{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T19:29:41Z","timestamp":1790882981531,"version":"4.1.0"},"reference-count":29,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2021,6,4]],"date-time":"2021-06-04T00:00:00Z","timestamp":1622764800000},"content-version":"unspecified","delay-in-days":3,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Canc\u00e9rop\u00f4le Provence-Alpes-C\u00f4te d\u2019Azur"},{"DOI":"10.13039\/100002491","name":"Bristol-Myers Squibb","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002491","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2021,4,26]]},"published-print":{"date-parts":[[2021,6]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Despite significant progress with antiprogrammed cell death protein 1 (PD-1) therapy, a substantial fraction of metastatic melanoma patients show upfront therapy resistance. Biomarkers for outcome are missing and the association of baseline immune function and clinical outcome remains to be determined. We assessed the in vitro nonspecific stimulation of immune response at baseline and during anti-PD-1 therapy for metastatic melanoma.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Previously untreated metastatic melanoma patients received nivolumab and radiotherapy as part of the multicentric phase II trial NIRVANA (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT02799901\">NCT02799901<\/jats:ext-link>). The levels of Th1, Th2 and Th17 cytokines on in vitro non-specific stimulation of innate and adaptive immune cells were measured in patient sera before treatment, and at week 2 and week 6 after the beginning of the treatment, and correlated with tumorous response, progression-free survival (PFS) and occurrence of immune-related adverse events (irAEs). The results in melanoma patients were compared with those of a cohort of 9 sex and age-matched healthy donors.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Seventeen patients were enrolled in this ancillary study. Median follow-up was 16 months (2.2\u201328.4). The 12-month PFS rate was 67.7%. The incidence of irAEs of any grade was 58.8%. Without in vitro stimulation no differences in cytokines levels were observed between responders and non-responders. On in vitro stimulation, metastatic patients had lower Th1 cytokine levels than healthy donors at baseline for tumor necrosis factor-\u03b1 and interferon-\u03b3 (IFN-\u03b3) (1136\u2009pg\/mL vs 5558\u2009pg\/mL, p&lt;0.0001; and 3894\u2009pg\/mL vs 17\u2009129\u2009pg\/mL, p=0.02, respectively). Responders exhibited increasing cytokine levels from baseline to week 6. Non-responders had lower interleukin 17A (IL-17A) levels at baseline than responders (7\u2009pg\/mL vs 32\u2009pg\/mL, p=0.03), and lower IFN-\u03b3 levels at week 6 (3.3\u2009ng\/mL vs 14.5\u2009ng\/mL, p=0.03). A lower level of IL-17A at week 2 and a lower level of IFN-\u03b3 at week 6 correlated with worse PFS (p=0.04\u2009and p=0.04 respectively). At baseline, patients who developed irAEs had higher IL-6 levels (19.3\u2009ng\/mL vs 9.2\u2009ng\/mL, p=0.03) and higher IL-17A levels (52.5\u2009pg\/mL vs 2.5\u2009pg\/mL, p=0.009) than those without irAEs.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Our findings indicate that cytokine levels after in vitro non-specific stimulation could be a promising biomarker to predict the outcome of PD-1 inhibition therapy.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2021-002512","type":"journal-article","created":{"date-parts":[[2021,6,4]],"date-time":"2021-06-04T11:35:10Z","timestamp":1622806510000},"page":"e002512","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":24,"title":["Baseline and early functional immune response is associated with subsequent clinical outcomes of PD-1 inhibition therapy in metastatic melanoma patients"],"prefix":"10.1136","volume":"9","clinical-trial-number":[{"clinical-trial-number":"nct02799901","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02799901","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Alexandre","family":"G\u00e9rard","sequence":"first","affiliation":[{"name":"Kidney-Immunology-Transplantation institute, C\u00f4te d\u2019Azur University, CHU Nice, Nice, Provence-Alpes-C\u00f4te d'Azur, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerome","family":"Doyen","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Centre Antoine-Lacassagne, C\u00f4te d\u2019Azur University, Nice, Provence-Alpes-C\u00f4te d'Azur, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"Cremoni","sequence":"additional","affiliation":[{"name":"Kidney-Immunology-Transplantation institute, C\u00f4te d\u2019Azur University, CHU Nice, Nice, Provence-Alpes-C\u00f4te d'Azur, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Bailly","sequence":"additional","affiliation":[{"name":"Department of Public Health, C\u00f4te d\u2019Azur University, CHU Nice, Nice, Provence-Alpes-C\u00f4te d'Azur, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Zorzi","sequence":"additional","affiliation":[{"name":"Department of Immunology, C\u00f4te d\u2019Azur University, CHU Nice, Nice, Provence-Alpes-C\u00f4te d'Azur, France"},{"name":"UR2CA, C\u00f4te d\u2019Azur University, Nice, Provence-Alpes-C\u00f4te d'Azur, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Ruetsch-Chelli","sequence":"additional","affiliation":[{"name":"Department of Immunology, C\u00f4te d\u2019Azur University, CHU Nice, Nice, Provence-Alpes-C\u00f4te d'Azur, France"},{"name":"INSERM U1065, C3M, C\u00f4te d\u2019Azur University, Nice, Provence-Alpes-C\u00f4te d'Azur, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vesna","family":"Brglez","sequence":"additional","affiliation":[{"name":"Department of Immunology, C\u00f4te d\u2019Azur University, CHU Nice, Nice, Provence-Alpes-C\u00f4te d'Azur, France"},{"name":"UR2CA, C\u00f4te d\u2019Azur University, Nice, Provence-Alpes-C\u00f4te d'Azur, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Picard-Gauci","sequence":"additional","affiliation":[{"name":"Department of Dermatology, C\u00f4te d\u2019Azur University, CHU Nice, Nice, Provence-Alpes-C\u00f4te d'Azur, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Troin","sequence":"additional","affiliation":[{"name":"Department of Dermatology, C\u00f4te d\u2019Azur University, CHU Nice, Nice, Provence-Alpes-C\u00f4te d'Azur, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent L.M.","family":"Esnault","sequence":"additional","affiliation":[{"name":"Kidney-Immunology-Transplantation institute, C\u00f4te d\u2019Azur University, CHU Nice, Nice, Provence-Alpes-C\u00f4te d'Azur, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thierry","family":"Passeron","sequence":"additional","affiliation":[{"name":"INSERM U1065, C3M, C\u00f4te d\u2019Azur University, Nice, Provence-Alpes-C\u00f4te d'Azur, France"},{"name":"Department of Dermatology, C\u00f4te d\u2019Azur University, CHU Nice, Nice, Provence-Alpes-C\u00f4te d'Azur, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henri","family":"Montaudi\u00e9","sequence":"additional","affiliation":[{"name":"INSERM U1065, C3M, C\u00f4te d\u2019Azur University, Nice, Provence-Alpes-C\u00f4te d'Azur, France"},{"name":"Department of Dermatology, C\u00f4te d\u2019Azur University, CHU Nice, Nice, Provence-Alpes-C\u00f4te d'Azur, 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