# Engineering the ER Stress Response to Promote the Survival and Cytotoxic Specificity of CAR T cells

> **NIH NIH F31** · YALE UNIVERSITY · 2021 · $46,036

## Abstract

PROJECT SUMMARY/ABSTRACT
 Chimeric antigen receptor (CAR) T cells have revolutionized cancer therapies and show incredible
responses in patients with relapsed or refractory B cell cancers, yet are ineffective in solid tumors. In order to
work in solid tumors, CAR T cells must be able to survive the immunosuppressive tumor microenvironment
(TME) and distinguish between antigens presented on tumor cells and healthy tissue. Both of these obstacles
can be overcome through clever synthetic engineering of the T cell using known biological circuits. We have
identified a pathway critical to the survival and function of multiple types of leukocytes and naturally turned on
during activation of CD8+ T cells, however surprisingly, it is not activated in the tumor microenvironment. Here,
I propose to synthetically activate this pathway in order to promote CD8+ CAR T cell cytotoxicity and on-target,
on-tumor specificity. Specifically, I will first explore multiple aspects of this signaling pathway and its ability to
promote CAR T cell survival and cytotoxicity under the stresses in the tumor microenvironment. As a second
strategy to improve CAR-T cell specificity for solid tumors, I will engineer a construct that selectively activates a
CAR in response to post-transcriptional regulation. Benefits of post-transcriptional regulation include speed of
activation, and amplification of signal. By making both the post-transcriptional regulator and the target
dependent on binding target cell antigens, I will functionally create an “AND” logic gate, requiring stimulation
from 2 separate antigens in order to facilitate CAR T cell killing. For both strategies I will first demonstrate their
efficacy in vitro with primary mouse and human cells simulating TME conditions, and then in vivo using a
syngeneic transplanted melanoma mouse model. Overall, I hypothesize that synthetic activation of this critical
T cell pathway will enhance CAR-T behavior and control in the solid TME.

## Key facts

- **NIH application ID:** 10212964
- **Project number:** 5F31CA247018-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Samuel Robert Kerr
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 5
- **Project period:** 2020-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10212964

## Citation

> US National Institutes of Health, RePORTER application 10212964, Engineering the ER Stress Response to Promote the Survival and Cytotoxic Specificity of CAR T cells (5F31CA247018-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10212964. Licensed CC0.

---

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