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

Abstract

BackgroundCMP-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.MethodsImmune 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.ResultsResults 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.ConclusionsThese 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.

Direct and indirect immune effects of CMP-001, a virus-like particle containing a TLR9 agonist

“…We recently demonstrated that the efficacy of CMP-001 depends on generation of an anti-Qβ antibody response which allows for opsonization of CMP-001, uptake by pDCs and subsequent production of IFN-α. 2 3 We also demonstrated the antitumor activity of CMP-001 in a mouse model is T cell dependent. 4 Nevertheless, much remains to be understood about the mechanism of action of CMP-001, how it alters various immune cells found in the TME and how it is the same or different from soluble TLR9 agonists.…”

“…Intratumoral injection of CMP-001, with the goal of altering the TME and successfully inducing Open access an in situ antitumor immune response, is showing considerable promise in early-phase clinical trials. [1][2][3][4] Encouraging results have also been found with intratumoral injection of soluble TLR9 agonists. 50 Despite this, the long-term feasibility of using soluble TLR9 agonists is limited by its sensitivity to nucleases and short half-life.…”

“…In situ immunization through local manipulation of the TME is showing promise in both preclinical studies and early clinical trials. [1][2][3][4] In situ immunization with TLR9 agonists is particularly attractive as they are potent immunostimulatory agents capable of inducing both innate and adaptive immunity. 5 6 In humans, TLR9 is expressed by plasmacytoid dendritic cells (pDCs) and B cells and can be activated by deoxynucleotides containing unmethylated CpG motifs.…”

Next‐Generation Vaccines: Nanoparticle‐Mediated DNA and mRNA Delivery

“…In fact, CMP‐001 dramatically enhanced tumor response to anti‐PD‐1 therapy and was shown to activate plasmacytoid dendritic cells (pDCs), as well as natural killer (NK) cells in a human papilloma virus‐positive (HPV+) tumor mouse model. [ 159 ] CMP‐001 is currently undergoing clinical trials in combination with PD‐1 blockade in multiple tumor types such as melanoma, colon, HNSCC, and lymphoma.…”

TLRs as a Promise Target Along With Immune Checkpoint Against Gastric Cancer

“…Combining anti-PD-1 with CMP-001 (a TLR-9 agonist) to treat head and neck squamous cell carcinoma (HNSCC) had a better effect and prolonged the survival time of mouse, compared with anti-PD-1 alone. And CMP-001+anti-PD-1 induced anti-tumor response depends on activation of CD8+ T cells (Cheng et al, 2020). In addition to depending on CD8+ cells, there are other mechanisms that promote the efficacy of checkpoint blockade therapy.…”