Interleukin-15-armoured GPC3 CAR T cells for patients with solid cancers.

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.