# Intratumoral Immune Activation Informs Rational CAR-T Cell Design

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2020 · $45,520

## Abstract

Project Summary: Immune therapies have significantly improved outcomes for cancer patients with poor
prognosis in recent years, in many cases providing complete remissions with no trace of residual disease.
However, these therapies are currently restricted to specific cancer types, and do not reach the majority of cancer
patients. The two most successful forms consist of either using blocking antibodies specific for inhibitory ligands
commonly expressed on T lymphocytes, allowing enhanced functionality of T cells, known as inhibitory
checkpoint blockade (ICB), or the engineering of autologous T cells to target tumors through chimeric antigen
receptors (CARs). Unfortunately, CAR T cell therapy has shown limited efficacy in solid tumors, and ICB is most
effective in tumors with pre-existing immune infiltrate and heavy mutational loads. Thus, significant innovation
is needed to extend the benefits of immune therapies to the majority of cancer patients. Our lab has
recently identified the structured RNA 7SL1 (RN7SL1) as capable of stimulating immune response genes in
tumor cells following secretion of the RNA by stromal cells. Although the 7SL1 RNA is not well studied in an
immune context, structured RNA is a well-known immunostimulatory motif. Thus, I hypothesize that
unshielded 7SL1 in the tumor microenvironment stimulates immune activation and contributes to ICB
responsiveness. Given that CAR T cell therapy has not been effective in solid tumors, engaging an endogenous
immune response similar to that seen following administration of ICB, which has shown efficacy in solid tumors,
is an attractive prospect. To that end I have designed a T cell-based system for delivering structured RNA directly
to the tumor microenvironment. I hypothesize that combining the production of stimulatory RNA with CAR
T cell functionality in the tumor microenvironment will stimulate endogenous immune responses and
improve the anti-tumor efficacy of CAR T cells in solid tumors. In order to test these hypotheses, I will use
fibroblast cell lines designed to secrete high or low levels of unshielded 7SL1 in the tumor microenvironment in
combination with current ICB regimens to determine the contribution of this stimulatory element to antitumor
immunity. Additionally, I will assay the efficacy of this newly developed T cell system using syngeneic tumor
models expressing a model antigen. These approaches will be complimented by genetic knock-out mouse
models to determine the importance of specific immune cell types in carrying out these anti-tumor responses. In
total, these experiments will serve to determine the importance of a novel immunostimulatory RNA to anti-tumor
immunity and test the functionality of a novel CAR T cell-based approach to anti-tumor immune activation.

## Key facts

- **NIH application ID:** 9878809
- **Project number:** 5F31CA228455-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Lexus Johnson
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2018-04-16 → 2021-04-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9878809

## Citation

> US National Institutes of Health, RePORTER application 9878809, Intratumoral Immune Activation Informs Rational CAR-T Cell Design (5F31CA228455-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9878809. Licensed CC0.

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