Adoptive Cellular Therapy for Multiple Myeloma Using CAR- and TCR-Transgenic T Cells: Response and Resistance

Abstract

Despite the substantial improvement of therapeutic approaches, multiple myeloma (MM) remains mostly incurable. However, immunotherapeutic and especially T cell-based approaches pioneered the therapeutic landscape for relapsed and refractory disease recently. Targeting B-cell maturation antigen (BCMA) on myeloma cells has been demonstrated to be highly effective not only by antibody-derived constructs but also by adoptive cellular therapies. Chimeric antigen receptor (CAR)-transgenic T cells lead to deep, albeit mostly not durable responses with manageable side-effects in intensively pretreated patients. The spectrum of adoptive T cell-transfer covers synthetic CARs with diverse specificities as well as currently less well-established T cell receptor (TCR)-based personalized strategies. In this review, we want to focus on treatment characteristics including efficacy and safety of CAR- and TCR-transgenic T cells in MM as well as the future potential these novel therapies may have. ACT with transgenic T cells has only entered clinical trials and various engineering strategies for optimization of T cell responses are necessary to overcome therapy resistance mechanisms. We want to outline the current success in engineering CAR- and TCR-T cells, but also discuss challenges including resistance mechanisms of MM for evading T cell therapy and point out possible novel strategies.

Immunotherapy for the treatment of multiple myeloma

“…TCR-modified T cells (TCR T cells) are native T cells with edited TCRs to recognize a specific tumor antigen presented on the major histocompatibility complex ( 85 ). While CAR T cells exclusively bind cell surface proteins, TCR T cells allow for targeting of both intracellular and extracellular antigens.…”

“…While CAR T cells exclusively bind cell surface proteins, TCR T cells allow for targeting of both intracellular and extracellular antigens. However, the major barrier to development is identification and generalizability of appropriate targets, as they are specific to each patient’s tumor antigens and HLA profile ( 85 ). In multiple myeloma, TCR T cells have been developed primarily targeting cancer testis antigens, such as NY-ESO-1, which is overexpressed in about one third of myeloma patients ( 86 ).…”

Harnessing the T Cell to Treat Multiple Myeloma: Dawn of a New Therapeutic Paradigm

“…While CAR T cell therapy has now been approved in MM, development is ongoing and other modalities are still being explored. For example, TCR-engineered cells are patient-derived T cells modified to target a specific tumor-associated antigen or neoantigen (102). Unlike CARs, whose artificial receptors allow efficacy independent of MHC presentation, which is often downregulated by immunosuppressive tumor cells, TCR-engineered T cells rely on native TCR biology (103).…”

“…Unlike CARs, whose artificial receptors allow efficacy independent of MHC presentation, which is often downregulated by immunosuppressive tumor cells, TCR-engineered T cells rely on native TCR biology (103). Production of TCR-engineered T cells is a similar process to CAR T production, expensive, and can take approximately 4-6 weeks to produce (102,104). TCR-engineered T cells have shown early promise in leukemia and are being evaluated in a few MM clinical trials in a small number of patients (102,(105)(106)(107).…”

“…Production of TCR-engineered T cells is a similar process to CAR T production, expensive, and can take approximately 4-6 weeks to produce (102,104). TCR-engineered T cells have shown early promise in leukemia and are being evaluated in a few MM clinical trials in a small number of patients (102,(105)(106)(107). One study, in which TCRs are engineered to target a shared sequence between antigens New York esophageal squamous cell carcinoma-1 (NY-ESO-1) and L-antigen family member 1 (LAGE-1), has reported an objective response rate of 80% at day 42 and median progression free survival of 13.5 months in 25 relapsed/refractory myeloma patients with at least one adverse cytogenetic abnormality (107).…”