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Merck
  • Preclinical evaluation of CD8+ anti-BCMA mRNA CAR T cells for treatment of multiple myeloma.

Preclinical evaluation of CD8+ anti-BCMA mRNA CAR T cells for treatment of multiple myeloma.

Leukemia (2020-07-08)
Liang Lin, Shih-Feng Cho, Lijie Xing, Kenneth Wen, Yuyin Li, Tengteng Yu, Phillip A Hsieh, Hailin Chen, Metin Kurtoglu, Yi Zhang, C Andrew Stewart, Nikhil Munshi, Kenneth C Anderson, Yu-Tzu Tai
摘要

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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Sigma-Aldrich
白细胞介素-2 人, IL-2, recombinant, expressed in E. coli, lyophilized powder, suitable for cell culture
Sigma-Aldrich
BCMA human, recombinant, expressed in E. coli, ≥98% (SDS-PAGE), ≥98% (HPLC), suitable for cell culture
Sigma-Aldrich
吖啶橙 盐酸盐 溶液, ≥95.0% (HPLC), 10 mg/mL in H2O
Sigma-Aldrich
人类 TNFRSF17 ELISA 试剂盒