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In situ immunization of a TLR9 agonist virus-like particle enhances anti-PD1 therapy
Journal article   Open access   Peer reviewed

In situ immunization of a TLR9 agonist virus-like particle enhances anti-PD1 therapy

Yinwen Cheng, Caitlin D Lemke-Miltner, Wattawan Wongpattaraworakul, Zhaoming Wang, Carlos H F Chan, Aliasger K Salem, George J Weiner and Andrean L Simons
Journal for immunotherapy of cancer, Vol.8(2), e000940
10/2020
DOI: 10.1136/jitc-2020-000940
PMCID: PMC7566437
PMID: 33060147
url
https://doi.org/10.1136/jitc-2020-000940View
Published (Version of record) Open Access

Abstract

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. 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. 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. 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 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. vaccination of CMP-001 was superior to unencapsulated G10 CpG-A ODN at suppressing both injected and uninjected (distant) tumors. 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. These results demonstrate that 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.
 Immunotherapy head and neck neoplasms dendritic cells immunologic adjuvants vaccination

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