# CD28-KITv CAR T cells with PD-1 dominant negative receptor

> **NIH CA UH3** · SLOAN-KETTERING INST CAN RESEARCH · 2026 · $2,639,991

## Abstract

PROJECT ABSTRACT
The success of chimeric antigen receptor (CAR) T-cell therapy in solid tumors requires antigen targets with no
on-target, off-tumor toxicity, effective tumor infiltration, cytotoxicity and proliferation in an immunosuppressive
environment, and revival of antigen stress-induced exhausted CAR T cells. We translated CD28-costimulated
CARs (M28z) that target mesothelin (MSLN), a cancer-associated antigen that we have documented
expression in majority of solid tumors; 64 patients have been treated to date, with no on-target, off-tumor
toxicity. Having demonstrated that regionally administered CAR T cells avoid pulmonary sequestration and
benefit from early antigen-activated CD4 helper CAR T-cell function, we delivered CAR T cells intrapleurally in
patients with malignant pleural mesothelioma (MPM), promoting tumor infiltration. To address T-cell
exhaustion, we either treated patients with anti-PD1 agent after CAR T cells or employed tumor-specific
checkpoint blockade by CAR T-cell intrinsic PD1 dominant negative receptor (PD1DNR); 34 patients have
been treated to date, with no CAR- or PD1DNR-related toxicities and with responses by imaging, and
increased survival. To promote IFNγ-mediated cytotoxicity shown to be essential for solid tumor killing, we
exploited a c-KIT mutation, D816V (KITv), as a costimulatory domain. KITv CAR T cells show antigen-
activation induced IFNγ signaling, enhanced cytotoxicity, and when added as signal 3 to CD28 (signal 2),
provide a synergistic function, resist TGFβ-mediated suppression, and prolong functional persistence.
Clinically available kinase inhibitors provide an on/off, tunable safety switch for KITv CAR T cells. To effectively
deliver these next-generation CAR T cells to solid tumors, we developed a translational strategy of non-
ablative, tumor-targeted radiation therapy (RT) to generate a chemokine gradient that facilitates systemically
administered CAR T-cell chemotaxis, tumor infiltration, proliferation, and pe

## Key facts

- **NIH application ID:** 11457454
- **Project number:** 4UH3CA290241-03
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Prasad S. Adusumilli
- **Activity code:** UH3 (R01, R21, SBIR, etc.)
- **Funding institute:** CA
- **Fiscal year:** 2026
- **Award amount:** $2,639,991
- **Award type:** 4N
- **Project period:** 2024-03-01T00:00:00 → 2029-02-28T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11457454

## Citation

> US National Institutes of Health, RePORTER application 11457454, CD28-KITv CAR T cells with PD-1 dominant negative receptor (4UH3CA290241-03). Retrieved via AI Analytics 2026-06-26 from https://api.ai-analytics.org/grant/nih/11457454. Licensed CC0.

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