Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape

Area of Science:

• Oncology
• Immunotherapy
• Cancer Biology

Background:

• Glioblastoma (GBM) recurrence after CAR T cell therapy is often driven by antigen escape due to heterogeneous tumor antigen expression.
• Targeting single tumor antigens with chimeric antigen receptor (CAR) T cells can lead to the emergence of antigen-negative tumor cells.

Purpose of the Study:

• To investigate the efficacy of a bispecific CAR T cell therapy designed to target two GBM antigens simultaneously, thereby overcoming antigen escape.
• To evaluate if a tandem CAR (TanCAR) molecule targeting HER2 and IL13Rα2 can improve antitumor activity and survival in preclinical GBM models.

Main Methods:

• Development of a novel tandem CAR (TanCAR) construct with HER2-binding scFv and IL13Rα2-binding IL-13 mutein exodomains.
• Assessment of patient-derived TanCAR T cell binding, cytotoxicity against autologous glioblastoma, and activation dynamics.
• In vivo evaluation of TanCAR T cell efficacy in a murine glioblastoma model.

Main Results:

• TanCAR T cells demonstrated specific binding to HER2 and IL13Rα2 and lysed autologous glioblastoma.
• Simultaneous engagement of HER2 and IL13Rα2 by TanCARs induced heterodimers, leading to superadditive T cell activation.
• TanCAR T cells exhibited sustained activity, mitigated antigen escape, enhanced antitumor efficacy, and improved survival in a preclinical GBM model.

Conclusions:

• Tandem CAR T cells targeting HER2 and IL13Rα2 offer a potential strategy to overcome antigen escape in glioblastoma.
• The augmented, bivalent immune synapse formed by TanCAR T cells enhances T cell functionality and therapeutic efficacy.
• TanCAR T cells represent a promising immunotherapy approach for improved glioblastoma control.