CAR-T cell therapy in multiple myeloma: Current limitations and potential strategies

Abstract

Over the last decade, the survival outcome of patients with multiple myeloma (MM) has been substantially improved with the emergence of novel therapeutic agents, such as proteasome inhibitors, immunomodulatory drugs, anti-CD38 monoclonal antibodies, selective inhibitors of nuclear export (SINEs), and T cell redirecting bispecific antibodies. However, MM remains an incurable neoplastic plasma cell disorder, and almost all MM patients inevitably relapse due to drug resistance. Encouragingly, B cell maturation antigen (BCMA)-targeted chimeric antigen receptor T (CAR-T) cell therapy has achieved impressive success in the treatment of relapsed/refractory (R/R) MM and brought new hopes for R/R MM patients in recent years. Due to antigen escape, the poor persistence of CAR-T cells, and the complicated tumor microenvironment, a significant population of MM patients still experience relapse after anti-BCMA CAR-T cell therapy. Additionally, the high manufacturing costs and time-consuming manufacturing processes caused by the personalized manufacturing procedures also limit the broad clinical application of CAR-T cell therapy. Therefore, in this review, we discuss current limitations of CAR-T cell therapy in MM, such as the resistance to CAR-T cell therapy and the limited accessibility of CAR-T cell therapy, and summarize some optimization strategies to overcome these challenges, including optimizing CAR structure, such as utilizing dual-targeted/multi-targeted CAR-T cells and armored CAR-T cells, optimizing manufacturing processes, combing CAR-T cell therapy with existing or emerging therapeutic approaches, and performing subsequent anti-myeloma therapy after CAR-T cell therapy as salvage therapy or maintenance/consolidation therapy.

Keywords: CAR-T cell exhaustion; CAR-T cell therapy; antigen escape; combinatorial therapy; immunosuppressive tumor microenvironment; relapse.

Figure 1

Potential therapeutic targets in multiple myeloma, including BCMA, CD138, CD38, CD19, GPRC5D, SLAMF7, APRIL, TACI, CD229, CD56, CD44v6, integrin β7, MUC1, FcRH5, Kappa light chain, CCR10, and NKG2D ligands.

Figure 2

The complexity of bone marrow microenvironment in MM. Multiple immunosuppressive cells are accumulated in bone marrow microenvironment and exhibit tumor supportive properties, including osteoclasts (OCs)such as osteoclasts (OCs), myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), regulatory B cells(Bregs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), and bone marrow stromal cells (BMSCs). These cells interact with surrounding MM cells through direct cell-to-cell contact or producing soluble factors, and then promote the proliferation, immune escape of MM cells as well as Drug resistance. Osteoclasts (OCs) are remarkably increased in the bone marrow microenvironment of MM patients and involved in the occurrence and development of myeloma bone disease. In addition, they produce APRIL, BAFF and IL-6 to promote MM cell proliferation and survival. Meanwhile, OCs act as antigen-presenting cells (APCs) in the bone marrow and exhibit immunosuppressive properties through up-regulating the expression of immune checkpoint molecules, such as PD-L1, CD38 and galectin 9. In turn, MM cells could promote bone resorption activity of OCs through the secretion of IL-6 and RANKL. Immunosuppressive Tregs and MDSCs, which express several immune inhibitory molecules, such as PD1, TIM3, and CD38, are significantly increased in MM bone marrow microenvironment and secrete TGF-β and IL-10 to promote the evasion of MM cells from immune surveillance. TAMs apparently infiltrate the bone marrow, and they promote angiogenesis and induce immune escape and drug resistance of MM cells. In addition, TANs also play an immunosuppressive role in MM bone marrow microenvironment through the release of neutrophil extracellular traps (NETs), which could contribute to tumor-associated thrombosis and tumor metastasis. Moreover, BMSCs show an inflammatory phenotype in MM microenvironment. On the one hand, they secrete several cytokines, such as APRIL, BAFF, IL-6, and RANKL; On the other hand, they induce the expression of anti-apoptotic proteins in MM cells, eventually promoting MM cell proliferation and drug resistance. Additionally, plasmacytoid dendritic cells (pDCs), NK cells, and NKT cells exhibit the decreased anti-myeloma activities in bone marrow microenvironment.

Figure 3

The interactions among CAR-T cells, tumor cells and immunosuppressive tumor microenvironment. On the one hand, tumor cells and immunosuppressive cells in bone marrow microenvironment induce CAR-T cell exhaustion through direct cell-to-cell contact, such as PD-1/PDL-1 pathway and Fas/FasL pathway. Immunosuppressive cells could also release immune inhibitory cytokines such as IL-10 and TGF-β to impact the cytotoxicity of CAR-T cells and promote the generation of Treg cells. In addition, BMSCs could protect MM cells against CAR-T cells through the up-regulation of anti-apoptosis proteins in MM cells.