Preclinical Evaluation of CD8+ Anti-Bcma mRNA CAR T-Cells for the Control of Human Multiple Myeloma

Chimeric antigen receptor (CAR) T cells targeting BCMA are positioned to transform treatment of multiple myeloma (MM), and virally-generated anti-BCMA CAR T cells have shown impressive early stage clinical results. However, the safety risk/benefit, manufacturing constraints, and relevant patient populations of viral anti-BCMA CAR T have yet to be fully defined. Here we present preclinical characterization of an autologous mRNA-generated anti-BCMA CAR T cell product (Descartes-08) designed to reduce safety risk and broaden the fitness-for-use of anti-BCMA CAR T cell therapy. Descartes-08 are autologous CD8+ T cells that express anti-BCMA CAR on up to 90% of cells with duration of CAR expression for several days with subsequent reduction in expression to background approximately 1 week after their generation. The manufacturing process is clinically scalable with high purity and viability of Descartes-08 following cryopreservation. Descartes-08 undergo cytotoxic degranulation and produce cytokines IFNg, TNFα, IL-2, in response to multiple BCMA-expressing multiple myeloma target cell lines in an effector-to-target-ratio-dependent manner. Furthermore, Descartes-08 kills MM lines that are both resistant and sensitive to lenalidomide and pomalidomide, and/or MM cells that are grown in the presence of bone marrow stromal cells that clinically support MM survival. Moreover, Descartes-08 are highly cytotoxic against MM cells from both newly-diagnosed and relapsed patients. The magnitude of cytolytic and cytokine responses correlates with duration of anti-BCMA CAR expression and declines after 4 days, indicating a temporal limit in activity that is predicted to dramatically decrease the risk of severe cytokine release syndrome. In a mouse model of disseminated human MM, Descartes-08 shows CAR-specific suppression of myeloma that is maintained throughout the duration of treatment. Taken together, these results illustrate features of RNA-generated anti-BCMA CAR T cells that promise key clinical advantages, thereby supporting ongoing clinical development of Descartes-08 for treatment of MM (NCT03448978).