PMID- 34312556 OWN - NLM STAT- MEDLINE DCOM- 20210916 LR - 20230205 IS - 1546-170X (Electronic) IS - 1078-8956 (Print) IS - 1078-8956 (Linking) VI - 27 IP - 8 DP - 2021 Aug 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. PG - 1419-1431 LID - 10.1038/s41591-021-01436-0 [doi] 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 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. CI - (c) 2021. The Author(s). FAU - Spiegel, Jay Y AU - Spiegel JY AUID- ORCID: 0000-0001-6491-0044 AD - Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA, USA. FAU - Patel, Shabnum AU - Patel S AUID- ORCID: 0000-0002-4782-9540 AD - Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. FAU - Muffly, Lori AU - Muffly L AUID- ORCID: 0000-0002-9887-6136 AD - Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA, USA. AD - Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. FAU - Hossain, Nasheed M AU - Hossain NM AUID- ORCID: 0000-0002-3278-655X AD - Division of Hematology/Oncology, Loyola University Medical Center, Chicago, IL, USA. FAU - Oak, Jean AU - Oak J AD - Department of Clinical Pathology, Stanford University School of Medicine, Stanford, CA, USA. FAU - Baird, John H AU - Baird JH AUID- ORCID: 0000-0001-8291-6546 AD - Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA, USA. FAU - Frank, Matthew J AU - Frank MJ AD - Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA, USA. FAU - Shiraz, Parveen AU - Shiraz P AD - Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA, USA. FAU - Sahaf, Bita AU - Sahaf B AD - Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. FAU - Craig, Juliana AU - Craig J AUID- ORCID: 0000-0002-5644-2292 AD - Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA, USA. FAU - Iglesias, Maria AU - Iglesias M AD - Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA, USA. FAU - Younes, Sheren AU - Younes S AD - Department of Clinical Pathology, Stanford University School of Medicine, Stanford, CA, USA. FAU - Natkunam, Yasodha AU - Natkunam Y AUID- ORCID: 0000-0002-9816-1018 AD - Department of Clinical Pathology, Stanford University School of Medicine, Stanford, CA, USA. FAU - Ozawa, Michael G AU - Ozawa MG AD - Department of Clinical Pathology, Stanford University School of Medicine, Stanford, CA, USA. FAU - Yang, Eric AU - Yang E AD - Department of Clinical Pathology, Stanford University School of Medicine, Stanford, CA, USA. FAU - Tamaresis, John AU - Tamaresis J AD - Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA. FAU - Chinnasamy, Harshini AU - Chinnasamy H AD - Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. FAU - Ehlinger, Zach AU - Ehlinger Z AD - Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. FAU - Reynolds, Warren AU - Reynolds W AD - Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. FAU - Lynn, Rachel AU - Lynn R AD - Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. AD - Lyell Immunopharma, San Francisco, CA, USA. FAU - Rotiroti, Maria Caterina AU - Rotiroti MC AD - Department of Pediatrics-Hematology/Oncology, Stanford University School of Medicine, Stanford, CA, USA. FAU - Gkitsas, Nikolaos AU - Gkitsas N AD - Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. FAU - Arai, Sally AU - Arai S AD - Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA, USA. FAU - Johnston, Laura AU - Johnston L AD - Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA, USA. FAU - Lowsky, Robert AU - Lowsky R AD - Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA, USA. FAU - Majzner, Robbie G AU - Majzner RG AUID- ORCID: 0000-0001-6969-8011 AD - Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. AD - Department of Pediatrics-Hematology/Oncology, Stanford University School of Medicine, Stanford, CA, USA. FAU - Meyer, Everett AU - Meyer E AD - Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA, USA. FAU - Negrin, Robert S AU - Negrin RS AD - Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA, USA. FAU - Rezvani, Andrew R AU - Rezvani AR AD - Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA, USA. FAU - Sidana, Surbhi AU - Sidana S AUID- ORCID: 0000-0003-3288-7614 AD - Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA, USA. FAU - Shizuru, Judith AU - Shizuru J AUID- ORCID: 0000-0003-3246-4726 AD - Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA, USA. FAU - Weng, Wen-Kai AU - Weng WK AD - Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA, USA. FAU - Mullins, Chelsea AU - Mullins C AD - Adaptive Biotechnologies, Seattle, WA, USA. FAU - Jacob, Allison AU - Jacob A AD - Adaptive Biotechnologies, Seattle, WA, USA. FAU - Kirsch, Ilan AU - Kirsch I AD - Adaptive Biotechnologies, Seattle, WA, USA. FAU - Bazzano, Magali AU - Bazzano M AD - IsoPlexis, Brantford, CT, USA. FAU - Zhou, Jing AU - Zhou J AD - IsoPlexis, Brantford, CT, USA. FAU - Mackay, Sean AU - Mackay S AD - IsoPlexis, Brantford, CT, USA. FAU - Bornheimer, Scott J AU - Bornheimer SJ AD - BD Biosciences, San Jose, CA, USA. FAU - Schultz, Liora AU - Schultz L AD - Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. AD - Department of Pediatrics-Hematology/Oncology, Stanford University School of Medicine, Stanford, CA, USA. AD - Pediatric Oncology Branch Center for Cancer Research, National Institutes of Health, Bethesda, MD, USA. FAU - Ramakrishna, Sneha AU - Ramakrishna S AUID- ORCID: 0000-0001-7445-3190 AD - Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. AD - Department of Pediatrics-Hematology/Oncology, Stanford University School of Medicine, Stanford, CA, USA. FAU - Davis, Kara L AU - Davis KL AUID- ORCID: 0000-0002-7182-2592 AD - Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. AD - Department of Pediatrics-Hematology/Oncology, Stanford University School of Medicine, Stanford, CA, USA. FAU - Kong, Katherine A AU - Kong KA AD - Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. FAU - Shah, Nirali N AU - Shah NN AUID- ORCID: 0000-0002-8474-9080 AD - Pediatric Oncology Branch Center for Cancer Research, National Institutes of Health, Bethesda, MD, USA. FAU - Qin, Haiying AU - Qin H AUID- ORCID: 0000-0001-5966-8812 AD - Pediatric Oncology Branch Center for Cancer Research, National Institutes of Health, Bethesda, MD, USA. FAU - Fry, Terry AU - Fry T AUID- ORCID: 0000-0001-8044-5226 AD - Pediatric Oncology Branch Center for Cancer Research, National Institutes of Health, Bethesda, MD, USA. AD - Department of Pediatrics-Hematology/Oncology, University of Colorado Anschutz and Children's Hospital Colorado, Denver, CO, USA. FAU - Feldman, Steven AU - Feldman S AD - Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. FAU - Mackall, Crystal L AU - Mackall CL AUID- ORCID: 0000-0001-6323-4304 AD - Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu. AD - Department of Pediatrics-Hematology/Oncology, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu. FAU - Miklos, David B AU - Miklos DB AUID- ORCID: 0000-0003-0717-4305 AD - Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA, USA. dmiklos@stanford.edu. AD - Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. dmiklos@stanford.edu. LA - eng SI - ClinicalTrials.gov/NCT03233854 GR - 75N92019D00018/HL/NHLBI NIH HHS/United States GR - U54 CA232568/CA/NCI NIH HHS/United States GR - P01 CA049605/CA/NCI NIH HHS/United States GR - P30 CA124435/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20210726 PL - United States TA - Nat Med JT - Nature medicine JID - 9502015 RN - 0 (Antigens, CD19) RN - 0 (CD19 molecule, human) RN - 0 (CD22 protein, human) RN - 0 (Sialic Acid Binding Ig-like Lectin 2) SB - IM MH - Adult MH - Aged MH - Antigens, CD19/*immunology MH - Disease Progression MH - Humans MH - *Immunotherapy, Adoptive/adverse effects MH - Lymphoma, B-Cell/immunology/*therapy MH - Middle Aged MH - Recurrence MH - Sialic Acid Binding Ig-like Lectin 2/*immunology PMC - PMC8363505 COIS- C.L.M. 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. 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. EDAT- 2021/07/28 06:00 MHDA- 2021/09/18 06:00 PMCR- 2021/07/26 CRDT- 2021/07/27 07:10 PHST- 2020/09/29 00:00 [received] PHST- 2021/06/09 00:00 [accepted] PHST- 2021/07/28 06:00 [pubmed] PHST- 2021/09/18 06:00 [medline] PHST- 2021/07/27 07:10 [entrez] PHST- 2021/07/26 00:00 [pmc-release] AID - 10.1038/s41591-021-01436-0 [pii] AID - 1436 [pii] AID - 10.1038/s41591-021-01436-0 [doi] PST - ppublish SO - Nat Med. 2021 Aug;27(8):1419-1431. doi: 10.1038/s41591-021-01436-0. Epub 2021 Jul 26.