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.
Highlights
Multiple myeloma (MM) is an hematological malignancy characterized by the clonal proliferation of malignant plasma cells [1]
Fundamental modifications in chimeric antigen receptors (CARs) design can be a promising strategy to reduce CAR T-cell toxicities. It is still not clear the influence of soluble antigens in CAR T-cell therapy, the existence of soluble proteins in serum of myeloma patients is being actively discussed as an obstacle for this immunotherapy
The selection of the antigenbinding domain is a key factor in CAR design to overcome abrogation of CAR T-cells by soluble protein
Summary
Multiple myeloma (MM) is an hematological malignancy characterized by the clonal proliferation of malignant plasma cells [1]. A fourth generation CAR T-cell product targeting multiple antigens, including CD38, and expressing simultaneously interleukin-7 (IL-7) and chemokine (C-C motif) ligand 19 (CCL19), is under clinical investigation for the treatment of relapsed/refractory MM patients (NCT03778346). Results from these CD38-targeted CAR T therapies have not been published to date. CD19 is the most widely studied target antigen for the development of CAR T therapies with two products (Kymriah and Yescarta) approved for the treatment of ALL and DLBCL, and multiple published and ongoing clinical trials [43]. CD19 expression in myeloma cells was assessed by flow cytometry and, as expected, the predominant myeloma population was Frontiers in Immunology | www.frontiersin.org
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
