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

Abstract

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.

invariant Natural Killer T cell therapy as a novel therapeutic approach in hematological malignancies

“…Several studies demonstrated that CAR iNKT cells were effective against multiple myeloma and they prolonged survival in murine models. O'Neal and colleague showed that the co-administration of long-acting IL-7: rhIL-7-hyFc and CAR iNKT targeting BMCA improved anti-myeloma activity in a preclinical study ( 178 ). CAR iNKT cells were demonstrated to be safe and able to infiltrate tumors in patients with neuroblastoma in the recent update of a phase I clinical trial ( 8 ).…”

rhIL-7-hyFc and hIL-2/TCB2c combination promotes an immune-stimulatory tumor microenvironment that improves antitumor efficacy of checkpoint inhibitors

“…Preclinical studies with rhIL-7-hyFc have shown that rhIL-7-hyFc enhances the antitumor efficacy of several anticancer strategies, including chemotherapy, radiotherapy, checkpoint inhibitors and adoptive cell therapies in murine tumor models. [12][13][14][15] In this work, we sought to explore the synergistic efficacy and complementary mechanisms achieved through a dual combination therapy using rhIL-7-hyFc and hIL-2/ TCB2c. A comprehensive understanding of the distinct functions of rhIL-7-hyFc and hIL-2/TCB2c is essential for the design of effective immunotherapeutic strategies and for fully harnessing the immune system's potential in combating cancer.…”