There are promising signs that chimeric antigen receptor (CAR) T-cell therapies might lead to meaningful advances in the therapy of multiple myeloma. However, investigators will first need to clear a number of key hurdles.
Chimeric antigen receptor (CAR) gene-modified T-cell therapy appears to have considerable promise for patients with multiple myeloma (MM), but the therapy is subject to a number of limitations, according to a new review article.
In the study, published in the journal Frontiers in Immunology, corresponding author Jose Antonio Pérez-Simón, MD, PhD, of Hospital Universitario Virgen del Rocío, in Spain, and colleagues discussed the latest research and the next steps forward in the development of the therapy.
A number of important therapeutic agents, including immunomodulatory drugs, have led to significant advances in the care of patients with MM. Yet, the investigators noted that the disease remains incurable, with patients subject to relapses, and lesser results in subsequent therapeutic efforts. In short, Pérez-Simón and colleagues said, new therapies are needed.
CAR T-cell therapy has shown encouraging results. Two anti-CD19 CAR T-cell therapies have been approved for the treatment of acute lymphoblastic leukemia (ALL) and diffuse large B cell lymphoma, and products are now in development to treat MM.
“B-cell maturation antigen (BCMA) is the predominantly used target against MM based on its high expression in the surface of malignant plasma cells and restricted expression in normal tissues/cells except for a low-level expression in mature B-cells,” the authors said. They said other potential targets being explored include CD38, CD138, CD19, and immunoglobulin kappa light chain (Ig-Kappa). In the paper, Pérez-Simón and co-authors outline the results of early efforts at those targets. The efforts generally have shown high response rates, but have failed to achieve durable responses, and have also been shown to have limitations such as lack of effectiveness, toxicities, and antigen loss, among others, the authors reported.
Toxicities can come in 1 of 2 ways. On-target, on-tumor toxicities occur when T-cells are recognized and activated against tumor cells and then are followed by the uncontrolled release of cytokines. On-target, off-tumor toxicities occur due to binding between a CAR T-cell and its target antigen expressed in normal cells. Novel approaches are currently under investigation to mitigate these toxicities.
One area of notable advancement, the authors reported, is increasing T-cell persistence by using less differentiated T-cells at higher frequencies, including
naive T-cells (TN), and stem cell memory T-cells (TSCM).
“Compared with conventional CAR T-cell products, less-differentiated CAR T-cells have shown a greater proliferation and killing capacity in preclinical studies,” Pérez-Simón and colleagues reported.
Looking forward, the authors said CAR T-cell therapy is likely to become a key therapeutic strategy in patients with relapsed/refractory MM.
“Development of novel strategies to increase long-term responses by combining CAR T-cell therapy with different drugs which increase antigen density specifically in myeloma cells avoiding antigen escape and toxicities is mandatory,” they wrote.
Another priority should be finding an effective bridging therapy for refractory patients who have undergone multiple previous lines of treatment as they await the generation of CAR T-cell products. It may even be possible to achieve better responses by initiating CAR T-cell therapy in earlier lines of treatment, the investigators said.
The authors concluded by saying that while many issues with CAR T-cell therapy in MM remain unresolved, the therapy’s full potential remains on the horizon.
García-Guerrero E, Sierro-Martínez B, Pérez-Simón JA. Overcoming chimeric antigen receptor (CAR) modified t-cell therapy limitations in multiple myeloma. Front Immunol. 2020;11:1128. Published 2020 Jun 5. doi:10.3389/fimmu.2020.01128