Chimeric antigen receptor (CAR) T-cell therapy remains limited to select centers that can carefully monitor adverse events. To broaden use of CAR T cells in community clinics and in a frontline setting, we developed a novel CD8+ CAR T-cell product, Descartes-08, with predictable pharmacokinetics for treatment of multiple myeloma. Descartes-08 is engineered by mRNA transfection to express anti-BCMA CAR for a defined length of time. Descartes-08 expresses anti-BCMA CAR for 1 week, limiting risk of uncontrolled proliferation; produce inflammatory cytokines in response to myeloma target cells; and are highly cytolytic against myeloma cells regardless of the presence of myeloma-protecting bone marrow stromal cells, exogenous a proliferation-inducing ligand, or drug resistance including IMiDs. The magnitude of cytolysis correlates with anti-BCMA CAR expression duration, indicating a temporal limit in activity. In the mouse model of aggressive disseminated human myeloma, Descartes-08 induces BCMA CAR-specific myeloma growth inhibition and significantly prolongs host survival (p < 0.0001). These preclinical data, coupled with an ongoing clinical trial of Descartes-08 in relapsed/refractory myeloma (NCT03448978) showing preliminary durable responses and a favorable therapeutic index, have provided the framework for a recently initiated trial of an optimized/humanized version of Descartes-08 (i.e., Descartes-11) in newly diagnosed myeloma patients with residual disease after induction therapy.
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The authors acknowledge the technical assistance from the flow cytometry facility at Dana-Farber Cancer Institute (DFCI). We thank Dr. Jiye Liu, Dr. Wenjuan Yang, and all other lab members, as well as the clinical research coordinators at the Jerome Lipper Multiple Myeloma Center and the LeBow Institute for Myeloma Therapeutics of the DFCI, for support and help in providing primary tumor specimens for this study.
This work was supported in part by grants from the National Institutes of Health Specialized Programs of Research Excellence (SPORE) P50 CA100707, P01CA155258, RO1 CA 207237, and RO1 CA 050947. This work was supported in part by Dr Miriam and Sheldon G. Adelson Medical Research Foundation and the Riney Family Multiple Myeloma Initiative. Dr. Kenneth C. Anderson is an American Cancer Society Clinical Research Professor.
Conflict of interest
MK, YZ, and CAS are employees of and hold stock interest in Cartesian Therapeutics. NM serves on advisory boards to Millennium-Takeda, Celgene, and Novartis. KCA serves on advisory boards Celgene, Millennium-Takeda, Bristol-Myers Squibb, Gilead Sciences, Janssen, and Sanofi-Aventis and is a Scientific founder of OncoPep and C4 Therapeutics. All other authors declare no competing financial interests.
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Lin, L., Cho, S., Xing, L. et al. Preclinical evaluation of CD8+ anti-BCMA mRNA CAR T cells for treatment of multiple myeloma. Leukemia (2020). https://doi.org/10.1038/s41375-020-0951-5