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

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Publication Year:
2021
Authors:
Jay Y Spiegel, Shabnum Patel, Lori Muffly, Nasheed M Hossain, Jean Oak, John H Baird, Matthew J Frank, Parveen Shiraz, Bita Sahaf, Juliana Craig, Maria Iglesias, Sheren Younes, Yasodha Natkunam, Michael G Ozawa, Eric Yang, John Tamaresis, Harshini Chinnasamy, Zach Ehlinger, Warren Reynolds, Rachel Lynn, Maria Caterina Rotiroti, Nikolaos Gkitsas, Sally Arai, Laura Johnston, Robert Lowsky, Robbie G Majzner, Everett Meyer, Robert S Negrin, Andrew R Rezvani, Surbhi Sidana, Judith Shizuru, Wen-Kai Weng, Chelsea Mullins, Allison Jacob, Ilan Kirsch, Magali Bazzano, Jing Zhou, Sean Mackay, Scott J Bornheimer, Liora Schultz, Sneha Ramakrishna, Kara L Davis, Katherine A Kong, Nirali N Shah, Haiying Qin, Terry Fry, Steven Feldman, Crystal L Mackall, David B Miklos
PubMed ID:
34312556
Funding Grants:
Public Summary:
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(lo) 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(-/lo) 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(-/lo) 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.
Scientific 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(lo) 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(-/lo) 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(-/lo) 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.