Mesothelin-targeted CAR-T therapy combined with irinotecan for the treatment of solid cancer.

Background: Chimeric antigen receptor (CAR) T cell therapy has shown promising results in treating blood cancers, but it has limited efficacy against solid tumors that express mesothelin (MSLN). One of the reasons is the immunosuppressive tumor microenvironment, which consists of physical barriers, multiple mechanisms of immune evasion, and various biochemical factors that favor tumor growth and survival. These factors reduce the antitumor activity of MSLN-targeted CAR T cells in clinical trials. Therefore, new therapeutic strategies are needed to enhance the effectiveness of MSLN-targeted CAR T cell therapy.

Methods: To investigate whether the antitumor efficacy of anti-MSLN CAR-T cells depends on the epitopes they recognize, we generated MSLN-targeted CAR T cells that bind to different regions of MSLN (Region I, II, III and Full length). We then evaluated the antitumor activity of MSLN-targeted CAR T cells alone or in combination with the chemotherapeutic drug irinotecan or an anti-PD-1 antibody in vitro and in vivo.

Results: We found that MSLN-targeted CAR T cells effectively killed MSLN-positive cancer cells (H9, H226 and Panc-1), but not MSLN-negative cells (A431) in vitro. In a mouse model of H9 tumor xenografts, all CAR T cells showed similar tumor suppression, but an MSLN-targeted scFv with Region I epitope, R47, performed slightly better. Combining irinotecan with CAR_R47 T cells enhanced tumor control synergistically in both H9 xenograft mice and patient-derived xenograft mice.

Conclusions: Our results suggest that irinotecan can enhance the antitumor activity of MSLN-targeted CAR T cells, and offer a promising combination therapy strategy for MSLN-positive solid tumors.