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

Shakoora A Sabree; Andrew P Voigt; Sue E Blackwell; Ajaykumar Vishwakarma; Michael S Chimenti; Aliasger K Salem; George J Weiner

doi:10.1136/jitc-2021-002484

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

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

Shakoora A Sabree, Andrew P Voigt, Sue E Blackwell, Ajaykumar Vishwakarma, Michael S Chimenti, Aliasger K Salem and George J Weiner

Journal for immunotherapy of cancer, Vol.9(6), p.e002484

06/03/2021

DOI: 10.1136/jitc-2021-002484

PMCID: PMC8183212

PMID: 34083419

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Abstract

BackgroundCMP-001, also known as vidutolimod, is a virus-like particle containing a TLR9 agonist that is showing promise in early clinical trials. Our group previously demonstrated that the immunostimulatory effects of CMP-001 are dependent on an anti-Qβ antibody response which results in opsonization of CMP-001 and uptake by plasmacytoid dendritic cells (pDCs) that then produce interferon (IFN)-α. IFN-α then leads to an antitumor T-cell response that is responsible for the in vivo efficacy of CMP-001. Here, we explore mechanisms by which the initial effects of CMP-001 on pDCs activate other cells that can contribute to development of an antitumor T-cell response.MethodsUptake of CMP-001 by various peripheral blood mononuclear cell (PBMC) populations and response to anti-Qβ-coated CMP-001 were evaluated by flow cytometry and single-cell RNA sequencing. Purified monocytes were treated with anti-Qβ-coated CMP-001 or recombinant IFN-α to evaluate direct and secondary effects of anti-Qβ-coated CMP-001 on monocytes.ResultsMonocytes had the highest per cell uptake of anti-Qβ-coated CMP-001 with lower levels of uptake by pDCs and other cell types. Treatment of PBMCs with anti-Qβ-coated CMP-001 induced upregulation of IFN-responsive genes including CXCL10, PDL1, and indoleamine-2,3-dioxygenase (IDO) expression by monocytes. Most of the impact of anti-Qβ-coated CMP-001 on monocytes was indirect and mediated by IFN-α, but uptake of anti-Qβ-coated CMP-001 altered the monocytic response to IFN-α and resulted in enhanced expression of PDL1, IDO, and CD80 and suppressed expression of CXCL10. These changes included an enhanced ability to induce autologous CD4 T-cell proliferation.ConclusionsAnti-Qβ-coated CMP-001 induces IFN-α production by pDCs which has secondary effects on a variety of cells including monocytes. Uptake of anti-Qβ-coated CMP-001 by monocytes alters their response to IFN-α, resulting in enhanced expression of PDL1, IDO and CD80 and suppressed expression of CXCL10. Despite aspects of an immunosuppressive phenotype, these monocytes demonstrated increased ability to augment autologous CD4 T-cell proliferation. These findings shed light on the complexity of the mechanism of action of anti-Qβ-coated CMP-001 and provide insight into pathways that may be targeted to further enhance the efficacy of this novel approach to immunotherapy.

Details

Title: Subtitle: Direct and indirect immune effects of CMP-001, a virus-like particle containing a TLR9 agonist
Creators: Shakoora A Sabree - Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA, USA
Andrew P Voigt - Department of Ophthalmology and Visual Sciences, The University of Iowa Hospitals and Clinics, Iowa City, IA, USA
Sue E Blackwell - Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA, USA
Ajaykumar Vishwakarma - Division of Pharmaceutics and Translational Therapeutics, The University of Iowa College of Pharmacy, Iowa City, IA, USA
Michael S Chimenti - Iowa Institute of Human Genetics, University of Iowa Carver College of Medicine, Iowa City, IA, USA
Aliasger K Salem - Division of Pharmaceutics and Translational Therapeutics, The University of Iowa College of Pharmacy, Iowa City, IA, USA
George J Weiner - Department of Internal Medicine, The University of Iowa Hospitals and Clinics, Iowa City, IA, USA
Resource Type: Journal article
Publication Details: Journal for immunotherapy of cancer, Vol.9(6), p.e002484
DOI: 10.1136/jitc-2021-002484
PMID: 34083419
PMCID: PMC8183212
NLM abbreviation: J Immunother Cancer
ISSN: 2051-1426
eISSN: 2051-1426
Grant note: name: NIH, award: P30 CA86862, P50 CA97274; name: Checkmate Pharmaceuticals; name: NCI Diversity Supplement
Language: English
Date published: 06/03/2021
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Hematology, Oncology, and Blood & Marrow Transplantation; The University of Iowa Institute for Vision Research; Pharmaceutical Sciences and Experimental Therapeutics; Craniofacial Anomalies Research Center; Dental Research; Chemical and Biochemical Engineering; Holden Comprehensive Cancer Center; Internal Medicine; Iowa Institute of Human Genetics
Record Identifier: 9984216697302771

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