Preclinical development of a next-generation CAR-T cell therapy for multiple myeloma.

In Belgium, two patients receive the diagnosis of multiple myeloma (MM) each day. Despite considerable therapeutic advances over the past decades, MM remains incurable. Drug resistance often leads to refractory disease and relapses. Therefore, there is an urgent need for novel treatment methods for MM. Immunotherapy has become an important asset in the treatment of various cancers, including MM. Chimeric antigen receptor (CAR)-T cell therapy has attracted much attention in recent years, most notably in B cell malignancies (BCMA). CAR-T cells are T lymphocytes that are genetically modified, predominantly by lentiviral or retroviral transduction, to express a CAR that can recognize virtually any surface epitope expressed on a cell. Results of early-phase clinical trials in MM, mainly targeted towards B cell maturation antigen, were promising with high clinical response rates, including complete responses. Unfortunately, responses are usually temporary and relapses have been described due to loss of BCMA expression following CAR-T therapy. In addition, serious adverse events that usually require hospitalization such as cytokine release syndrome are frequently reported. Hence, there is a general consensus that CAR-T cell-based immunotherapy can only become a "viable" therapeutic option in the future if these 3 challenges are adequately addressed: improving efficacy (challenge 1) while reducing toxicity (challenge 2) and costs (challenge 3).The general objective of this project is to develop a next-generation CAR-T cell treatment for multiple myeloma (MM). The hypothesis of this study is that targeting multiple antigens will broaden the anti-tumor immune response and, thus, enhance efficacy of the treatment by reducing the chance of immune escape. Incorporation of immune checkpoint downregulation and enhancement of their co-stimulatory and migratory function can potentially further augment the anti-tumoral properties of the CAR-T cells. Considering potential adverse events, we envisage mRNA electroporation and the use of gamma/delta (γδ) T cells as improvements to the safety and overall costs of CAR-T cell therapy. In summary, we envision a more effective, safer and economically viable CAR-T cell therapy.

Keywords:CHIMERIC ANTIGEN RECEPTORS, IMMUNOTHERAPY, MULTIPLE MYELOMA

Disciplines:Hematology, Applied immunology, Cancer therapy