# Project 2: Combined CAR-T cell therapy

> **NIH NIH P50** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $429,640

## Abstract

PROJECT 2: ABSTRACT
Remarkable clinical responses have been reported in B-cell malignancies by adoptive transfer of T cells
redirected with a chimeric antigen receptor (CAR) specific for the CD19 antigen. However, developing CAR-Ts
for the treatment of solid tumors including pancreatic ductal adenocarcinoma (PDAC) is challenging because:
(1) PDAC-associated antigens that are targetable by CAR-Ts are limited, generally not exclusively expressed
by PDAC, and act as passengers, not as drivers of tumorigenesis, allowing for antigenic drift; (2) CAR-Ts are
defective in their capacity to invade stroma-rich tumors such as PDAC; (3) PDAC tumor microenvironment
(TME) is highly immunosuppressive. In this proposal we aim at solving these critical issues. We have identified
B7-H3 (CD276) as a suitable target for chimeric antigen receptor (CAR) T cells in PDAC. B7-H3 is a tumor-
promoting transmembrane protein aberrantly expressed in 60% to 93% of PDAC, melanoma, leukemia, breast,
prostate and ovarian cancer, while limited expression is seen on normal healthy tissues. We have developed
and tested B7-H3.CAR-Ts in xenogeneic and immunocompetent mouse models of PDAC showing antitumor
activity and safety. Thus in Aim 1 we propose to develop a phase I clinical study in patients with PDAC to
assess safety and antitumor activity of B7-H3.CAR-Ts that also include the inducible caspase9 (iC9) as a
safety switch to terminate the activity of B7-H3.CAR-Ts in case of toxicity. In Aim 2 we propose to develop in
preclinical models CAR-Ts in which T cells are not be only rendered tumor specific through the CAR
expression, but are also equipped to overcome the desmoplastic nature of PDAC. Specifically, B7-H3.CAR-Ts
will be further engineered to re-express the enzyme heparanase (HPSE), which is defective in CAR-Ts
generated for clinical use. Furthermore, we will explore if the glucose-regulated protein of 94 kDa (gp96 or
Grp94), which is a member of the heat shock protein (HSP) 90 family (HSP90B1) can also be used as
additional target in PDAC to prevent tumor escape due to antigen loss when one single antigen is targeted. In
Aim 3 we propose to reprogram macrophages and myeloid derived suppressor cells (MDSC) to a non-
immunosuppressive state by using potent and orally bioavailable TAM RTK small molecule inhibitors
developed at University of North Carolina (IND #128236). We will thus perform preclinical studies to evaluate
whether TAM RTK signaling inhibition in macrophages and MDSC would favor the antitumor activity of B7-
H3.CAR-Ts. If successful, this strategy will be included into a second phase of the proposed Phase I clinical
study with B7-H3.CAR-Ts.

## Key facts

- **NIH application ID:** 10911131
- **Project number:** 5P50CA257911-03
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Gianpietro Dotti
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $429,640
- **Award type:** 5
- **Project period:** 2022-09-16 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10911131

## Citation

> US National Institutes of Health, RePORTER application 10911131, Project 2: Combined CAR-T cell therapy (5P50CA257911-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10911131. Licensed CC0.

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