Abstract 1699: Direct and indirect immune effects of CMP-001, a virus like particle containing a TLR9 agonist

Abstract

Abstract Background: CMP-001, a virus-like particle (VLP) containing a TLR9 agonist encapsulated by the Qb capsid, is showing promise in early clinical trials when administered intratumorally. Prior work by our group has demonstrated the immunostimulatory effects of CMP-001 are dependent on generation of an anti-Qb antibody response which results in opsonization of CMP-001 by plasmacytoid dendritic cells (pDCs) and production of IFNa. The in vivo efficacy of CMP-001-mediated in situ immunization is T cell dependent. Here, we explore the mechanisms by which the initial effects of CMP-001 on pDCs can activate other cell populations that can contribute to development of an anti-tumor T cell response. Methods: Uptake of CMP-001 by various cell populations was evaluated by flow cytometry. Gene expression by various immune cell subsets in response to CMP-001 treatment was measured by single cell RNA sequencing (scRNAseq) of normal donor human PBMCs. Additional in vitro experiments were conducted to evaluate direct and secondary effects of CMP-001 on various immune cell subsets. Results: Anti-Qb antibody-coated CMP-001 were taken up extensively by monocytes with lower levels of uptake by B cells and pDCs. Antibody-coated CMP-001 induced upregulation of interferon-responsive genes and molecules by various cell types including CXCL10, PDL1, and IDO. Much of the impact of CMP-001 plus anti-Qb on monocytes was indirect and mediated by type I interferon. Expression by purified monocytes of PDL1 and IDO was increased in response to IFNa after treatment with CMP-001 plus anti-Qb whereas CXCL10 expression was decreased. Conclusions: CMP-001 plus anti-Qb induces production of type I interferon by pDCs. Type I interferon has secondary effects on a variety of cell types including monocytes which produce cytokines such as CXCL10 that can potentially impact the development of an anti-tumor T cell response. Uptake of anti-Qb-coated CMP-001 by monocytes has little direct effect on the monocytes. However, uptake of these particles by monocytes does alter the monocyte's response to type I interferon and results in enhanced expression of IDO and PDL1, and suppressed expression of CXCL10, consistent with generation of an immunosuppressive phenotype. These findings shed light on the complexity of the immune response to CMP-001, and provide insight into potential pathways that may be targeted in conjunction with CMP-001 to further enhance the efficacy of this novel approach to immunotherapy. Citation Format: Shakoora Sabree, Andrew Voigt, George J. Weiner, Sue Blackwell. Direct and indirect immune effects of CMP-001, a virus like particle containing a TLR9 agonist [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1699.