Programmed death-1 inhibition increases vaccine-induced T-cell infiltration in patients with prostate cancer
Background 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 instabil...
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BMJ Publishing Group
2025-06-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/6/e010851.full |
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| author | Colin Pritchard Renee N Donahue Jeffrey Schlom James L Gulley Ravi A Madan Fatima Karzai Amy Hankin Jennifer L Marté Ismail Baris Turkbey Yo-Ting Tsai Manuk Manukyan Moniquea Williams William Dahut Shania Bailey Wiem Lassoued Michell Manu Peter Pinto Daniel Burnett Elisabetta Xue Kenneth D Canubas Antonios Papanicolau-Sengo Zhigang Kang Sam Sater |
| author_facet | Colin Pritchard Renee N Donahue Jeffrey Schlom James L Gulley Ravi A Madan Fatima Karzai Amy Hankin Jennifer L Marté Ismail Baris Turkbey Yo-Ting Tsai Manuk Manukyan Moniquea Williams William Dahut Shania Bailey Wiem Lassoued Michell Manu Peter Pinto Daniel Burnett Elisabetta Xue Kenneth D Canubas Antonios Papanicolau-Sengo Zhigang Kang Sam Sater |
| author_sort | Colin Pritchard |
| collection | DOAJ |
| description | Background 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 (NCT02933255).Methods 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.Results 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+ T helper cell and CD8+ 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+ and CD8+ 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+ and CD8+ T cells but reductions in total CD4+ and CD8+ T cells.Conclusion 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.Trial registration number NCT02933255. |
| format | Article |
| id | doaj-art-bb58f9403a04497e8df6a944f3fcbb5a |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-bb58f9403a04497e8df6a944f3fcbb5a2025-08-20T03:27:07ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-06-0113610.1136/jitc-2024-010851Programmed death-1 inhibition increases vaccine-induced T-cell infiltration in patients with prostate cancerColin Pritchard0Renee N Donahue1Jeffrey Schlom2James L Gulley3Ravi A Madan4Fatima Karzai5Amy Hankin6Jennifer L Marté7Ismail Baris Turkbey8Yo-Ting Tsai9Manuk Manukyan10Moniquea Williams11William Dahut12Shania Bailey13Wiem Lassoued14Michell Manu15Peter Pinto16Daniel Burnett17Elisabetta Xue18Kenneth D Canubas19Antonios Papanicolau-Sengo20Zhigang Kang21Sam Sater227 Department of Laboratory Medicine and Pathology and Brotman Baty Institute for Precision Medicine, University of Washington, Seattle, Washington, USA1 Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA1 Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USANCI, National Institutes of Health, Bethesda, Maryland, USA2 Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA2 Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA2 Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA1 Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA3 Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA1 Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA5 Clinical Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA2 Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA2 Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA1 Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA1 Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA5 Clinical Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA8 Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA1 Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA1 Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA1 Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA4 Special volunteer at the Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA6 OMICS Technology Facility, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA1 Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USABackground 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 (NCT02933255).Methods 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.Results 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+ T helper cell and CD8+ 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+ and CD8+ 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+ and CD8+ T cells but reductions in total CD4+ and CD8+ T cells.Conclusion 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.Trial registration number NCT02933255.https://jitc.bmj.com/content/13/6/e010851.full |
| spellingShingle | Colin Pritchard Renee N Donahue Jeffrey Schlom James L Gulley Ravi A Madan Fatima Karzai Amy Hankin Jennifer L Marté Ismail Baris Turkbey Yo-Ting Tsai Manuk Manukyan Moniquea Williams William Dahut Shania Bailey Wiem Lassoued Michell Manu Peter Pinto Daniel Burnett Elisabetta Xue Kenneth D Canubas Antonios Papanicolau-Sengo Zhigang Kang Sam Sater Programmed death-1 inhibition increases vaccine-induced T-cell infiltration in patients with prostate cancer Journal for ImmunoTherapy of Cancer |
| title | Programmed death-1 inhibition increases vaccine-induced T-cell infiltration in patients with prostate cancer |
| title_full | Programmed death-1 inhibition increases vaccine-induced T-cell infiltration in patients with prostate cancer |
| title_fullStr | Programmed death-1 inhibition increases vaccine-induced T-cell infiltration in patients with prostate cancer |
| title_full_unstemmed | Programmed death-1 inhibition increases vaccine-induced T-cell infiltration in patients with prostate cancer |
| title_short | Programmed death-1 inhibition increases vaccine-induced T-cell infiltration in patients with prostate cancer |
| title_sort | programmed death 1 inhibition increases vaccine induced t cell infiltration in patients with prostate cancer |
| url | https://jitc.bmj.com/content/13/6/e010851.full |
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