In situ immunization of a TLR9 agonist virus-like particle enhances anti-PD1 therapy
Background CMP-001 is a novel Toll-like receptor-9 agonist that consists of an unmethylated CpG-A motif-rich G10 oligodeoxynucleotide (ODN) encapsulated in virus-like particles. In situ vaccination of CMP-001 is believed to activate local tumor-associated plasmacytoid dendritic cells (pDCs) leading...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2020-10-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/2/e000940.full |
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| author | Zhaoming Wang George J Weiner Yinwen Cheng Caitlin D Lemke-Miltner Wattawan Wongpattaraworakul Carlos H F Chan Aliasger K Salem Andrean L Simons |
| author_facet | Zhaoming Wang George J Weiner Yinwen Cheng Caitlin D Lemke-Miltner Wattawan Wongpattaraworakul Carlos H F Chan Aliasger K Salem Andrean L Simons |
| author_sort | Zhaoming Wang |
| collection | DOAJ |
| description | Background CMP-001 is a novel Toll-like receptor-9 agonist that consists of an unmethylated CpG-A motif-rich G10 oligodeoxynucleotide (ODN) encapsulated in virus-like particles. In situ vaccination of CMP-001 is believed to activate local tumor-associated plasmacytoid dendritic cells (pDCs) leading to type I interferon secretion and tumor antigen presentation to T cells and systemic antitumor T cell responses. This study is designed to investigate if CMP-001 would enhance head and neck squamous cell carcinoma (HNSCC) tumor response to anti-programmed cell death protein-1 (anti-PD-1) therapy in a human papilloma virus-positive (HPV+) tumor mouse model.Methods Immune cell activation in response to CMP-001±anti-Qβ was performed using co-cultures of peripheral blood mononuclear cells and HPV+/HPV- HNSCC cells and then analyzed by flow cytometry. In situ vaccination with CMP-001 alone and in combination with anti-PD-1 was investigated in C57BL/6 mice-bearing mEERL HNSCC tumors and analyzed for anti-Qβ development, antitumor response, survival and immune cell recruitment. The role of antitumor immune response due to CMP-001+anti-PD-1 treatment was investigated by the depletion of natural killer (NK), CD4+ T, and CD8+ T cells.Results Results showed that the activity of CMP-001 on immune cell (pDCs, monocytes, CD4+/CD8+ T cells and NK cells) activation depends on the presence of anti-Qβ. A 2-week ‘priming’ period after subcutaneous administration of CMP-001 was required for robust anti-Qβ development in mice. In situ vaccination of CMP-001 was superior to unencapsulated G10 CpG-A ODN at suppressing both injected and uninjected (distant) tumors. In situ vaccination of CMP-001 in combination with anti-PD-1 therapy induced durable tumor regression at injected and distant tumors and significantly prolonged mouse survival compared with anti-PD-1 therapy alone. The antitumor effect of CMP-001+anti-PD-1 was accompanied by increased interferon gamma (IFNγ)+ CD4+/CD8+ T cells compared with control-treated mice. The therapeutic and abscopal effect of CMP-001+ anti-PD-1 therapy was completely abrogated by CD8+ T cell depletion.Conclusions These results demonstrate that in situ vaccination with CMP-001 can induce both local and abscopal antitumor immune responses. Additionally, the antitumor efficacy of CMP-001 combined with α-PD-1 therapy warrants further study as a novel immunotherapeutic strategy for the treatment of HNSCC. |
| format | Article |
| id | doaj-art-c3dc7d83db9b40159de5cdcb3819d943 |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-10-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-c3dc7d83db9b40159de5cdcb3819d9432025-08-20T02:13:56ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-10-018210.1136/jitc-2020-000940In situ immunization of a TLR9 agonist virus-like particle enhances anti-PD1 therapyZhaoming Wang0George J Weiner1Yinwen Cheng2Caitlin D Lemke-Miltner3Wattawan Wongpattaraworakul4Carlos H F Chan5Aliasger K Salem6Andrean L Simons71Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA3 Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, Iowa, USA1 Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, Iowa, USA4 Department of Internal Medicine, The University of Iowa, Iowa City, Iowa, USA2 Department of Pathology, The University of Iowa, Iowa City, Iowa, USA3 Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, Iowa, USA3 Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, Iowa, USA1 Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, Iowa, USABackground CMP-001 is a novel Toll-like receptor-9 agonist that consists of an unmethylated CpG-A motif-rich G10 oligodeoxynucleotide (ODN) encapsulated in virus-like particles. In situ vaccination of CMP-001 is believed to activate local tumor-associated plasmacytoid dendritic cells (pDCs) leading to type I interferon secretion and tumor antigen presentation to T cells and systemic antitumor T cell responses. This study is designed to investigate if CMP-001 would enhance head and neck squamous cell carcinoma (HNSCC) tumor response to anti-programmed cell death protein-1 (anti-PD-1) therapy in a human papilloma virus-positive (HPV+) tumor mouse model.Methods Immune cell activation in response to CMP-001±anti-Qβ was performed using co-cultures of peripheral blood mononuclear cells and HPV+/HPV- HNSCC cells and then analyzed by flow cytometry. In situ vaccination with CMP-001 alone and in combination with anti-PD-1 was investigated in C57BL/6 mice-bearing mEERL HNSCC tumors and analyzed for anti-Qβ development, antitumor response, survival and immune cell recruitment. The role of antitumor immune response due to CMP-001+anti-PD-1 treatment was investigated by the depletion of natural killer (NK), CD4+ T, and CD8+ T cells.Results Results showed that the activity of CMP-001 on immune cell (pDCs, monocytes, CD4+/CD8+ T cells and NK cells) activation depends on the presence of anti-Qβ. A 2-week ‘priming’ period after subcutaneous administration of CMP-001 was required for robust anti-Qβ development in mice. In situ vaccination of CMP-001 was superior to unencapsulated G10 CpG-A ODN at suppressing both injected and uninjected (distant) tumors. In situ vaccination of CMP-001 in combination with anti-PD-1 therapy induced durable tumor regression at injected and distant tumors and significantly prolonged mouse survival compared with anti-PD-1 therapy alone. The antitumor effect of CMP-001+anti-PD-1 was accompanied by increased interferon gamma (IFNγ)+ CD4+/CD8+ T cells compared with control-treated mice. The therapeutic and abscopal effect of CMP-001+ anti-PD-1 therapy was completely abrogated by CD8+ T cell depletion.Conclusions These results demonstrate that in situ vaccination with CMP-001 can induce both local and abscopal antitumor immune responses. Additionally, the antitumor efficacy of CMP-001 combined with α-PD-1 therapy warrants further study as a novel immunotherapeutic strategy for the treatment of HNSCC.https://jitc.bmj.com/content/8/2/e000940.full |
| spellingShingle | Zhaoming Wang George J Weiner Yinwen Cheng Caitlin D Lemke-Miltner Wattawan Wongpattaraworakul Carlos H F Chan Aliasger K Salem Andrean L Simons In situ immunization of a TLR9 agonist virus-like particle enhances anti-PD1 therapy Journal for ImmunoTherapy of Cancer |
| title | In situ immunization of a TLR9 agonist virus-like particle enhances anti-PD1 therapy |
| title_full | In situ immunization of a TLR9 agonist virus-like particle enhances anti-PD1 therapy |
| title_fullStr | In situ immunization of a TLR9 agonist virus-like particle enhances anti-PD1 therapy |
| title_full_unstemmed | In situ immunization of a TLR9 agonist virus-like particle enhances anti-PD1 therapy |
| title_short | In situ immunization of a TLR9 agonist virus-like particle enhances anti-PD1 therapy |
| title_sort | in situ immunization of a tlr9 agonist virus like particle enhances anti pd1 therapy |
| url | https://jitc.bmj.com/content/8/2/e000940.full |
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