Abstract
Oncolytic virotherapy is a promising new tool for cancer treatment, but direct lytic destruction of tumor cells is not sufficient and must be accompanied by strong immune activation to elicit anti-tumor immunity. We report here the creation of a novel replication-competent recombinant oncolytic herpes simplex virus type 1 (VG161) that carries genes coding for IL-12, IL-15, and IL-15 receptor alpha subunit, along with a peptide fusion protein capable of disrupting PD-1/PD-L1 interactions. The VG161 virus replicates efficiently and exhibits robust cytotoxicity in multiple tumor cell lines. Moreover, the encoded cytokines and the PD-L1 blocking peptide work cooperatively to boost immune cell function. In vivo testing in syngeneic CT26 and A20 tumor models reveals superior efficacy when compared to a backbone virus that does not express exogenous genes. Intratumoral injection of VG161 induces abscopal responses in non-injected distal tumors and grants resistance to tumor re-challenge. The robust anti-tumor effect of VG161 is associated with T cell and NK cell tumor infiltration, expression of Th1 associated genes in the injection site, and increased frequency of splenic tumor-specific T cells. VG161 also displayed a superb safety profile in GLP acute and repeated injection toxicity studies performed using cynomolgus monkeys. Overall, we demonstrate that VG161 can induce robust oncolysis and stimulate a robust anti-tumor immune response without sacrificing safety.
Highlights
A diverse range of oncolytic viruses (OVs) has shown efficacy in preclinical studies
Cells were infected with VG161 for 72 h at MOI ranging from 0.04 to 1, and cell viability was quantified by MTT assay
These results are consistent with cytotoxicity data for the parental virus HSV-345 (ICP34.5 deleted Herpes simplex virus type 1 (HSV-1) strain 17), which shows dramatically impaired cell killing in mouse tumor cell lines 4T1 and CT26 when compared to the human colon adenocarcinoma cell line LS174T (Figure S1A)
Summary
A diverse range of oncolytic viruses (OVs) has shown efficacy in preclinical studies (reviewed in [1,2]). Only two OVs have cleared the hurdle of regulatory approval, consisting of the adenovirus H101 approved in China to treat head and neck cancer (4) and Talimogene laherparepvec (T-VEC) approved by the FDA for the treatment of advanced melanoma. It has become clear that direct infection and lysis of tumor cells is often not sufficient to generate a durable anti-tumor response. T-VEC was optimized for immunotherapy by expressing the cytokine granulocyte macrophage colony-stimulating factor (GM-CSF) and can generate systemic anti-tumor immunity as evidenced by observations of tumor regression in noninjected lesions [3,4,5,6,7]. It is apparent that a more robust immune response must be elicited in addition to potent oncolysis for an OV therapy to achieve long-lasing efficacy in the clinic
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