Clinical and Translational Resource and Technology Insights A chimeric antigen receptor uniquely recognizing MICA/B stress proteins provides an effective to solid tumors

Background: The advent of chimeric antigen receptor (CAR) T cell ther-apies has transformed the treatment of hematological malignancies; however, broader therapeutic success of CAR T cells has been limited in solid tumors because of their frequently heterogeneous composition. Stress proteins in the MICA and MICB (MICA/B) family are broadly ex-pressed by tumor cells following DNA damage but are rapidly shed to evade immune detection. Methods: We have developed a novel CAR targeting the conserved a3 domain of MICA/B (3MICA/B CAR) and incorporated it into a multi-plexed-engineered induced pluripotent stem cell (iPSC)-derived natu-ral killer (NK) cell (3MICA/B CAR iNK) that expressed a shedding -resis-tant form of the CD16 Fc receptor to enable tumor recognition through two major targeting receptors. Findings: We demonstrated that 3MICA/B CAR mitigates MICA/B shedding and inhibition via soluble MICA/B while simultaneously exhib-iting antigen-specific anti-tumor reactivity across an expansive library of human cancer cell lines. Pre-clinical assessment of 3MICA/B CAR iNK cells demonstrated potent antigen-specific in vivo cytolytic activity against both solid and hematological xenograft models, which was further enhanced in combination with tumor-targeted therapeutic anti-bodies that activate the CD16 Fc receptor. Conclusions: Our work demonstrated 3MICA/B CAR iNK cells to be a promising multi-antigen-targeting cancer immunotherapy approach intended for solid tumors. Funding: Funded by Fate Therapeutics and NIH (R01CA238039).