Potent anti‐leukemia activities of humanized CD19‐targeted Chimeric antigen receptor T (CAR‐T) cells in patients with relapsed/refractory acute lymphoblastic leukemia

Abstract

Chimeric antigen receptor T (CAR-T) cell therapy has shown promising results for relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL). The immune response induced by murine single-chain variable fragment (scFv) of the CAR may limit CAR-T cell persistence and thus increases the risk of leukemia relapse. In this study, we developed a novel humanized scFv from the murine FMC63 antibody. A total of 18 R/R ALL patients with or without prior murine CD19 CAR-T therapy were treated with humanized CD19-targeted CAR-T cells (hCART19s). After lymphodepletion chemotherapy with cyclophosphamide and fludarabine, the patients received a single dose (1 × 10 /kg) of autologous hCART19s infusion. Among the 14 patients without previous CAR-T therapy, 13 (92.9%) achieved complete remission (CR) or CR with incomplete count recovery (CRi) on day 30, whereas 1 of the 3 patients who failed a second murine CAR-T infusion achieved CR after hCART19s infusion. At day 180, the overall and leukemia-free survival rates were 65.8% and 71.4%, respectively. The cumulative incidence of relapse was 22.6%, and the nonrelapse mortality rate was 7.1%. During treatment, 13 patients developed grade 1-2 cytokine release syndrome (CRS), 4 patients developed grade 3-5 CRS, and 1 patient experienced reversible neurotoxicity. These results indicated that hCART19s could induce remission in patients with R/R B-ALL, especially in patients who received a reinfusion of murine CAR-T.

Systematic testing and specificity mapping of alloantigen-specific chimeric antigen receptors in T regulatory cells

“…Mouse-derived CARs can be highly effective, but T cells expressing humanized or fully human CARs have increased cell persistence and efficacy (40), and decreased side effects (17,(19)(20)(21)(22)41). To date, there has been no comprehensive investigation of the applicability of bioinformatic methods for humanizing mAbs for use in CAR constructs.…”

T-cells “à la CAR-T(e)” – Genetically engineering T-cell response against cancer

“…While one may surmise that humanization could harm CAR structure and function, the function of selected humanized or fully-human scFv was shown to be on par or even superior to their murine counterparts [171]. Johnson et al, successfully targeted EGFRvIII with a humanized scFv which was shown functionally superior to the murine 3C10 scFv [172].…”

CD22 CAR T-cell therapy in refractory or relapsed B acute lymphoblastic leukemia

“…Loss or mutation of CD19 are frequently observed, which hamper the secondary application of CD19 CAR T-cell therapy [4,[10][11][12][13][14]. Even in some treatment-failure cases which preserves high CD19 expression on leukemia cells, a secondary infusion of CD19 CAR T-cells has not been reproducibly successful, which may be partly due to immune-mediated clearance of murine-derived CARs [15][16][17]. Therefore, new therapeutic methods are required for r/r patients who have failed previous CD19 CAR T-cell therapy.…”