Overcoming Chimeric Antigen Receptor (CAR) Modified T-Cell Therapy Limitations in Multiple Myeloma

Abstract

Multiple myeloma (MM) remains an incurable disease regardless of recent advances in the field. Therefore, a substantial unmet need exists to treat patients with relapsed/refractory myeloma. The use of novel agents such as daratumumab, elotuzumab, carfilzomib, or pomalidomide, among others, usually cannot completely eradicate myeloma cells. Although these new drugs have had a significant impact on the prognosis of MM patients, the vast majority ultimately become refractory or can no longer be treated due to toxicity of prior treatment, and thus succumb to the disease. Cellular therapies represent a novel approach with a unique mechanism of action against myeloma with the potential to defeat drug resistance and achieve long-term remissions. Genetic modification of cells to express a novel receptor with tumor antigen specificity is currently being explored in myeloma. Chimeric antigen receptor gene-modified T-cells (CAR T-cells) have shown to be the most promising approach so far. CAR T-cells have shown to induce durable complete remissions in other advanced hematologic malignancies like acute lymphocytic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). With this background, significant efforts are underway to develop CAR-based therapies for MM. Currently, several antigen targets, including CD138, CD19, immunoglobulin kappa (Ig-Kappa) and B-cell maturation antigen (BCMA), are being used in clinical trials to treat myeloma patients. Some of these trials have shown promising results, especially in terms of response rates. However, the absence of a plateau is observed in most studies which correlates with the absence of durable remissions. Therefore, several potential limitations such as lack of effectiveness, off-tumor toxicities, and antigen loss or interference with soluble proteins could hamper the efficacy of CAR T-cells in myeloma. In this review, we will focus on clinical outcomes reported with CAR T-cells in myeloma, as well as on CAR T-cell limitations and how to overcome them with next generation of CAR T-cells.

Harnessing the Immune System Against Multiple Myeloma: Challenges and Opportunities

“…A major determinant of successful CAR-T therapy is the identification of the appropriate antigen, which is uniquely and highly expressed by MM cells, in order to avoid adverse events. Specifically, the main challenge of CAR-T therapy is the appropriate target selection, which is critical in the management of on-target, off-tumor toxicity to avoid excess cytokine release after target recognition on non-malignant cells ( 79 ). Similarly, the major on-target, on-tumor adverse events of CAR-T cells include cytokine release syndrome (CRS) characterized by fever, hypotension and/or renal failure, as well as neurotoxicity ( 80 ); and are mainly due to the CAR-T cell activation and expansion and uncontrolled cytokine release ( 79 ).…”

“…Specifically, the main challenge of CAR-T therapy is the appropriate target selection, which is critical in the management of on-target, off-tumor toxicity to avoid excess cytokine release after target recognition on non-malignant cells ( 79 ). Similarly, the major on-target, on-tumor adverse events of CAR-T cells include cytokine release syndrome (CRS) characterized by fever, hypotension and/or renal failure, as well as neurotoxicity ( 80 ); and are mainly due to the CAR-T cell activation and expansion and uncontrolled cytokine release ( 79 ). Importantly, clinical experience has now shown that targeting interleukin-6 and use of dexamethasone can treat these toxicities ( 23 , 24 , 77 , 81 ).…”

“…Importantly, clinical experience has now shown that targeting interleukin-6 and use of dexamethasone can treat these toxicities ( 23 , 24 , 77 , 81 ). Nonetheless, several strategies have been developed to overcome these toxicities and include either modifications of CAR-T cell activation kinetics to maintain activation and cytokine release under a controlled level, or approaches to restrict the recognition of normal cells by optimizing CAR-T/tumor cells interaction ( 79 ). Among several antigens including CD19, CD138 and SLAMF7, B-cell maturation antigen (BCMA) represents the most promising to date due to its high selective expression on normal plasma and MM cells ( 82 , 83 ).…”

Chimeric Antigen Receptor T Cell Therapy and Its Significance in Multiple Myeloma

“…CD19 expression is usually seen in myeloma stem cells and is absent in mature plasma cells. Premature cells with CD19 expression are responsible for disease progression, drug resistance, relapse, and reduced survival in MM [ 25 ]. CD19 CAR T cells (CTL019) target both CD19 and stem-cell antigens that are co-expressed in myeloma propagating cells (MPC), resulting in a favorable outcome [ 26 ].…”

“…GPRC5D expression is independent of BCMA expression making anti-GPRC5D CAR T cells an alternative therapy in case of relapse after anti-BCMA therapy [ 34 ]. Table 1 summarizes the aforementioned target antigens and their role in CAR T cell therapy [ 8 , 11 , 15 - 17 , 20 - 21 , 25 , 29 , 32 , 34 ].…”