Updates on CAR T cell therapy in multiple myeloma

Abstract

Multiple myeloma (MM) is a hematological cancer characterized by the abnormal proliferation of plasma cells. Initial treatments often include immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies (mAbs). Despite salient progress in diagnosis and treatment, most MM patients typically have a median life expectancy of only four to five years after starting treatment. In recent developments, the success of chimeric antigen receptor (CAR) T-cells in treating B-cell malignancies exemplifies a new paradigm shift in advanced immunotherapy techniques with promising therapeutic outcomes. Ide-cel and cilta-cel stand as the only two FDA-approved BCMA-targeted CAR T-cells for MM patients, a recognition achieved despite extensive preclinical and clinical research efforts in this domain. Challenges remain regarding certain aspects of CAR T-cell manufacturing and administration processes, including the lack of accessibility and durability due to T-cell characteristics, along with expensive and time-consuming processes limiting health plan coverage. Moreover, MM features, such as tumor antigen heterogeneity, antigen presentation alterations, complex tumor microenvironments, and challenges in CAR-T trafficking, contribute to CAR T-cell exhaustion and subsequent therapy relapse or refractory status. Additionally, the occurrence of adverse events such as cytokine release syndrome, neurotoxicity, and on-target, off-tumor toxicities present obstacles to CAR T-cell therapies. Consequently, ongoing CAR T-cell trials are diligently addressing these challenges and barriers. In this review, we provide an overview of the effectiveness of currently available CAR T-cell treatments for MM, explore the primary resistance mechanisms to these treatments, suggest strategies for improving long-lasting remissions, and investigate the potential for combination therapies involving CAR T-cells.

Keywords: Antigen heterogeneity; CAR T-cell; Combination therapy; Multiple myeloma; Toxicities; Tumor microenvironment.

Fig. 1

Overview of Effectiveness and Challenges in CAR T-cell Therapy for Multiple Myeloma. A Manufacturing and Administration of CAR T-cells: This section highlights strategies for optimizing production and functionality, innovations in genetic modification, allogeneic CAR T-cell development, and early therapy implementation to ease healthcare system burdens. B Multiple myeloma Characteristics in CAR T-cell Therapy: It addresses the challenges posed by the heterogeneous nature of the disease and the immunosuppressive tumor microenvironment. Solutions include expanding antigen targets, using gamma-secretase inhibitors, surmounting immune checkpoints, and improving CAR T-cell trafficking. C Clinical Considerations and Safety Management: This part emphasizes the importance of managing CAR T-cell toxicity and enhancing safety features. It suggests combining pharmacological agents and supplementary treatments to improve overall therapy outcomes

Fig. 2

BCMA Transfer Mechanism in CAR T Cell Therapy. A Direct Contact: CAR T cells engineered to target BCMA form an immunological synapse with tumor cells, facilitating molecular exchange. B Trogocytosis: Membrane fragments containing BCMA are transferred from tumor cells to CAR T cells during synapse formation via trogocytosis, enhancing T cell activation. C BCMA Recognition: Transferred BCMA molecules are recognized by CARs on T cell surfaces, initiating T cell activation and tumor cell destruction. D Implications: While BCMA transfer boosts T cell killing, trogocytosis may inadvertently lead to fratricide, reducing therapy efficacy

Fig. 3

APRIL-based CAR T-cells. A APRIL and BAFF bind to BAFF-R, TACI, and BCMA receptors which leads to the expression of PDL-1 on the cancer cell and induces T cell exhaustion usingof PD-1 on the T-cell surface. B APRIL-base CARs can bind to the BCMA and TACI expressing multiple myeloma cells and inducing tumor shrinkage. The APRIL CAR should create a trimer protein to bind to the receptor, similar to APRIL binding to its target as a trimer protein. However, in TRiPIL CAR, an APRIL trimer protein serves as the binding domain so that oligomerization is not required to bind to receptors. TriPIL CAR is a superior choice for targeting MM cells

Fig. 4

Managing tumor heterogeneity. A VHH-based CAR targeting two epitopes of the same antigen. B CAR T-cell targeting novel antigens like SLAMF7 C. Co-infusion of two distinct CAR T-cells targeting different antigens. D CAR T-cell expression two distinct CARs targeting different antigens. E Bispecific CAR T-cells targeting two different antigens. Recognition of each target antigen leads to T-cell activation and tumor shrinkage

Fig. 5

Approaches to mitigating the toxicity linked with CAR T-cell therapy directly. A The HSV-TK safety switch and its mode of action. Ganciclovir (GCV) administration leads to HSV-TK gene activation and its conversion to GCV-monophosphate (MP) and eventually further phosphorylated to convert to a toxic GCV-trisphosphate (TP). GCV-TP disrupts DNA synthesis, selectively eliminating CAR T cells. B The inducible caspase 9 (iCasp9) suicide switch and its mechanism. Dimerizing drug administration induces iCasp molecules (FK506) to form dimers, activating downstream apoptotic cascades, and resulting in CAR T cell death. C Examples of mAb-based safety switches and their functions. Co-expression of CAR and cell surface proteins such as EGFRt and CD20 facilitates selective CAR T cell elimination through pharmaceutical-grade mAbs like Cetuximab and Rituximab, which engage immune effector cells or complement fixation cells via mechanisms such as antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) upon specific mAb introduction