{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T18:28:45Z","timestamp":1791224925446,"version":"4.1.0"},"reference-count":39,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2025,6,22]],"date-time":"2025-06-22T00:00:00Z","timestamp":1750550400000},"content-version":"unspecified","delay-in-days":21,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100018937","name":"Bavarian Nordic","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100018937","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the National Cancer Institute, National Institutes of Health","award":["75N91019D00024"],"award-info":[{"award-number":["75N91019D00024"]}]},{"name":"Intramural Research Program of the Center for Cancer Research, NCI, NIH","award":["ZIA BC 010666"],"award-info":[{"award-number":["ZIA BC 010666"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,2,26]]},"published-print":{"date-parts":[[2025,6]]},"abstract":"\n Background<\/jats:title>\n \n Prostate cancer (PC) is the most frequently diagnosed cancer in men worldwide, making up 21% of all cancer cases. Although generally slow-growing, 370,000 men die from PC yearly. Immune checkpoint inhibitors (ICIs) are currently only indicated for the rare cases of microsatellite instability high or tumor mutation burden high disease. Combination therapy strategies that induce immune responses may expand the utility of ICIs. Here, we investigated the safety and efficacy of PROSTVAC, a therapeutic cancer vaccine that targets prostate-specific antigen (PSA), in combination with the programmed cell death protein-1 inhibitor nivolumab (\n NCT02933255<\/jats:ext-link>\n ).\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n We enrolled two cohorts in this trial (phase 1 and 2), both treated with PROSTVAC vaccine and nivolumab. The lead-in cohort had 12 patients with metastatic castration-resistant PC (mCRPC); the neoadjuvant cohort included 12 patients with localized PC who were candidates for radical prostatectomy (RP). We assessed tumor-infiltrating lymphocytes and programmed death-ligand 1 expression in matched formalin-fixed paraffin-embedded samples from baseline biopsies and RP samples. We measured changes in peripheral blood serum analytes, immune cell subsets and antigen-specific T cells targeting PSA, brachyury, and MUC-1 in both cohorts.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n In the lead-in cohort, two patients had a prolonged complete radiographic response by Response Evaluation Criteria in Solid Tumors V.1.1. In the neoadjuvant cohort, CD4\n +<\/jats:sup>\n T helper cell and CD8\n +<\/jats:sup>\n T-cell densities were increased by >2-fold in RP samples compared with baseline in most patients (91% and 83% of patients, respectively). Proliferation of CD4\n +<\/jats:sup>\n and CD8\n +<\/jats:sup>\n T cells also increased in RP samples compared with baseline. Most patients from both cohorts (lead-in and neoadjuvant) had a >2-fold increase in PSA-specific (82% and 58%), MUC-1-specific (64% and 73%), and brachyury-specific (70% and 82%) T cells after therapy. In peripheral blood, we detected increases in proliferative CD4\n +<\/jats:sup>\n and CD8\n +<\/jats:sup>\n T cells but reductions in total CD4\n +<\/jats:sup>\n and CD8\n +<\/jats:sup>\n T cells.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n Neoadjuvant PROSTVAC in combination with nivolumab is associated with increased intratumoral T-cell infiltrates, increased circulating tumor-associated antigen-specific T cells, and with radiographic and biochemical responses in the mCRPC setting. Our findings support the idea that the addition of a vaccine to a tumor-associated antigen might improve the clinical activity of immune checkpoint inhibition.<\/jats:p>\n <\/jats:sec>\n \n Trial registration number<\/jats:title>\n \n NCT02933255<\/jats:ext-link>\n .\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1136\/jitc-2024-010851","type":"journal-article","created":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T03:15:13Z","timestamp":1750648513000},"page":"e010851","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":10,"title":["Programmed death-1 inhibition increases vaccine-induced T-cell infiltration in patients with prostate cancer"],"prefix":"10.1136","volume":"13","clinical-trial-number":[{"clinical-trial-number":"nct02933255","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02933255","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-5742-6982","authenticated-orcid":false,"given":"Wiem","family":"Lassoued","sequence":"first","affiliation":[{"name":"Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5106-8636","authenticated-orcid":false,"given":"Ravi A","family":"Madan","sequence":"additional","affiliation":[{"name":"Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Xue","sequence":"additional","affiliation":[{"name":"Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9063-1806","authenticated-orcid":false,"given":"Daniel","family":"Burnett","sequence":"additional","affiliation":[{"name":"Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth D","family":"Canubas","sequence":"additional","affiliation":[{"name":"Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shania","family":"Bailey","sequence":"additional","affiliation":[{"name":"Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer L","family":"Mart\u00e9","sequence":"additional","affiliation":[{"name":"Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7556-1633","authenticated-orcid":false,"given":"Yo-Ting","family":"Tsai","sequence":"additional","affiliation":[{"name":"Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6828-3073","authenticated-orcid":false,"given":"Renee N","family":"Donahue","sequence":"additional","affiliation":[{"name":"Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ismail Baris","family":"Turkbey","sequence":"additional","affiliation":[{"name":"Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonios","family":"Papanicolau-Sengo","sequence":"additional","affiliation":[{"name":"Special volunteer at the Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moniquea","family":"Williams","sequence":"additional","affiliation":[{"name":"Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Hankin","sequence":"additional","affiliation":[{"name":"Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuk","family":"Manukyan","sequence":"additional","affiliation":[{"name":"Clinical Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michell","family":"Manu","sequence":"additional","affiliation":[{"name":"Clinical Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhigang","family":"Kang","sequence":"additional","affiliation":[{"name":"OMICS Technology Facility, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin","family":"Pritchard","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology and Brotman Baty Institute for Precision Medicine, University of Washington, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Dahut","sequence":"additional","affiliation":[{"name":"Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3244-1332","authenticated-orcid":false,"given":"Fatima","family":"Karzai","sequence":"additional","affiliation":[{"name":"Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7932-4072","authenticated-orcid":false,"given":"Jeffrey","family":"Schlom","sequence":"additional","affiliation":[{"name":"Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam","family":"Sater","sequence":"additional","affiliation":[{"name":"Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Pinto","sequence":"additional","affiliation":[{"name":"Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6569-2912","authenticated-orcid":false,"given":"James L","family":"Gulley","sequence":"additional","affiliation":[{"name":"Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2025,6,22]]},"reference":[{"key":"2026052722353924000_13.6.e010851.1","doi-asserted-by":"publisher","DOI":"10.14740\/wjon1191"},{"key":"2026052722353924000_13.6.e010851.2","doi-asserted-by":"crossref","DOI":"10.1186\/s40425-016-0198-x","article-title":"The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of prostate carcinoma","volume":"4","author":"McNeel","year":"2016","journal-title":"J Immunother Cancer"},{"key":"2026052722353924000_13.6.e010851.3","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1093\/jnci\/djaa021","article-title":"Putting the Pieces Together: Completing the Mechanism of Action Jigsaw for Sipuleucel-T","volume":"112","author":"Madan","year":"2020","journal-title":"J Natl Cancer Inst"},{"key":"2026052722353924000_13.6.e010851.4","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2022-006628","article-title":"Vaccinating against cancer: getting to prime time","volume":"11","author":"Chang","year":"2023","journal-title":"J Immunother Cancer"},{"key":"2026052722353924000_13.6.e010851.5","unstructured":"Gulley J . Immunotherapy for castration-resistant prostate cancer. UpToDate; 2023. Available: https:\/\/www.uptodate.com\/contents\/immunotherapy-for-castration-resistant-prostate-cancer [Accessed Feb 2024]."},{"key":"2026052722353924000_13.6.e010851.6","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.19.01638"},{"key":"2026052722353924000_13.6.e010851.7","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2016.69.1584"},{"key":"2026052722353924000_13.6.e010851.8","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1902651116"},{"key":"2026052722353924000_13.6.e010851.9","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1001\/jamaoncol.2018.5801","article-title":"Analysis of the Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade","volume":"5","author":"Abida","year":"2019","journal-title":"JAMA Oncol"},{"key":"2026052722353924000_13.6.e010851.10","doi-asserted-by":"crossref","DOI":"10.1186\/s40425-018-0342-x","article-title":"Significance and implications of FDA approval of pembrolizumab for biomarker-defined disease","volume":"6","author":"Boyiadzis","year":"2018","journal-title":"J Immunother Cancer"},{"key":"2026052722353924000_13.6.e010851.11","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1001294"},{"key":"2026052722353924000_13.6.e010851.12","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2020-000655","article-title":"Neoadjuvant PROSTVAC prior to radical prostatectomy enhances T-cell infiltration into the tumor immune microenvironment in men with prostate cancer","volume":"8","author":"Abdul Sater","year":"2020","journal-title":"J Immunother Cancer"},{"key":"2026052722353924000_13.6.e010851.13","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2009.25.0597"},{"key":"2026052722353924000_13.6.e010851.14","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-009-0782-8"},{"key":"2026052722353924000_13.6.e010851.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.juro.2007.05.117"},{"key":"2026052722353924000_13.6.e010851.16","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-13-0108"},{"key":"2026052722353924000_13.6.e010851.17","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.18.02031"},{"key":"2026052722353924000_13.6.e010851.18","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-19-0183"},{"key":"2026052722353924000_13.6.e010851.19","first-page":"41","article-title":"Identification and characterization of a human agonist cytotoxic T-lymphocyte epitope of human prostate-specific antigen","volume":"8","author":"Terasawa","year":"2002","journal-title":"Clin Cancer Res"},{"key":"2026052722353924000_13.6.e010851.20","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-013-1494-7"},{"key":"2026052722353924000_13.6.e010851.21","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-014-1603-2"},{"key":"2026052722353924000_13.6.e010851.22","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2022-005813","article-title":"First-in-human phase Ib trial of M9241 (NHS-IL12) plus avelumab in patients with advanced solid tumors, including dose expansion in patients with advanced urothelial carcinoma","volume":"11","author":"Strauss","year":"2023","journal-title":"J Immunother Cancer"},{"key":"2026052722353924000_13.6.e010851.23","doi-asserted-by":"crossref","DOI":"10.1186\/s40425-018-0473-0","article-title":"Myocarditis in a patient treated with Nivolumab and PROSTVAC: a case report","volume":"6","author":"Monge","year":"2018","journal-title":"J Immunother Cancer"},{"key":"2026052722353924000_13.6.e010851.24","doi-asserted-by":"crossref","DOI":"10.1080\/2162402X.2019.1648170","article-title":"Polyfunctional tumor-reactive T cells are effectively expanded from non-small cell lung cancers, and correlate with an immune-engaged T cell profile","volume":"8","author":"De Groot","year":"2019","journal-title":"Oncoimmunology"},{"key":"2026052722353924000_13.6.e010851.25","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)02268-7"},{"key":"2026052722353924000_13.6.e010851.26","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1038\/s41586-023-06063-y","article-title":"Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer","volume":"618","author":"Rojas","year":"2023","journal-title":"Nature New Biol"},{"key":"2026052722353924000_13.6.e010851.27","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2024-009595","article-title":"Hypothesis: the generation of T cells directed against neoepitopes employing immune-mediating agents other than neoepitope vaccines","volume":"12","author":"Schlom","year":"2024","journal-title":"J Immunother Cancer"},{"key":"2026052722353924000_13.6.e010851.28","doi-asserted-by":"publisher","DOI":"10.1038\/s41391-021-00340-5"},{"key":"2026052722353924000_13.6.e010851.29","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-14-0027"},{"key":"2026052722353924000_13.6.e010851.30","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-20-2974"},{"key":"2026052722353924000_13.6.e010851.31","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2022.10.001"},{"key":"2026052722353924000_13.6.e010851.32","doi-asserted-by":"crossref","DOI":"10.1172\/JCI151239","article-title":"Randomized trial of neoadjuvant vaccination with tumor-cell lysate induces T cell response in low-grade gliomas","volume":"132","author":"Ogino","year":"2022","journal-title":"J Clin Invest"},{"key":"2026052722353924000_13.6.e010851.33","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-1187"},{"key":"2026052722353924000_13.6.e010851.34","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-021-26940-2","article-title":"Neoadjuvant PD-1 blockade induces T cell and cDC1 activation but fails to overcome the immunosuppressive tumor associated macrophages in recurrent glioblastoma","volume":"12","author":"Lee","year":"2021","journal-title":"Nat Commun"},{"key":"2026052722353924000_13.6.e010851.35","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2023.1125111","article-title":"Changes of peripheral T cell subsets in melanoma patients with immune-related adverse events","volume":"14","author":"M\u00fcller","year":"2023","journal-title":"Front Immunol"},{"key":"2026052722353924000_13.6.e010851.36","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1200\/PO.19.00399","article-title":"CDK12-Altered Prostate Cancer: Clinical Features and Therapeutic Outcomes to Standard Systemic Therapies, Poly (ADP-Ribose) Polymerase Inhibitors, and PD-1 Inhibitors","volume":"4","author":"Antonarakis","year":"2020","journal-title":"JCO Precis Oncol"},{"key":"2026052722353924000_13.6.e010851.37","doi-asserted-by":"crossref","first-page":"3200","DOI":"10.1158\/1078-0432.CCR-24-0400","article-title":"Evaluating Immune Checkpoint Blockade in Metastatic Castration-Resistant Prostate Cancers with Deleterious CDK12 Alterations in the Phase 2 IMPACT Trial","volume":"30","author":"Nguyen","year":"2024","journal-title":"Clin Cancer Res"},{"key":"2026052722353924000_13.6.e010851.38","doi-asserted-by":"crossref","first-page":"2518","DOI":"10.1200\/JCO.2022.40.16_suppl.2518","article-title":"Phase II evaluation of the combination of PDS0101, M9241, and bintrafusp alfa in patients with HPV 16+ malignancies","volume":"40","author":"Strauss","year":"2022","journal-title":"JCO"},{"key":"2026052722353924000_13.6.e010851.39","doi-asserted-by":"crossref","first-page":"S984","DOI":"10.1016\/j.annonc.2024.08.1712","article-title":"1631P Results from the quick efficacy seeking trial (QuEST1) arm combining BN-brachyury (BNVax) + bintrafusp alfa (BA) + nogapendekin alfa inbakicept-pmln (N-803) in castration-resistant prostate cancer (CRPC)","volume":"35","author":"Redman","year":"2024","journal-title":"Ann Oncol"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2024-010851","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T05:36:00Z","timestamp":1779946560000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2024-010851"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6]]},"references-count":39,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6,22]]},"published-print":{"date-parts":[[2025,6]]}},"alternative-id":["10.1136\/jitc-2024-010851"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2024-010851","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6]]}}}