{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T21:17:24Z","timestamp":1793395044717,"version":"4.5.0"},"reference-count":36,"publisher":"BMJ","issue":"2","license":[{"start":{"date-parts":[[2020,10,6]],"date-time":"2020-10-06T00:00:00Z","timestamp":1601942400000},"content-version":"unspecified","delay-in-days":5,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"the National Key Research and Development Program of China","award":["2018YFC1313400"],"award-info":[{"award-number":["2018YFC1313400"]}]},{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["U1804281, 81771781 and 81702810"],"award-info":[{"award-number":["U1804281, 81771781 and 81702810"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2020,9,13]]},"published-print":{"date-parts":[[2020,10]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Tumor relapse due to mutation in <jats:italic>CD19<\/jats:italic> can hinder the efficacy of chimeric antigen receptor (CAR)-T cell therapy. Herein, we focused on lymphoma patients whose B cells exhibited a point mutation in <jats:italic>CD19<\/jats:italic> of B cells after CAR-T cell infusion.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>The CAR-T and CD19<jats:sup>+<\/jats:sup> B cells from peripheral blood or bone marrow were assessed using flow cytometry. Genome sequencing was conducted to identify the molecular characteristics of CAR-T and CD19<jats:sup>+<\/jats:sup> B cells from pre-relapse and postrelapse samples. CD19 in CARs comprising single chain fragments variable (scFV) antibody with FMC63 or 21D4 was constructed. The cytotoxic efficacy of CAR-T cells was also evaluated via in vitro and in vivo experiments.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>A patient with high-grade B cell lymphoma exhibited complete response, but the lymphoma relapsed in her left breast at 6 months after <jats:italic>CD19<\/jats:italic> CAR (FMC63)-T cell infusion. A mutation was found in exon 3 of <jats:italic>CD19<\/jats:italic> (p.163. R-L) in malignant B cells of the patient. In two lymphoma patients who exhibited resistance to CAR-T cell therapy, a mutation was detected in exon 3 of <jats:italic>CD19<\/jats:italic> (p.174. L-V). Functional analysis revealed that FMC63 CAR-T cells exhibited antitumor ability against wild-type CD19<jats:sup>+<\/jats:sup> cells but were unable to eradicate these two types of mutated CD19<jats:sup>+<\/jats:sup> cells. Interestingly, 21D4 CAR-T cells were potentially capable of eradicating these mutated CD19<jats:sup>+<\/jats:sup> cells and exhibiting high antitumor capacity against CD19<jats:sup>+<\/jats:sup> cells with loss of exon 1, 2, or 3.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>These findings suggest that point mutation can facilitate immune escape from CAR-T cell therapy and that alternative CAR-T cells can effectively eradicate the mutated B cells, providing an individualized therapeutic approach for lymphoma patients showing relapse.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2020-001150","type":"journal-article","created":{"date-parts":[[2020,10,6]],"date-time":"2020-10-06T17:40:45Z","timestamp":1602006045000},"page":"e001150","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":83,"title":["Point mutation in 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