Open AccessPreclinical evaluation of CD8+ anti-BCMA mRNA CAR T cells for treatment of multiple myeloma
Author(s) -
Liang Lin,
ShihFeng Cho,
Lijie Xing,
Kenneth Wen,
Yuyin Li,
Tengteng Yu,
Phillip Hsieh,
Hailin Chen,
Metin Kurtoğlu,
Yi Zhang,
Charles A. Stewart,
Nikhil C. Munshi,
Kenneth C. Anderson,
Yu Tzu Tai
Publication year - 2020
Publication title -
leukemia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.539
H-Index - 192
eISSN - 1476-5551
pISSN - 0887-6924
DOI - 10.1038/s41375-020-0951-5
Subject(s) - multiple myeloma , medicine , stromal cell , cd8 , chimeric antigen receptor , minimal residual disease , cancer research , bone marrow , immunology , cytolysis , cytotoxic t cell , oncology , t cell , antigen , biology , immune system , in vitro , biochemistry
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.