CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial. Journal Article

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Authors: Spiegel, JY; Patel, S; Muffly, L; Hossain, NM; Oak, J; Baird, JH; Frank, MJ; Shiraz, P; Sahaf, B; Craig, J; Iglesias, M; Younes, S; Natkunam, Y; Ozawa, MG; Yang, E; Tamaresis, J; Chinnasamy, H; Ehlinger, Z; Reynolds, W; Lynn, R; Rotiroti, MC; Gkitsas, N; Arai, S; Johnston, L; Lowsky, R; Majzner, RG; Meyer, E; Negrin, RS; Rezvani, AR; Sidana, S; Shizuru, J; Weng, WK; Mullins, C; Jacob, A; Kirsch, I; Bazzano, M; Zhou, J; Mackay, S; Bornheimer, SJ; Schultz, L; Ramakrishna, S; Davis, KL; Kong, KA; Shah, NN; Qin, H; Fry, T; Feldman, S; Mackall, CL; Miklos, DB
Article Title: CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial.
Abstract: Despite impressive progress, more than 50% of patients treated with CD19-targeting chimeric antigen receptor T cells (CAR19) experience progressive disease. Ten of 16 patients with large B cell lymphoma (LBCL) with progressive disease after CAR19 treatment had absent or low CD19. Lower surface CD19 density pretreatment was associated with progressive disease. To prevent relapse with CD19 or CD19 disease, we tested a bispecific CAR targeting CD19 and/or CD22 (CD19-22.BB.z-CAR) in a phase I clinical trial ( NCT03233854 ) of adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) and LBCL. The primary end points were manufacturing feasibility and safety with a secondary efficacy end point. Primary end points were met; 97% of products met protocol-specified dose and no dose-limiting toxicities occurred during dose escalation. In B-ALL (n?=?17), 100% of patients responded with 88% minimal residual disease-negative complete remission (CR); in LBCL (n?=?21), 62% of patients responded with 29% CR. Relapses were CD19 in 50% (5 out of 10) of patients with B-ALL and 29% (4 out of 14) of patients with LBCL but were not associated with CD22 disease. CD19/22-CAR products demonstrated reduced cytokine production when stimulated with CD22 versus CD19. Our results further implicate antigen loss as a major cause of CAR T cell resistance, highlight the challenge of engineering multi-specific CAR T cells with equivalent potency across targets and identify cytokine production as an important quality indicator for CAR T cell potency.
Journal Title: Nature medicine
ISSN: 1546-170X; 1078-8956
Publisher: Unknown  
Date Published: 2021