# Mechanisms regulating chimeric antigen receptor T-cell activity in cancer

> **NIH NIH K08** · WASHINGTON UNIVERSITY · 2022 · $238,135

## Abstract

PROJECT SUMMARY
 The proposed research focuses on defining the molecular regulators of chimeric antigen receptor (CAR) T-
cell activity against cancer. CAR therapy has generated great enthusiasm in light of its efficacy in the treatment
of B-cell neoplasms, however significant limitations still prevent its broader success. Approximately ½ of
patients with non-Hodgkin lymphoma do not respond, reflecting a failure of cytotoxicity, and many patients
with acute lymphoblastic leukemia relapse after treatment due to a failure of CAR T-cell persistence. The
studies proposed aim to determine how these essential T-cell functions are regulated in CAR T cells.
Preliminary data suggest that death receptors, surface proteins that initiate apoptosis, are essential in CAR T-
cell cytotoxicity. Using molecular profiling and gene editing of T-cell and tumor samples from Penn's CAR
clinical trials, I will define the mechanistic role of death receptors in CAR-driven cytotoxicity and tumor escape.
Persistence is mediated by the formation of immune memory, and data show that CARs activate cellular
programs that suppress memory formation. The studies outlined in this proposal will utilize xenograft mouse
models of human leukemia to determine how CAR activation of the PI3K signaling pathway impedes formation
of memory cells and impairs CAR T-cell persistence. Using clinical trial samples, this work will further aim to
identify additional molecular pathways that limit persistence using proteomic and phosphoproteomic analysis.
 The goal of the proposed five-year training program is the development of my independent research career
as a physician-scientist focused on cellular immunotherapies. I completed residency training in Internal
Medicine and am in my final year of fellowship training in Hematology/Oncology. I am now expanding my
scientific expertise in molecular biology and immunology, as well as clinical expertise in allogeneic
hematopoietic cell transplantation. My goal for the near future is to develop the skills necessary to drive a
distinctive program of scientific investigation. Specifically, I seek to gain expertise in genome editing,
proteomics and computational biology through didactic and practical training in order to augment my scientific
skillset and establish independence. My long-term goal is to enhance the efficacy of T-cell immunotherapy and
improve outcomes for patients with hematologic cancers. I will be mentored by Dr. Carl June, an international
leader in cellular immunotherapy who is well equipped to provide me with the mentorship I need to succeed.
To add breadth and depth to my scientific and career guidance, I have assembled a Mentoring Committee
composed of exceptional scientists. The University of Pennsylvania had led the field of cellular immunotherapy
science and clinical practice, and provides the ideal environment for my training as a cell therapy investigator.
 The proposed studies have the potential to provide critical insight into C...

## Key facts

- **NIH application ID:** 10460171
- **Project number:** 5K08CA237740-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Nathan Singh
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $238,135
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10460171

## Citation

> US National Institutes of Health, RePORTER application 10460171, Mechanisms regulating chimeric antigen receptor T-cell activity in cancer (5K08CA237740-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10460171. Licensed CC0.

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