Autocrine p40 enhances the efficacy of CLDN18.2 CAR-T cells in gastrointestinal cancer

Abstract

Gastrointestinal cancers (GICs), including gastric cancer (GC) and pancreatic cancer (PC), have high mortality rates and limited therapeutic options. The treatment of these two cancers still faces many challenges, especially due to their high genetic heterogeneity and genomic instability. Claudin 18.2 (CLDN18.2) is highly restricted in normal tissues but is frequently upregulated in gastrointestinal cancers, making it an attractive target for chimeric antigen receptor-T (CAR-T) cell therapy against GICs, with encouraging results in phase I trials. However, enhancing CAR-T cell efficacy requires overcoming several challenges, including T cells expansion, persistence, exhaustion, and the suppressive tumor microenvironment (TME). We developed a novel CAR-T construct combining a CLDN18.2-specific CAR with the human p40 subunit (CLDN18.2-p40 CAR) to improve antitumor efficacy. Our finding demonstrated that CLDN18.2-p40 CAR-T cells exhibited greater persistence, reduced differentiation, enhanced cytotoxicity, and improved long-term survival in vitro compared with conventional CAR-T cells. In vivo, treatment with CLDN18.2-p40 CAR-T cells led to enhanced tumor cell lysis, sustained cytotoxicity, and increased tumor infiltration, resulting in significant tumor regression in both xenograft and syngeneic mice models. RNA-sequencing revealed an enrichment of pro-inflammatory pathways related to leukocyte migration and chemotaxis in the tumor tissue, aligning with the observed increase in T cell infiltration. This study underscored the pivotal role of the p40 subunit in enhancing the phenotype, persistence, and migration of CAR-T cells, and ameliorating the TME, identifying CLDN18.2-p40 CAR-T as a potentially more effective therapy for improving the clinical outcomes of patients with GIC.

Keywords

Gastrointestinal cancer / Genomic instability / CAR-T cell therapy / Claudin 18.2 / p40 / Tumor microenvironment / Medical and Health Sciences / Immunology / Oncology and Carcinogenesis

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Funding

National Natural Science Foundation of China(82030076, 82470229)

Shenzhen Clinical Research Center of Hematology(LCYSSQ20220823091401002)

Sanming Project of Medicine in Shenzhen(SZSM202111004)

Shenzhen Key Laboratory Foundation(ZDSYS20200811143757022)

Medicine Plus Program of Shenzhen University(000003011601)

RIGHTS & PERMISSIONS

Shenzhen University School of Medicine; Fondazione Istituto FIRC di Oncologia Molecolare