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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\n                    <jats:sup>\u2212<\/jats:sup>\n                    or CD19\n                    <jats:sup>lo<\/jats:sup>\n                    disease, we tested a bispecific CAR targeting CD19 and\/or CD22 (CD19-22.BB.z-CAR) in a phase I clinical trial (\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03233854\">NCT03233854<\/jats:ext-link>\n                    ) 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                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200917), 100% of patients responded with 88% minimal residual disease-negative complete remission (CR); in LBCL (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200921), 62% of patients responded with 29% CR. Relapses were CD19\n                    <jats:sup>\u2212\/lo<\/jats:sup>\n                    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\n                    <jats:sup>\u2212\/lo<\/jats:sup>\n                    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.\n                  <\/jats:p>","DOI":"10.1038\/s41591-021-01436-0","type":"journal-article","created":{"date-parts":[[2021,7,26]],"date-time":"2021-07-26T12:05:31Z","timestamp":1627301131000},"page":"1419-1431","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":601,"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"],"prefix":"10.1038","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6491-0044","authenticated-orcid":false,"given":"Jay 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C.L.M. is a founder of, holds equity in and receives consulting fees from Lyell Immunopharma and Syncopation Life Sciences. She has also received consulting fees from NeoImmune Tech, Nektar Therapeutics, Immatics, GlaxoSmithKline and Apricity Health and royalties from Juno Therapeutics for the CD22-CAR. She holds equity in Vor Biopharma and Apricity Health. D.B.M. has consulted for Kite-Gilead, Juno Therapeutics-Celgene-Bristol Myers Squibb, Novartis and Adaptive Biotechnologies. He has received research for Kite-Gilead and Adaptive Biotechnologies. S.F. has consulted for Lonza PerMed, Gradalis, Obsidian and Samsara Biocapital. L.M. has consulted for Amgen, Pfizer and Kite-Gilead. She has received research funding from Adaptive Biotechnologies, Astellas Pharma, Servier and Baxalta. S.P. has consulted for Cellares. R.S.N. has consulted for Kuur Therapeutics, who are developing CAR invariant NKT cells, and CoImmune, who are developing CAR cytokine-induced killer cells. A.R.R. has received research support from Pharmacyclics and performed a one-time ad hoc scientific advisory board role for Nohla and Koledio. He is a medical expert witness for the U.S. Department of Justice; his brother works for Johnson & Johnson. H.Q. is an inventor on a patent application for CD19\/22-CAR T cells and holds several patent applications in the area of CAR T cell immunotherapy. She has also received royalties from Lentigen via the NIH for the thymic stromal lymphopoietin receptor-CARs. I.K., C.M. and A.J. are full-time employees and shareholders of Adaptive Biotechnologies. R.G.M. holds several patent applications in the area of CAR T cell immunotherapy and is a consultant for Lyell Immunopharma, Xyphos Biosciences, GammaDelta Therapeutics, Zai Lab and Aptorum Group. The other authors declare no conflicts of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}