specific T cell response, irreversible dysfunction of previously activated T
cells, or local immunosuppressive mechanisms. A therapeutic vaccine capable of boosting or inducing de novo
functional T cell responses to neoantigens could be beneficial alone, or in combination with ICI or other
modalities that overcome immunosuppression in the tumor microenvironment. Putative neoantigens are
prevalent in NSCLC due to the high mutation burden, and may be superior to self-antigens as vaccine targets
because the T cell repertoire capable of responding is not affected by central tolerance mechanisms.
Moreover, multiple neoantigens can theoretically be targeted by a vaccine, which could overcome
heterogeneity in antigen and MHC expression on tumors, and in the quality of a single neoantigen. Multiple
candidate neoantigens can be identified using whole exome sequencing of tumors to detect coding mutations,
and algorithms that predict peptides likely to bind to MHC molecules. Initial clinical applications of therapeutic
neoantigen vaccines in melanoma have recently provided proof-of-principle, and revealed the potential of this
personalized approach to cancer immunotherapy.
 We have developed a novel approach to neoantigen vaccination that utilizes the systemic administration of
autologous T cells engineered to express cancer-specific mutations (Tvax). This strategy was suggested by
clinical data from our lab showing that adoptive transfer of human T cells expressing transgenes encoding
foreign proteins induced potent CD8+ and CD4+ T cell responses specific for the transgene product that were
boosted by subsequent infusions, even in patients with severely compromised immunity. T cells provide a
versatile platform for personalized medicines, including cell based vaccines because they can be easily
genetically modified and expanded in cGMP conditions, safely administered systemically, and traffic efficiently
to lymph node sites to deliver antigens where immune responses are initiated. This project will translate this
unique approach for vaccination to neoantigens in preclinical models and patients with NSCLC.

## Key facts

- **NIH application ID:** 10601293
- **Project number:** 6P50CA228944-04
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** STANLEY R. RIDDELL
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $83,022
- **Award type:** 6
- **Project period:** 2019-08-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10601293

## Citation

> US National Institutes of Health, RePORTER application 10601293, Project 2: Targeting Neoantigens for Lung Cancer Immunotherapy (6P50CA228944-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10601293. Licensed CC0.

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