Inducing expression of ICOS-L by oncolytic adenovirus to enhance tumor-specific bi-specific antibody efficacy

• Published in: Journal of translational medicine Vol. 22; no. 1; pp. 250 - 14
• Main Authors: Saffarzadeh, Neshat, Foord, Emelie, O’Leary, Eoghan, Mahmoun, Rand, Birkballe Hansen, Thomas, Levitsky, Victor, Poiret, Thomas, Uhlin, Michael
• Format: Journal Article
• Language: English
• Published: London BioMed Central 07.03.2024; BioMed Central Ltd; BMC
• Subjects: Adenoviruses; Analysis; Antibodies; Bi-specific antibody; Biomedical and Life Sciences; Biomedicine; Bispecific antibodies; Cancer therapies; CD4 antigen; CD8 antigen; Cell; Cell activation; Cell proliferation; Cell surface; Clinical trials; Colony-stimulating factor; Control; Degranulation; FDA approval; Flow cytometry; Genetic engineering; Genotype & phenotype; Granulocyte-macrophage colony-stimulating factor; ICOS; Identification and classification; Immunotherapy; Ligands; Lymphocytes; Lymphocytes T; Macrophage colony stimulating factor; Medicine/Public Health; Melanoma; Metastases; Oncolysis; Oncolytic virus; Proteins; Skin cancer; T cell; tissue and gene therapy; Tumors; Viral proteins; Viruses; γ-Interferon; Sweden; Bi-specific antibody; Oncolytic virus; ICOS; T cell; Immunotherapy
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-024-05049-2

Background Intratumoral injection of oncolytic viruses (OVs) shows promise in immunotherapy: ONCOS-102, a genetically engineered OV that encodes Granulocyte–Macrophage Colony-Stimulating Factor (GM-CSF) demonstrated efficacy in early clinical trials, enhancing T cell infiltration in tumors. This suggests OVs may boost various forms of immunotherapy, including tumor-specific bi-specific antibodies (BsAbs). Methods Our study investigated in vitro, how ONCOS-204, a variant of ONCOS-virus expressing the ligand of inducible T-cell co-stimulator (ICOSL), modulates the process of T cell activation induced by a BsAb. ONCOS-102 was used for comparison. Phenotypic and functional changes induced by combination of different OVs, and BsAb in T cell subsets were assessed by flow cytometry, viability, and proliferation assays. Results Degranulation and IFNγ and TNF production of T cells, especially CD4 + T cells was the most increased upon target cell exposure to ONCOS-204. Unexpectedly, ONCOS-204 profoundly affected CD8 + T cell proliferation and function through ICOS-L/ICOS interaction. The effect solely depended on cell surface expression of ICOS-L as soluble ICOSL did not induce notable T cell activity. Conclusions Together, our data suggests that oncolytic adenoviruses encoding ICOSL may enhance functional activity of tumor-specific BsAbs thereby opening a novel avenue for clinical development in immunotherapeutics.