{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T05:35:40Z","timestamp":1775194540940,"version":"3.50.1"},"reference-count":47,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2022,6,15]],"date-time":"2022-06-15T00:00:00Z","timestamp":1655251200000},"content-version":"unspecified","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004334","name":"Merck","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004334","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009812","name":"Princess Margaret Cancer Foundation.","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100009812","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2022,5,20]]},"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Recent studies have demonstrated that T cells can induce vasodilation in a choline-acetyltransferase dependent manner, leading to an increase in T cell migration to infected tissues in response to viral infection, but its role in cancer is unclear. Choline acetyltransferase catalyzes the production of acetylcholine from choline and acetyl-CoA, however, acetylcholine is challenging to quantify due to its extremely short half-life while choline is stable. This study aims to correlate serum choline levels in patients with advanced solid tumors receiving pembrolizumab with treatment outcomes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Blood samples were collected at baseline and at week 7 (pre-cycle 3) in patients treated with pembrolizumab in the INvestigator-initiated Phase 2 Study of Pembrolizumab Immunological Response Evaluation phase II trial (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT02644369\">NCT02644369<\/jats:ext-link>). Samples were analyzed for choline and circulating tumor DNA (ctDNA). Multivariable Cox models were used to assess the association between choline and overall survival (OS) and progression-free survival (PFS) when including \u0394ctDNA<jats:sub>C3<\/jats:sub> (the change in ctDNA from baseline to cycle 3), cohort, PD-L1 expression and tumor mutation burden (TMB). An independent validation cohort from the LIBERATE study (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT03702309\">NCT03702309<\/jats:ext-link>) included patients on early phase trials treated with a PD-1 inhibitor.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>A total of 106 pts were included in the analysis. With a median follow-up of 12.6 months, median PFS and OS were 1.9 and 13.7 months, respectively. An increase in serum choline level at week 7 compared with baseline (\u0394choline<jats:sub>C3<\/jats:sub>) in 81 pts was significantly associated with a better PFS (aHR 0.48, 95%\u2009CI 0.28 to 0.83, p=0.009), and a trend toward a better OS (aHR 0.64, 95%\u2009CI 0.37 to 1.12, p=0.119). A combination of \u0394ctDNA<jats:sub>C3<\/jats:sub> and \u0394choline<jats:sub>C3<\/jats:sub> was prognostic for both OS and PFS. Multivariable analyses show \u0394choline<jats:sub>C3<\/jats:sub> was a prognostic factor for PFS independent of \u0394ctDNA<jats:sub>C3<\/jats:sub>, cohort, PD-L1 and TMB. In the independent validation cohort (n=51), an increase in serum choline at cycle 2 was associated with a trend to improved PFS.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>This is the first exploratory report of serum choline levels in pan-cancer patients receiving pembrolizumab. The association between improved PFS and \u0394choline<jats:sub>C3<\/jats:sub> suggests a possible role for the cholinergic system in the regulation of antitumor immunity. Further pre-clinical and clinical studies are required to validate this finding.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Trial registration number<\/jats:title>\n                  <jats:p>\n                     <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT03702309\">NCT03702309<\/jats:ext-link>.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2021-004378","type":"journal-article","created":{"date-parts":[[2022,6,15]],"date-time":"2022-06-15T12:51:46Z","timestamp":1655297506000},"page":"e004378","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":22,"title":["Increase in serum choline levels predicts for improved progression-free survival (PFS) in patients with advanced cancers receiving pembrolizumab"],"prefix":"10.1136","volume":"10","clinical-trial-number":[{"clinical-trial-number":"nct02644369","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct03702309","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct03702309","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02644369","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02644369","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct03702309","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct01215864","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1962-7893","authenticated-orcid":false,"given":"Geoffrey Alan","family":"Watson","sequence":"first","affiliation":[{"name":"Division of Medical Oncology and Hematology, University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enrique","family":"Sanz-Garcia","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology and Hematology, University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen-Jiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology and Hematology, University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhihui Amy","family":"Liu","sequence":"additional","affiliation":[{"name":"Biostatistics, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada"},{"name":"University of Toronto Dalla Lana School of Public Health, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"SY Cindy","family":"Yang","sequence":"additional","affiliation":[{"name":"Medical Biophysics, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ben","family":"Wang","sequence":"additional","affiliation":[{"name":"Laboratory Medicine and Pathobiology, University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shaofeng","family":"Liu","sequence":"additional","affiliation":[{"name":"Immunology, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shawn","family":"Kubli","sequence":"additional","affiliation":[{"name":"Immunology, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hal","family":"Berman","sequence":"additional","affiliation":[{"name":"Laboratory Medicine and Pathobiology, University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Pfister","sequence":"additional","affiliation":[{"name":"Laboratory Medicine and Pathobiology, University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sofia","family":"Genta","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology and Hematology, University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3034-3042","authenticated-orcid":false,"given":"Anna","family":"Spreafico","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology and Hematology, University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aaron R","family":"Hansen","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology and Hematology, University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philippe L","family":"Bedard","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology and Hematology, University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4405-5890","authenticated-orcid":false,"given":"Stephanie","family":"Lheureux","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology and Hematology, University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Albiruni","family":"Abdul Razak","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology 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University of Toronto, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lillian L","family":"Siu","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology and Hematology, University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4581-8848","authenticated-orcid":false,"given":"Eric","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology and Hematology, University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, 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