CLDN18.2 in lung adenocarcinoma as a promising target of chimeric antigen receptor T cells

An autologous chimeric antigen receptor T (CAR-T) cell therapeutic modality, specifically directed toward Claudin 18.2 (CLDN18.2), was successfully established for lung adenocarcinoma (LUAD).

Employing a multimodal integrative approach that combines bulk RNA sequencing datasets, and immunomodulatory factors in LUAD were identified. To verify the function of CLDN18.2 in regulating T cell infiltration, the CLDN18.2 gene was knocked out in the A549 cell culture model with CRISPR-Cas9, and a set of CLDN18.2^-/- clones was thereby established. Functional evaluations of CAR-T lymphocytes targeting CLDN18.2 were performed both ex vivo and in vivo. Ultimately, our team aimed to examine whether the antineoplastic efficacy of CLDN18.2-directed CAR-T cells could be further potentiated by combination with a concomitant anti-PD-1 antibody.

CLDN18.2 was designated as a putative critical target molecule regulating immune responses in LUAD. Validation experiments utilizing cellular and tissue specimens confirmed that CLDN18.2 expression was elevated in LUAD-derived cells and tissues. Moreover, in vitro CLDN18.2 knockdown suppressed the oncogenic biological abilities of LUAD cells. In vivo studies demonstrated that CLDN18.2-CAR-T therapy induced a gradual and substantial reduction in tumor growth burden. CLDN18.2-CAR-T cells converted immune-cold immunosuppressive tumors into immune-hot immune-activating tumors, and when co-administered with anti-PD1 agents, this therapeutic strategy significantly enhanced the antitumor response.

Our findings demonstrated that CLDN18.2-directed CAR-T cells exhibit potential as a potent therapeutic strategy for management of LUAD expressing CLDN18.2.