{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T22:00:49Z","timestamp":1790805649885,"version":"4.1.0"},"reference-count":41,"publisher":"BMJ","issue":"1","license":[{"start":{"date-parts":[[2022,1,12]],"date-time":"2022-01-12T00:00:00Z","timestamp":1641945600000},"content-version":"unspecified","delay-in-days":11,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["P50CA107399"],"award-info":[{"award-number":["P50CA107399"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005189","name":"Leukemia and Lymphoma Society","doi-asserted-by":"publisher","award":["TRP 6611-20"],"award-info":[{"award-number":["TRP 6611-20"]}],"id":[{"id":"10.13039\/100005189","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2021,12,4]]},"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Adoptive transfer of CD19-specific chimeric antigen receptor (CD19CAR) T cells can induce dramatic disease regression in patients with B cell malignancies. CD19CAR T cell therapy may be limited by insufficient engraftment and persistence, resulting in tumor relapse. We previously demonstrated a proof of principle that cytomegalovirus (CMV)-specific T cells can be isolated and enriched prior to CD19CAR transduction to produce CMV-CD19CAR T cells, and that these CMV-CD19CAR T cells can be expanded in vivo through CMV vaccination, resulting in better tumor control in a murine model. Here we developed a clinical platform for generating CMV-CD19CAR T cells.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Peripheral blood mononuclear cells (PBMCs) collected from CMV-seropositive healthy donors were stimulated with a good manufacturing practices-grade PepTivator overlapping CMVpp65 peptide pool and enriched for CMV-responsive interferon \u03b3 (IFN\u03b3)+T cells using IFN\u03b3 Catchmatrix, within the CliniMACS Prodigy Cytokine Capture System (Miltenyi Biotec). Resulting CMV-specific T cells were transduced with a lentiviral vector encoding a second generation CD19R:CD28:\u03b6\/EGFRt CAR and expanded with interleukin 2 (IL-2) and IL-15 for 15 days before characterization.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>CMV-specific T cells were enriched from 0.8%\u00b10.5 of input PBMC to 76.3%\u00b111.6 in nine full-scale qualification runs (absolute yield of 4.2\u00b13.3\u00d710<jats:sup>6<\/jats:sup> IFN\u03b3+T cells from an input of 1\u00d710<jats:sup>9<\/jats:sup> PBMCs). Average CD19CAR transduction efficiency of CMV-specific T cells was 27.0%\u00b114.2 in the final products, which underwent rapid expansion, resulting in a total cell dose of 6.2\u00b10.9 \u00d7 10<jats:sup>6<\/jats:sup> CD19CAR-tranduced T cells with CMV specificity (ie, functionally bispecific). CMV-CD19CAR T cells were polyclonal, expressed memory markers but had low expression of exhaustion markers, responded to both CD19 and CMVpp65 stimulation with rapid proliferation and exhibited antigen-specific effector functions against both CD19-expressing tumors and CMVpp65 antigen. The final products passed release criteria for clinical use.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>We demonstrated the feasibility of our large-scale platform for generating CMV-CD19CAR T cells for clinical application. We plan to initiate a clinical trial at City of Hope using CMV-CD19CAR T cells for patients with intermediate\/high-grade B cell non-Hodgkin\u2019s lymphoma immediately after autologous hematopoietic cell transplantation followed by vaccination with a novel CMV vaccine based on Modified Vaccinia Ankara (Triplex) 28 days and 56 days post-T cell infusion.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2021-003461","type":"journal-article","created":{"date-parts":[[2022,1,13]],"date-time":"2022-01-13T11:22:05Z","timestamp":1642072925000},"page":"e003461","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":20,"title":["Large-scale manufacturing and characterization of CMV-CD19CAR T cells"],"prefix":"10.1136","volume":"10","clinical-trial-number":[{"clinical-trial-number":"nct02506933","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02146924","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02153580","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct01953900","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Xiuli","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Urak","sequence":"additional","affiliation":[{"name":"Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Walter","sequence":"additional","affiliation":[{"name":"Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Guan","sequence":"additional","affiliation":[{"name":"Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianxu","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vibhuti","family":"Vyas","sequence":"additional","affiliation":[{"name":"Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng-Hsuan","family":"Chien","sequence":"additional","affiliation":[{"name":"Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenna","family":"Gittins","sequence":"additional","affiliation":[{"name":"Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1672-2684","authenticated-orcid":false,"given":"Mary C","family":"Clark","sequence":"additional","affiliation":[{"name":"Department of Clinical Translational Project Development, City of Hope, Duarte, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally","family":"Mokhtari","sequence":"additional","affiliation":[{"name":"Department of Clinical Translational Project Development, City of Hope, Duarte, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelo","family":"Cardoso","sequence":"additional","affiliation":[{"name":"Center for Gene Therapy, Hematological Malignancy and Stem Cell Transplantation Institute, City of Hope, Duarte, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Don J","family":"Diamond","sequence":"additional","affiliation":[{"name":"Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Zaia","sequence":"additional","affiliation":[{"name":"Center for Gene Therapy, Hematological Malignancy and Stem Cell Transplantation Institute, City of Hope, Duarte, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen J","family":"Forman","sequence":"additional","affiliation":[{"name":"Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryotaro","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, 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