# Directing the metabolic fate of CAR T cells

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $432,308

## Abstract

Project Summary / Abstract
The goal of this project is to develop the next generation of targeted T-cells with chimeric
antigen receptors (CARs) for use in carcinomas and hematologic malignancies. Therefore,
these studies address the cancer epidemic that afflicts the population in the United States. CAR
T cells are now beginning to show activity in a number of pilot clinical trials and they have
significant potential for therapy of many cancers that are currently incurable. However two
issues have emerged that provide a barrier to further rapid progress in the field: 1) the
persistence of CAR T cells in patients with solid cancer has been limited, unlike the case with
CARs that target CD19; 2) T cells become exhausted, become anergic or die in the toxic tumor
microenvironment, unlike the case of hematologic malignancies, where CAR T cells have
continued to function for at least 5 years in responding patients. Our preliminary data indicates
that the metabolic profiles of CAR T cells can be altered at will by changing the design of the
signaling domain in the CAR construct. In this project, we will use the principles of synthetic
biology and the tools of lentiviral vector technology, mRNA electroporation technology, and
clustered regularly interspaced short palindromic repeat (CRISPR) and CRISPR associated
protein 9 (Cas9) technology to adapt the metabolism of T cells in order to promote survival in
harsh tumor microenvironments. The theme of the project is that T cells with more potent and
sustained antitumor effects can be designed to resist metabolic checkpoints such as hypoxia,
hyperkalemia, acidosis, and glucose deprivation. In summary, these overlapping studies will
test the central hypothesis that synthetically enhanced CAR T cells will improve CAR
immunotherapy compared to therapy with currently available CAR T cells. At the conclusion of
this project, a next generation of metabolically enhanced CAR T cells will be available for testing
in pilot clinical trials in patients with advanced pancreatic cancer.

## Key facts

- **NIH application ID:** 9868284
- **Project number:** 5R01CA226983-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** CARL H. JUNE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $432,308
- **Award type:** 5
- **Project period:** 2018-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9868284

## Citation

> US National Institutes of Health, RePORTER application 9868284, Directing the metabolic fate of CAR T cells (5R01CA226983-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9868284. Licensed CC0.

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