# A New Approach to Modulating CAR T Cell Activity

> **NIH NIH R21** · UNIVERSITY OF VIRGINIA · 2022 · $28,341

## Abstract

Abstract
Chimeric antigen receptor (CAR) T cells targeting CD19 are highly effective in children with
refractory/relapsed acute lymphoblastic leukemia (ALL), including those with primary
refractory or CNS disease. Current CAR T cell therapies infuse patients with T cells
constitutively expressing CARs, which are not susceptible to any controllable regulation.
Cytokine release syndrome (CRS) and CAR-associated neurotoxicity (CAN), both of which
can be fatal, arise from uncontrolled CAR T cell activation and expansion. While a few
pharmacological management approaches have been attempted to overcome this issue, they
are often suboptimal. In addition, chronic B-cell aplasia from persistent CD19 CAR T cells
requires monthly infusions of immunoglobulin, which is burdensome and expensive, especially
for pediatric patients facing potentially a lifetime need. Here, we propose to develop a system
for controllable CAR T cells that can be turned on and off as needed. We have previously
demonstrated that exogenous expression of the tyrosine phosphatase SHP-1 acts as a
negative regulator to dampen T cell activation. Recently, we have developed an inducible and
reversible protein degradation system for SHP-1 by adapting the plant Auxin-induced degron
(AID) system for T cells. Combining these two tools in Aim 1, we propose to develop CD19
CAR T cells that will be kept basally dormant through overexpression of SHP-1. However,
upon administration of Auxin, the CAR T cells can be temporarily and reversibly activated
through the degradation of SHP-1. As the doses of Auxin sufficient to activate the AID system
had no significant toxicities in humans, we do not foresee a problem translating this system
into the clinic. In Aim 2, we will examine the efficacy of this novel CAR T cell system in a murine
model of ALL. In Aim 3, we will expand the studies to test whether this regulatable CAR T cells
system can control and/or limit CAR T cell-associated toxicities using a muring model of ALL,
CRS and neurotoxicity. Such an exogenously regulatable CAR T cell system may provide
clinicians a tool to avoid/limit severe CRS and CAN, and allow repopulation of the B-cell
compartment after a sufficient treatment course. This approach will greatly enhance the safety
of CD19 CAR T cells and is likely applicable to CARs for other malignancies, including solid
tumors, where on-target, off-tissue cytotoxicity is more problematic.

## Key facts

- **NIH application ID:** 10365202
- **Project number:** 1R21CA267955-01
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Ulrike Lorenz
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $28,341
- **Award type:** 1
- **Project period:** 2022-06-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10365202

## Citation

> US National Institutes of Health, RePORTER application 10365202, A New Approach to Modulating CAR T Cell Activity (1R21CA267955-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10365202. Licensed CC0.

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