Combination of HDAC inhibition and cytokine enhances therapeutic HPV vaccine therapy
Background Human papillomavirus (HPV)-associated malignancies continue to present a major health concern despite the development of prophylactic vaccines. Standard therapies offer limited benefit to patients with advanced-stage disease. Despite improved outcomes with programmed cell death protein-1...
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BMJ Publishing Group
2025-05-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/5/e011074.full |
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| author | Jeffrey Schlom James L Gulley Caroline Jochems Sofia R Gameiro Wiem Lassoued Daniel Burnett Lisa K Poppe Nicholas Roller Miriam Marlene Medina-Enríquez Katherine E Lothstein Asma S Khelifa Masaya Miyamoto |
| author_facet | Jeffrey Schlom James L Gulley Caroline Jochems Sofia R Gameiro Wiem Lassoued Daniel Burnett Lisa K Poppe Nicholas Roller Miriam Marlene Medina-Enríquez Katherine E Lothstein Asma S Khelifa Masaya Miyamoto |
| author_sort | Jeffrey Schlom |
| collection | DOAJ |
| description | Background Human papillomavirus (HPV)-associated malignancies continue to present a major health concern despite the development of prophylactic vaccines. Standard therapies offer limited benefit to patients with advanced-stage disease. Despite improved outcomes with programmed cell death protein-1 (PD-1) targeted therapies, treatment resistance and modest response rates highlight a significant unmet need to develop novel therapies for these patients. PDS0101 (designated HPV vaccine) is a liposomal nanoparticle HPV16-specific therapeutic vaccine that has been shown to generate strong HPV-specific responses in preclinical and clinical studies. Here we assess the efficacy of this HPV vaccine in combination with the tumor-targeting immunocytokine NHS-IL12 (PDS01ADC), plus either αPD-1 or the class I histone deacetylase inhibitor Entinostat.Methods Mice bearing HPV16+, αPD-1 refractory TC-1 and mEER tumors were treated with HPV vaccine, NHS-IL12, and either αPD-1 or Entinostat to determine antitumor efficacy and survival benefits. A comprehensive analysis of the tumor microenvironment was performed using flow cytometry, multiplex immunofluorescence, chemokine and cytokine assessment, and single-cell RNA sequencing with T-cell receptor (TCR) enrichment.Results Combination of HPV vaccine and NHS-IL12 with either Entinostat or αPD-1 yielded significant antitumor activity and prolonged survival in αPD-1 refractory models of HPV16+ cancer, with superior activity employing Entinostat versus αPD-1 combination. Entinostat triple therapy increased overall and HPV16-specific tumor CD8+ T-cell infiltration with heightened cytotoxicity. TCR sequencing revealed a CD8+ T-cell clone unique to vaccine-treated cohorts, which displayed an enriched cytotoxic transcriptional profile with triple therapy. These effects were paralleled by strong differentiation of tumor-associated macrophages (TAMs) towards pro-inflammatory, antitumor M1-like cell states. Single-cell transcriptomic analysis indicated all three agents were required for highest modulation of both CD8+ T cells and TAMs conducive to tumor control. A biomarker signature reflecting the preclinical findings was found to be associated with improved survival in patients with HPV-associated malignancies.Conclusion Together, these findings provide a rationale for the combination of HPV vaccine, NHS-IL12, and Entinostat in the clinical setting for patients with HPV16-associated malignancies. |
| format | Article |
| id | doaj-art-a191095d8ba04fd39d1bd7b0b6d77d43 |
| institution | DOAJ |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-a191095d8ba04fd39d1bd7b0b6d77d432025-08-20T03:11:51ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-05-0113510.1136/jitc-2024-011074Combination of HDAC inhibition and cytokine enhances therapeutic HPV vaccine therapyJeffrey Schlom0James L Gulley1Caroline Jochems2Sofia R Gameiro3Wiem Lassoued4Daniel Burnett5Lisa K Poppe6Nicholas Roller7Miriam Marlene Medina-Enríquez8Katherine E Lothstein9Asma S Khelifa10Masaya Miyamoto11Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USACenter for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USAAff1 0000 0004 1936 8075grid.48336.3aLaboratory of Tumor Immunology and Biology, Center for Cancer ResearchNational Cancer Institute, National Institutes of Health 10 Center Drive, Room 8B09 Bethesda MD USACenter for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USACenter for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USACenter for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USACenter for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USACenter for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USACenter for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USACenter for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USACenter for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USACenter for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USABackground Human papillomavirus (HPV)-associated malignancies continue to present a major health concern despite the development of prophylactic vaccines. Standard therapies offer limited benefit to patients with advanced-stage disease. Despite improved outcomes with programmed cell death protein-1 (PD-1) targeted therapies, treatment resistance and modest response rates highlight a significant unmet need to develop novel therapies for these patients. PDS0101 (designated HPV vaccine) is a liposomal nanoparticle HPV16-specific therapeutic vaccine that has been shown to generate strong HPV-specific responses in preclinical and clinical studies. Here we assess the efficacy of this HPV vaccine in combination with the tumor-targeting immunocytokine NHS-IL12 (PDS01ADC), plus either αPD-1 or the class I histone deacetylase inhibitor Entinostat.Methods Mice bearing HPV16+, αPD-1 refractory TC-1 and mEER tumors were treated with HPV vaccine, NHS-IL12, and either αPD-1 or Entinostat to determine antitumor efficacy and survival benefits. A comprehensive analysis of the tumor microenvironment was performed using flow cytometry, multiplex immunofluorescence, chemokine and cytokine assessment, and single-cell RNA sequencing with T-cell receptor (TCR) enrichment.Results Combination of HPV vaccine and NHS-IL12 with either Entinostat or αPD-1 yielded significant antitumor activity and prolonged survival in αPD-1 refractory models of HPV16+ cancer, with superior activity employing Entinostat versus αPD-1 combination. Entinostat triple therapy increased overall and HPV16-specific tumor CD8+ T-cell infiltration with heightened cytotoxicity. TCR sequencing revealed a CD8+ T-cell clone unique to vaccine-treated cohorts, which displayed an enriched cytotoxic transcriptional profile with triple therapy. These effects were paralleled by strong differentiation of tumor-associated macrophages (TAMs) towards pro-inflammatory, antitumor M1-like cell states. Single-cell transcriptomic analysis indicated all three agents were required for highest modulation of both CD8+ T cells and TAMs conducive to tumor control. A biomarker signature reflecting the preclinical findings was found to be associated with improved survival in patients with HPV-associated malignancies.Conclusion Together, these findings provide a rationale for the combination of HPV vaccine, NHS-IL12, and Entinostat in the clinical setting for patients with HPV16-associated malignancies.https://jitc.bmj.com/content/13/5/e011074.full |
| spellingShingle | Jeffrey Schlom James L Gulley Caroline Jochems Sofia R Gameiro Wiem Lassoued Daniel Burnett Lisa K Poppe Nicholas Roller Miriam Marlene Medina-Enríquez Katherine E Lothstein Asma S Khelifa Masaya Miyamoto Combination of HDAC inhibition and cytokine enhances therapeutic HPV vaccine therapy Journal for ImmunoTherapy of Cancer |
| title | Combination of HDAC inhibition and cytokine enhances therapeutic HPV vaccine therapy |
| title_full | Combination of HDAC inhibition and cytokine enhances therapeutic HPV vaccine therapy |
| title_fullStr | Combination of HDAC inhibition and cytokine enhances therapeutic HPV vaccine therapy |
| title_full_unstemmed | Combination of HDAC inhibition and cytokine enhances therapeutic HPV vaccine therapy |
| title_short | Combination of HDAC inhibition and cytokine enhances therapeutic HPV vaccine therapy |
| title_sort | combination of hdac inhibition and cytokine enhances therapeutic hpv vaccine therapy |
| url | https://jitc.bmj.com/content/13/5/e011074.full |
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