Enhancing the iNKT cell immunotherapy platform by combining optimised CAR endodomains with novel iNKT engagers

Their distinct biological features including their stereotypical CD1d-restricted TCR and ability to swiftly bridge and activate innate and adoptive T cell immunity underpin their potential for off-the-shelf therapy and pleiotropic anti-tumor effects. Accordingly, chimeric antigen receptor (CAR)-iNKT outperform CAR-T counterparts in preclinical models of blood cancers including myeloma and solid tumors.

However, optimal designs of CARs that would maximise the activity of CAR-iNKT against myeloma and their combination with orthogonal therapeutic modalities that would expand their anti-myeloma potency have not been investigated. Here, we find that underpinned by enhanced avidity, amongst five different 2nd and 3rd generation CAR endodomains, BCMA CD28z CAR-iNKT exert the highest anti-myeloma activity in vivo. Increased avidity and anti-myeloma activity of CD28z CAR-iNKT is dependent on a novel cross talk between plexin D1 (PLXND1) on CAR-iNKT and semaphorin 4A (SEMA4A) on myeloma cells in vivo as well as in vitro.