Bispecific CAR T cells targeting CD19 and CD22 are effective but do not wholly prevent relapse with CD19− disease.
Major Finding: Bispecific CAR T cells targeting CD19 and CD22 are effective but do not wholly prevent relapse with CD19− disease.
Concept: CD19 loss, but not CD22 loss, was a mechanism of resistance to this CD19- and CD22-targeted therapy.
Impact: Antigen loss plays a key role in CAR T resistance, and further optimization of multispecific CAR T cells is needed.
Chimeric antigen receptor (CAR) T cells have produced remarkable results in certain malignancies. However, 30% to 95% of patients with B-cell acute lymphoblastic leukemia (B-ALL) treated with CD19-directed CAR T-cell therapies ultimately relapse with CD19− or CD19lo disease. Spiegel, Patel, Muffly, and colleagues noted that immunohistochemistry did not identify patients at risk for CD19−/lo relapse following treatment with CD19 CAR T-cell therapy but quantitative flow cytometry did, pointing to the limitations of immunohistochemistry in assessing antigen expression and the importance of antigen-low relapse.To try to circumvent CD19 antigen escape, they developed CAR T cells targeting both CD19 and CD22 and conducted a phase I trial in 39 adult patients with relapsed or refractory CD19+ B-ALL (17 patients) or large B-cell lymphoma (LBCL; 22 patients). Safety and toxicity were similar to CD19- or CD22-directed CAR T-cell treatment without dose-limiting toxicity. Among the 21 patients with LBCL who received the recommended phase II dose, the overall response rate was 62%, the complete response rate was 29%, and the median overall survival was 22.5 months. Among the 17 patients with B-ALL who received the recommended phase II dose, the overall response rate was 100%, the minimal residual disease–negative complete response rate was 88%, and the median overall survival was 11.8 months. Interestingly, among 10 patients whose B-ALL recurred and 14 patients whose LBCL recurred, 50% and 29% had relapse with CD19lo or CD19− disease, respectively, but none had relapse with CD22lo or CD22− disease, suggesting insufficient immune pressure by the bispecific CAR T cells on the CD22 target. Along these lines, CD22 single-chain variable fragment (scFv) ligation in the bispecific CAR induced less IL2 and TNFα secretion than CD19 scFv ligation, suggesting that cytokine production by CAR T cells may be predictive of potency in the clinical setting, Together, this work provides further evidence for antigen loss as a mechanism of relapse after CAR T-cell therapy and suggests that further optimization of multispecific CAR constructs is warranted.
Spiegel JY, Patel S, Muffly L, Hossain NM, Oak J, Baird JH, 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. Nat Med 2021;27:1419–31.
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