K12-ligand-based CAR T cell therapy for CD7-positive T cell malignancies.

Chimeric antigen receptor (CAR)-based therapy is of interest for relapsed or refractory (r/r) T cell acute lymphoblastic leukemia (T-ALL) and T cell lymphomas. A prominent target antigen for this is the receptor CD7, which is expressed in ∼95% of T-ALL, ∼50% of peripheral T cell lymphomas, as well as 10% of acute myeloid leukemias. Here, we preclinically evaluated and compared CD7-targeted ligand K12-based CAR-T to an scFvCD7-based CAR-T construct. K12 CAR-T cells produced significantly higher interferon gamma (IFN-γ) after CD7 activation compared to scFv-CD7 CAR-T cells. Similarly, in a Jurkat(NFAT-luc) reporter cell line expressing the respective CAR, CD7-induced luminescence was significantly higher by the K12 CAR than the scFv-CD7 CAR. K12 CAR-T treatment selectively and specifically eliminated a panel of CD7-positive, but not CD7-negative, cell lines and eliminated acute-T-cell-leukemia-patient-derived and acute myeloid leukemia blasts in an effector-to-target ratio-dependent manner. Further, K12 CAR-T cells had prominent anti-leukemic activity in an intravenously (i.v.) injected Jurkat leukemia mouse model, with no detectable disease in three out of five mice treated with K12 CAR-T. Therefore, K12 CAR T cell therapy might be of use for the treatment of r/r patients with CD7-positive T cell leukemia/lymphoma and acute myeloid leukemia (AML).