Anti-myeloma efficacy of CAR-iNKT is enhanced with a long-acting IL-7, rhIL-7hyFc.

Multiple myeloma (MM), a malignancy of mature plasma cells, remains incurable. BCMA is the lead protein target for chimeric antigen receptor (CAR) therapy because of high expression on most MM with limited expression on other cell types resulting in favorable "on target-off tumor" toxicity. The response rate to autologous BCMA CAR-T therapy is high; however, it is not curative and is associated with risk of cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS). Outcomes in BCMA CAR-T treated patients may improve with allogeneic CAR-T which offer higher cell fitness and reduced time to treatment. However, to prevent risk of graft versus host disease (GvHD), allogenic BCMA CAR-T requires genetic deletion of the T-cell receptor (TCR) which has potential for unexpected functional or phenotype changes. Invariant natural killer T (iNKT) cells have an invariant TCR that do not cause GvHD and as a result can be used in allogeneic setting without need for TCR gene editing. We demonstrate significant anti-myeloma activity of BCMA CAR-iNKT in a xenograft mouse model of myeloma. We found that a long-acting IL-7, rhIL-7-hyFc significantly prolonged survival and reduced tumor burden in BCMA CAR-iNKT treated mice in both a primary and a re-challenge setting. Further, in CRS in vitro assays, CAR-iNKT induced less IL-6 than CAR-T, suggesting reduced likelihood for CAR-iNKT cell therapy to induce CRS in patients. These data suggest BCMA CAR-iNKT are potentially a safer, effective alternative to BCMA-CAR-T and BCMA CAR-iNKT efficacy is further potentiated with rhIL-7-hyFc.