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Updated: Jun 28, 2025
A Real-time Potency Assay for Chimeric Antigen Receptor T Cells Targeting Solid and Hematological Cancer Cells
Published on: November 12, 2019
Interleukin-15-armored GPC3-CAR T cells for patients with solid cancers
David Steffin1,2,3,4, Nisha Ghatwai1,2, Antonino Montalbano1,2
1Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
Abstract:
Interleukin-15 (IL15) promotes the survival of T lymphocytes and enhances the antitumor properties of CAR T cells in preclinical models of solid neoplasms in which CAR T cells have limited efficacy1-4. Glypican-3 (GPC3) is expressed in a group of solid cancers5-10, and here we report the first evaluation in humans of the effects of IL15 co-expression on GPC3-CAR T cells. Cohort 1 patients (NCT02905188/NCT02932956) received GPC3-CAR T cells, which were safe but produced no objective antitumor responses and reached peak expansion at two weeks. Cohort 2 patients (NCT05103631/NCT04377932) received GPC3-CAR T cells that co-expressed IL15 (15.CAR), which mediated significantly increased cell expansion and induced a disease control rate of 66% and antitumor response rate of 33%. Infusion of 15.CAR T cells was associated with increased incidence of cytokine release syndrome, which was rapidly ameliorated by activation of the inducible caspase 9 safety switch. Compared to non-responders, tumor-infiltrating 15.CAR T cells from responders showed repression of SWI/SNF epigenetic regulators and upregulation of FOS and JUN family members as well as genes related to type I interferon signaling. Collectively, these results demonstrate that IL15 increases the expansion, intratumoral survival, and antitumor activity of GPC3-CAR T cells in patients.
Insights
Interleukin-15 (IL15) co-expression significantly improved CAR T cell efficacy against solid tumors. This enhanced CAR T cell therapy demonstrated increased expansion and antitumor activity in patients.
Area of Science:
- Immunotherapy
- Oncology
- Cellular Therapy
Background:
- Chimeric antigen receptor (CAR) T cells show limited efficacy in solid tumors.
- Interleukin-15 (IL15) is known to enhance T lymphocyte survival and CAR T cell antitumor properties.
- Glypican-3 (GPC3) is a target antigen expressed in several solid cancers.
Approach:
- Evaluated the safety and efficacy of GPC3-CAR T cells in human patients (Cohort 1).
- Assessed the impact of IL15 co-expression (15.CAR T cells) on GPC3-CAR T cell expansion and antitumor activity (Cohort 2).
- Investigated the molecular mechanisms underlying treatment response, including epigenetic and signaling pathway changes.
Key Points:
- GPC3-CAR T cells alone were safe but ineffective in solid tumors.
- Co-expression of IL15 with GPC3-CAR T cells (15.CAR) significantly increased cell expansion and demonstrated antitumor activity (33% response rate, 66% disease control rate).
- Cytokine release syndrome was manageable with a safety switch; responders showed specific epigenetic and gene expression profiles in tumor-infiltrating T cells.
Conclusions:
- IL15 co-expression enhances the expansion, intratumoral survival, and antitumor activity of GPC3-CAR T cells in patients with GPC3-expressing solid tumors.
- This strategy represents a promising advancement for CAR T cell therapy in solid malignancies.
- Further research into the identified molecular pathways could optimize future immunotherapy strategies.
