# IL-15 and -21 armored GPC3-specific CAR T cells for children with solid tumors

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $601,989

## Abstract

CAR T cells can induce remarkable antitumor responses in patients with hematologic cancers but have been
largely ineffective in patients with solid tumors. Several barriers limit CAR T efficacy in solid malignancies
including the limited number of safe solid tumor-specific antigens and an immunosuppressive tumor
microenvironment (TME) that lacks supporting stimuli. Furthermore, it remains unknown how CAR T cells
influence the evolution of immune escape mechanisms in the human TME. We developed and tested a set of
chimeric antigen receptors (CARs) that 1) target glypican-3 (GPC3), a tumor antigen selectively expressed by
several pediatric solid tumors but not non-malignant tissues, and 2) co-express interleukin-15 (IL15) and IL21,
cytokines that are important for T cell survival, expansion, persistence, and retention of antitumor effector
functionality. We found that T cells co-expressing a second generation GPC3-CAR and IL15 (15.GPC3-CAR)
have significantly improved expansion, persistence, and antitumor activity compared to GPC3-CAR T cells, and
that co-expression of both IL15 and IL21 (15.21.GPC3-CAR) further enhances these properties in preclinical
models. Additionally, our preclinical studies showed that 15.21.GPC3-CAR T cells uniquely maintain expression
of T cell factor-1, which protects CAR T cells from exhaustion and preserves proliferative capacity following
repeated GPC3-mediated activation. Since the safety and efficacy parameters of these cytokine-expressing CAR
T cells in humans are unknown, we propose to evaluate 15.GPC3-CAR and 15.21.GPC3-CAR T cells in
sequential phase 1 studies using Bayesian Optimal Interval dose escalation in children with relapsed or refractory
GPC3-positive solid tumors. Our multidisciplinary team has already generated promising safety and efficacy
results treating children with T cells expressing the GPC3-CAR alone. We hypothesize that 15.GPC3-CAR and
15.21.GPC3-CAR T cells will be safe and that co-expression of IL15 with IL21 will enable GPC3-CAR T cells to
overcome the inhibitory TME, resulting in robust expansion, persistence, and durable antitumor responses. In
Aim 1, we will evaluate the safety of 15.GPC3-CAR and 15.21.GPC3-CAR T cells in children with GPC3-positive
solid tumors. In Aim 2, we will determine the in vivo persistence and antitumor activity of CAR T cells. Finally, in
Aim 3, through the evaluation of CAR T cell products, peripheral blood samples, and post-infusion tumor
biopsies, we will define the transcriptomic and phenotypic profiles of GPC3-CAR T cells, cancer cells, and non-
neoplastic stromal cells. We will identify survival programs in CAR T cells and define immune escape
mechanisms in the TME using single-cell RNA sequencing, flow cytometry, and COdetection-by-inDEXing.
Through the proposed research, we will determine the safety, in vivo expansion and persistence, and antitumor
activity of our therapeutic cells. The results will identify survival programs in CAR T cells and immune es...

## Key facts

- **NIH application ID:** 10749884
- **Project number:** 5R01CA258866-03
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Andras A. Heczey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $601,989
- **Award type:** 5
- **Project period:** 2022-01-17 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10749884

## Citation

> US National Institutes of Health, RePORTER application 10749884, IL-15 and -21 armored GPC3-specific CAR T cells for children with solid tumors (5R01CA258866-03). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10749884. Licensed CC0.

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