Bispecific CAR T cells against EpCAM and inducible ICAM-1 overcome antigen heterogeneity and generate superior anti-tumor responses
Menée in vitro et à l'aide de modèles murins de tumeurs, cette étude met en évidence l'intérêt de lymphocytes CAR-T bi-spécifiques ciblant les protéines EpCAM et ICAM-1 pour surmonter l'hétérogénéité antigénique des cellules cancéreuses et induire des réponses anti-tumorales supérieures à celles générées par les autres types de lymphocytes CAR-T
Adoptive transfer of chimeric antigen receptor (CAR) T cells has demonstrated unparalleled responses in hematological cancers, yet antigen escape and tumor relapse occur frequently. CAR T-cell therapy for patients with solid tumors faces even greater challenges due to the immunosuppressive tumor environment and antigen heterogeneity. Here, we developed a bispecific CAR to simultaneously target epithelial cell adhesion molecule (EpCAM) and intercellular adhesion molecule 1 (ICAM-1) in order to overcome antigen escape and to improve the durability of tumor responses. ICAM-1 is an adhesion molecule inducible by inflammatory cytokines and elevated in many types of tumors. Our study demonstrates superior efficacy of bispecific CAR T cells compared to CAR T cells targeting a single primary antigen. Bispecific CAR T achieved more durable anti-tumor responses in tumor models with either homogenous or heterogenous expression of EpCAM. We also showed that the activation of CAR T cells against EpCAM in tumors led to upregulation of ICAM-1, which rendered tumors more susceptible to ICAM-1 targeting by bispecific CAR T cells. Our strategy of additional targeting of ICAM-1 may have broad applications in augmenting the activity of CAR T cells against primary tumor antigens that are prone to antigen loss or downregulation.