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

• Published in: Nature medicine Vol. 27; no. 8; pp. 1419 - 1431
• Main Authors: Spiegel, Jay Y., Patel, Shabnum, Muffly, Lori, Hossain, Nasheed M., Oak, Jean, Baird, John H., Frank, Matthew J., Shiraz, Parveen, Sahaf, Bita, Craig, Juliana, Iglesias, Maria, Younes, Sheren, Natkunam, Yasodha, Ozawa, Michael G., Yang, Eric, Tamaresis, John, Chinnasamy, Harshini, Ehlinger, Zach, Reynolds, Warren, Lynn, Rachel, Rotiroti, Maria Caterina, Gkitsas, Nikolaos, Arai, Sally, Johnston, Laura, Lowsky, Robert, Majzner, Robbie G., Meyer, Everett, Negrin, Robert S., Rezvani, Andrew R., Sidana, Surbhi, Shizuru, Judith, Weng, Wen-Kai, Mullins, Chelsea, Jacob, Allison, Kirsch, Ilan, Bazzano, Magali, Zhou, Jing, Mackay, Sean, Bornheimer, Scott J., Schultz, Liora, Ramakrishna, Sneha, Davis, Kara L., Kong, Katherine A., Shah, Nirali N., Qin, Haiying, Fry, Terry, Feldman, Steven, Mackall, Crystal L., Miklos, David B.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2021; Nature Publishing Group
• Subjects: 631/67/1059/2325; 692/308/2779/109/1940; 692/699/1541/1990/283/2125; 692/699/67/1059/2325; 692/699/67/1990/291; Acute lymphoblastic leukemia; Adult; Aged; Antigens; Antigens, CD19 - immunology; Antimitotic agents; Antineoplastic agents; B-cell lymphoma; Biomedical and Life Sciences; Biomedicine; Cancer Research; Care and treatment; CD19 antigen; CD22 antigen; Chimeric antigen receptors; Cytokines; Development and progression; Diagnosis; Disease Progression; Dosage and administration; Humans; Immunotherapy, Adoptive - adverse effects; Infectious Diseases; Leukemia; Lymphatic leukemia; Lymphocytes; Lymphocytes T; Lymphoma; Lymphoma, B-Cell - immunology; Lymphoma, B-Cell - therapy; Lymphomas; Metabolic Diseases; Middle Aged; Minimal residual disease; Molecular Medicine; Neurosciences; Patients; Recurrence; Remission; Sialic Acid Binding Ig-like Lectin 2 - immunology; Target recognition; Testing; Toxicity; United States
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/s41591-021-01436-0

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. Bispecific CAR T cells targeting CD19 and CD22 exhibit clinical activity and low toxicity in patients with large B cell lymphoma and B cell acute lymphoblastic leukemia, with relapses associated with loss of CD19 but not CD22.