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Interleukin-15-armoured 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, TX, USA.
Abstract:
Interleukin-15 (IL-15) promotes the survival of T lymphocytes and enhances the antitumour properties of chimeric antigen receptor (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 evaluation in humans of the effects of IL-15 co-expression on GPC3-expressing CAR T cells (hereafter GPC3 CAR T cells). Cohort 1 patients ( NCT02905188 and NCT02932956 ) received GPC3 CAR T cells, which were safe but produced no objective antitumour responses and reached peak expansion at 2 weeks. Cohort 2 patients ( NCT05103631 and NCT04377932 ) received GPC3 CAR T cells that co-expressed IL-15 (15.CAR), which mediated significantly increased cell expansion and induced a disease control rate of 66% and antitumour response rate of 33%. Infusion of 15.CAR T cells was associated with increased incidence of cytokine release syndrome, which was controlled with IL-1/IL-6 blockade or rapidly ameliorated by activation of the inducible caspase 9 safety switch. Compared with non-responders, tumour-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 of genes related to type I interferon signalling. Collectively, these results demonstrate that IL-15 increases the expansion, intratumoural survival and antitumour activity of GPC3 CAR T cells in patients.
Insights
Interleukin-15 (IL-15) enhances chimeric antigen receptor (CAR) T-cell therapy for solid tumors. Co-expressing IL-15 with GPC3 CAR T-cells improved patient responses and tumor infiltration.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Chimeric antigen receptor (CAR) T-cells show limited efficacy in solid tumors.
- Glypican-3 (GPC3) is a target antigen in several solid cancers.
- Interleukin-15 (IL-15) supports T-cell survival and anti-tumor activity.
Purpose of the Study:
- To evaluate the safety and efficacy of GPC3-specific CAR T-cells co-expressing IL-15 in patients with GPC3-expressing solid tumors.
- To assess the impact of IL-15 on CAR T-cell expansion, persistence, and anti-tumor activity in vivo.
Main Methods:
- Phase I/II clinical trials (NCT02905188, NCT02932956, NCT05103631, NCT04377932) involving patients receiving GPC3 CAR T-cells with or without IL-15 co-expression.
- Monitoring of CAR T-cell expansion, persistence, and anti-tumor responses.
- Analysis of tumor-infiltrating T-cells from responders and non-responders.
Main Results:
- GPC3 CAR T-cells alone were safe but lacked anti-tumor activity.
- GPC3 CAR T-cells co-expressing IL-15 (15.CAR) demonstrated significantly increased cell expansion and persistence.
- 15.CAR T-cells achieved a 66% disease control rate and a 33% objective response rate.
- Increased incidence of cytokine release syndrome (CRS) was manageable with IL-1/IL-6 blockade or a safety switch.
- Responders showed distinct T-cell infiltration profiles, including epigenetic regulator repression and interferon signaling pathway activation.
Conclusions:
- IL-15 co-expression significantly enhances the anti-tumor efficacy of GPC3 CAR T-cells in solid tumors.
- 15.CAR T-cells represent a promising therapeutic strategy for GPC3-positive malignancies.
- Further investigation into the mechanisms of T-cell response and resistance is warranted.
