TCR-like antibody and GITR signaling lead to effective CAR-T against solid tumor

Chimeric antigen receptor T cell (CAR-T) therapy is one of the great success stories of cellular immunotherapy for blood cancers (e.g., B cell leukemias, lymphomas, and multiple myeloma) but has remained ineffective for solid tumors. The failure of CAR-T in solid tumor models is partly due to the immunosuppressive nature of the tumor microenvironment (TME), and the choice of target is also a likely contributor. Most tumor-specific or tumor-associated antigens are intracellular proteins that cannot be simply targeted by antibodies, unlike B cell antigen CD19 or B cell maturation antigen that are targeted by CARs in current clinical use. In this issue of Molecular Therapy, Wang and co-workers 1 Wang L. Matsumoto M. Akahori Y. Seo N. Shirakura K. Kato T. Katsumoto Y. Miyahara Y. Shiku H. Preclinical Evaluation of a Novel CAR-T Therapy 1 Utilizing a scFv Antibody Highly Specific to MAGE-A4p230-239/HLA-A∗02:01 Complex. Mol. Ther. 2024; 32: 734-748 Abstract Full Text Full Text PDF Scopus (1) Google Scholar used a different approach: a novel intracellular signaling domain and an Fv targeting a major histocompatibility complex -peptide (pMHC) complex, the T cell receptor's (TCR's) target, to achieve promising pre-clinical control of a solid tumor in an immunodeficient mouse model. Preclinical evaluation of a novel CAR-T therapy utilizing a scFv antibody highly specific to MAGE-A4p230-239/HLA-A∗02:01 complexWang et al.Molecular TherapyJanuary 19, 2024In BriefMiyahara and colleagues reported that the intracellular tumor antigen MAGE-A4 could be targeted by a novel CAR-T cell therapy utilizing an antibody with high affinity and specificity for the MAGE-A4p230-239/HLA-A∗02:01 complex. Additionally, the intracellular domain of GITR in CAR constructs enhanced in vivo function compared with CD28 and 4-1BB. Full-Text PDF Open Access