Combining BCMA-targeting CAR T cells with TCR-engineered T-cell therapy to prevent immune escape of multiple myeloma
Tassilo L A Wachsmann, Miranda H. Meeuwsen, Dennis F.G. Remst, Karen Buchner, Anne K. Wouters, Renate S. Hagedoorn, J.H. Frederik Falkenburg, Mirjam H.M. Heemskerk
Abstract
Although initially effective, patients frequently relapse from B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor (CAR) T-cell therapy and survival after relapse is limited. [1][2]2][3][4] Part of relapses after CAR T-cell therapy can be attributed to the heterogeneity of multiple myeloma (MM). 5BCMA is often nonuniformly expressed within tumors, 6 allowing for CAR-mediated immunoediting and outgrowth of BCMA low or BCMA (-/-) MM cells. [7][8]8][9] The efficacy of BCMA-targeting CAR T cells may further be compromised by BCMA shedding and trogocytosis. 10,11As an attempt to design a potentially curative approach, strategies targeting additional MM antigens are currently being developed. 12Other surface antigens targetable by CARs include SLAMF7 13 and CD38, 14 but their expression on non-B-cell lineage cells potentially compromises their safety profile.G protein-coupled receptor class C group 5 member D (GPRC5D) is an alternative surface antigen with a safe expression profile, and GPRC5Dtargeting CAR T cells have recently entered the clinical stage. 15,16Although GRPC5D-targeting CAR T cells induced clinical responses, most patients eventually relapsed.Similar to BCMA-targeting CAR T-cell therapy, relapse was associated with the loss of GPRC5D expression.