编码新表位的溶瘤麻疹病毒联合 CAR 疗法增强对实体瘤细胞的靶向

Despite the success of cell therapy in treating hematological malignancies, the treatment of solid tumors remains challenging due to the tumor microenvironment (TME) and a lack of suitable antigens. To address this, we investigated a putative octapeptide neoepitope generated by proteolytic cleavage of the stress-induced protein MHC class I polypeptide-related sequence B (MICB). Antibodies developed via the hybridoma technique exhibited high affinity and specificity toward the octapeptide. Detection of the octapeptide was enhanced by inserting an -helical linker before the transmembrane domain, improving accessibility on stably transduced cells.

Two chimeric antigen receptor (CAR) constructs with differing single-chain variable fragment (scFv) chain orientations were expressed in primary T and natural killer (NK) cells, showing antigen-specific cytotoxicity, particularly when incorporating the rigid linker. Variations in sensitivity between CARs influenced killing efficacy and activation profiles.

Oncolytic measles virus (MV) was used as a vector encoding the membrane-anchored octapeptide, selectively infecting tumor cells and enhancing CAR-T cell-mediated cytotoxicity. Combined use of CAR-T and (CAR-)NK cells demonstrated increased persistence of immune cells as well as potent and sustained antitumor effects following MV infection.

This study underscores the potential of neoepitope-based CAR therapy for targeting solid tumor cells and highlights the potential synergistic effects of combining cell therapy with virotherapy for improved therapeutic outcomes.