TY - JOUR TI - CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial AU - Spiegel, Jay Y. AU - Patel, Shabnum AU - Muffly, Lori AU - Hossain, Nasheed M. AU - Oak, Jean AU - Baird, John H. AU - Frank, Matthew J. AU - Shiraz, Parveen AU - Sahaf, Bita AU - Craig, Juliana AU - Iglesias, Maria AU - Younes, Sheren AU - Natkunam, Yasodha AU - Ozawa, Michael G. AU - Yang, Eric AU - Tamaresis, John AU - Chinnasamy, Harshini AU - Ehlinger, Zach AU - Reynolds, Warren AU - Lynn, Rachel AU - Rotiroti, Maria Caterina AU - Gkitsas, Nikolaos AU - Arai, Sally AU - Johnston, Laura AU - Lowsky, Robert AU - Majzner, Robbie G. AU - Meyer, Everett AU - Negrin, Robert S. AU - Rezvani, Andrew R. AU - Sidana, Surbhi AU - Shizuru, Judith AU - Weng, Wen-Kai AU - Mullins, Chelsea AU - Jacob, Allison AU - Kirsch, Ilan AU - Bazzano, Magali AU - Zhou, Jing AU - Mackay, Sean AU - Bornheimer, Scott J. AU - Schultz, Liora AU - Ramakrishna, Sneha AU - Davis, Kara L. AU - Kong, Katherine A. AU - Shah, Nirali N. AU - Qin, Haiying AU - Fry, Terry AU - Feldman, Steven AU - Mackall, Crystal L. AU - Miklos, David B. T2 - Nature Medicine AB - 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 CD19lo 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. DA - 2021/07/26/ PY - 2021 DO - 10.1038/s41591-021-01436-0 DP - www.nature.com SP - 1 EP - 13 J2 - Nat Med LA - en SN - 1546-170X ST - CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies UR - https://www.nature.com/articles/s41591-021-01436-0 Y2 - 2021/07/26/17:11:54 ER -