Antigen loss a primary cause of CAR T cell resistance

Spiegel JY, Patel S, Muffly L, et al. CAR T Cells With Dual Targeting of CD19 and CD22 in Adult Patients With Recurrent or Refractory B Cell Malignancies: A Phase 1 Trial. Nature Medicine. 2021; 27: 1419 (doi: 10.1038/s41591-021-01436-0).

Antigen loss is a significant cause of CAR T cell resistance, research shows. A phase 1 clinical trial sought to prevent relapse with CD19- or CD19lo disease by testing bispecific chimeric antigen receptor (CAR) T cells that targeted CD19 and/or CD22 proteins in 38 patients with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) and large B cell lymphoma (LBCL). Overall, the primary endpoints — manufacturing feasibility and safety — were met, with 97% of products meeting protocol-specified dose and no dose-limiting toxicities occurring during dose escalation. In all, 100% of the 17 patients with B-ALL patients responded with 88% minimal residual disease-negative complete remission (CR). For LBCL, 62% of 21 patients responded with 29% CR. Relapses were CD19-/lo in 5 out of 10 B-ALL patients and 4 out of 14 LBCL patients, absent any connection to CD22-/lo disease. Compared with CD19, CD19/22-CAR products showed lower cytokine production when stimulated with CD22. The findings point to the daunting task of engineering multi-specific CAR T cells with equivalent cross-target potency, the researchers report.

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