Engineering TCR-directed T-cells for the treatment of multiple myeloma

Multiple myeloma (MM) is a virtually incurable plasma cell malignancy characterized by malignant cells that expand within the tumor-permissive bone marrow (BM) microenvironment. Novel strategies are urgently needed to improve the outcomes of patients with difficult-to-treat and therapy-refractory disease. The ability to genetically manipulate T-cells and the introduction of adoptive cellular therapies (ACTs) has improved the treatment of relapsed and/or refractory (RR)MM. Emerging evidence supports the efficacy of ACTs as early lines of cancer treatment, potentially even as an alternative to autologous hematopoietic stem cell transplantation. Chimeric antigen receptor (CAR) T-cell therapies based upon genetically engineered patient-derived T-cells are utilized in routine clinical practice, however severe toxicities, therapeutic resistance, exorbitant costs, a cumbersome manufacturing process and production logistics limits their broader application. Tumor-infiltrating lymphocytes (TILs) can also mediate tumor regression and lead to durable responses, but wider efficacy is restricted by limited accessibility, reduced proliferative capacity and low effector function. In this context, autologous T-cells engineered to express T-cell receptors (TCRs) represent an intriguing option to improve MM treatment. Immunoproteasomes represent an essential cornerstone of adaptive immunity and are required for the efficient processing of antigenic peptides presented by MHC class I (MHC-I) molecules to cytotoxic CD8⁺ T-lymphocytes (CTLs). Recent studies have demonstrated that immunoproteasome activation increases the presentation of tumor-specific neo-antigens, thereby offering a potential strategy to improve the antimyeloma effects of T-cell-mediated immunotherapies. Here, we discuss advantages and strategies that support the administration of TCR-engineered T-cells for the treatment of MM. This review focuses on the role of immunoproteasome dependent antigen processing in shaping the myeloma immunopeptidome and enabling TCR-based immunotherapy. We discuss how modulation of neoantigen presentation may inform the design of TCR-engineered T cells and related immunotherapeutic strategies for MM.