# Rational in situ programming of cancer vaccine-responding T-cell clones

> **NIH NIH R01** · FRED HUTCHINSON CANCER CENTER · 2021 · $384,876

## Abstract

Project Summary
Currently no method exists that would allow physicians to rapidly and reliably establish T-cell immunity against
tumor antigens. Bioinformatics tools can predict antigens on cancer cells that are recognized by T cells, but the
vaccines based on them often fail because the immunized individuals have too few T cells with the appropriate
receptors or lack them altogether. The overall goal of our research proposal is to resolve this problem by
developing injectable nanoreagents that introduce into the peripheral T-cell repertoire engineered T-cell
receptors (TCRs) that optimally bind the most prevalent vaccine epitope. Specifically, we hypothesize that a
customized specificity can be programmed into T cell populations by combining anti-cancer vaccines with
techniques that genetically enable endogenous CD8 T cells to express TCRs specific for the vaccines. We
further hypothesize that we can use this platform to program CD4 T helper cells with defined MHC class-II-
restricted TCRs, and thereby improve tumor-specific CD8 lymphocyte and B cell responses to tumor antigens
compared to conventional immunization methods. Our multidisciplinary team of immunologists, bioengineers
and geneticists has already established that intramuscularly injected nanoparticles can deliver engineered TCR
genes into host T cells so they recognize cancer vaccine antigen. Following rapid vaccine-induced expansion,
nanoparticle-programmed T cells ultimately differentiate into long-lived memory T cells. Our long-term goal is
to develop a full suite of nanoparticles drugs that would allow physicians to rapidly establish anti-cancer
immunity by introducing exogenous antigen-specific TCRs into the patient's T-cell pool. As essential steps
toward achieving this goal, we propose the following Specific Aims: (1) To test the wider applicability and long-
term safety of programming vaccine specificity into CD8+ T cells, (2) to quantify the degree to which host
CD4+ T cells programmed with TCRs to cancer-vaccine antigens boost the immune response, and (3) to
determine if providing optimized CD4 T-cell help and reversing tumor immune evasion mechanisms enables in
situ programmed vaccine-specific T cells to eradicate disease. We believe that data, reagents, and technology
systems generated by our research will provide a conceptual framework for the design of a broad repertoire of
gene modification systems designed to generate selective immunity against any type of cancer. Using these in
the clinic could make cancer vaccines not only more effective, but also reduce the likelihood of vaccine failure.

## Key facts

- **NIH application ID:** 10601347
- **Project number:** 6R01CA261858-02
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** Matthias Stephan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $384,876
- **Award type:** 6
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10601347

## Citation

> US National Institutes of Health, RePORTER application 10601347, Rational in situ programming of cancer vaccine-responding T-cell clones (6R01CA261858-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10601347. Licensed CC0.

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