Induction of Durable Antitumor Response by a Novel Oncolytic Herpesvirus Expressing Multiple Immunomodulatory Transgenes

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.

In Situ Cancer Vaccination and Immunovirotherapy Using Oncolytic HSV

“…Depletion of CD4 + T cells or IFNγ abrogated combination efficacy, whereas anti-CD8 reduced responses to the level seen with R-123 alone, and NK cell depletion had only a modest effect [ 171 ]. VG161 encodes four transgenes (IL-12, IL-15, IL-15Rα, and PD-L1 blocker) in a backbone deleted for γ34.5 and the terminal repeat [ 60 ]. In a bilateral A20 model, mVG161 treatment only resulted in improved inhibition of non-injected tumors versus VG160 (no transgenes).…”

“…In a bilateral A20 model, mVG161 treatment only resulted in improved inhibition of non-injected tumors versus VG160 (no transgenes). Although tumor-infiltrating immune cells and tumor-specific IFNγ-expressing splenocytes in vitro were increased after mVG161 treatment in CT26 tumor-bearing mice, the differences compared to VG160 were not significant [ 60 ]. VG161 is currently in phase I clinical trials in China for patients with advanced solid tumors (NCT04758897) and liver cancer (NCT04806464).…”

Strategies to Optimise Oncolytic Viral Therapies: The Role of Natural Killer Cells

“…OVs have also been manipulated to secrete selected cytokines [ 82 , 83 , 84 ] and chemokines [ 85 ] to augment NK responses and improve OV efficacy. Engineered oncolytic HSV [ 82 ] and vaccinia virus [ 83 ] that secrete interleukin(IL)-15, a cytokine that preferentially stimulates NK cell and CD8 T cell function and proliferation, were both shown to improve OV effectiveness compared to unmodified viruses, with [ 83 ] and without [ 82 ] combination with immune checkpoint inhibitors.…”

“…Engineered oncolytic HSV [ 82 ] and vaccinia virus [ 83 ] that secrete interleukin(IL)-15, a cytokine that preferentially stimulates NK cell and CD8 T cell function and proliferation, were both shown to improve OV effectiveness compared to unmodified viruses, with [ 83 ] and without [ 82 ] combination with immune checkpoint inhibitors. Additional transgenes have also been inserted to create an oncolytic HSV (VG161) that enabled the concurrent expression of IL-12, IL-15 and IL-15 receptor alpha subunit, and showed improved effectiveness in two syngeneic in vivo models [ 84 ]. CCL5 is a key chemokine that induces chemotaxis of NK and other immune cells to inflammatory sites and cancer, and CCL5-expressing oncolytic vaccinia virus was shown to promote NK cell infiltration and anti-tumour activity, a xenograft model of colonic cancer [ 85 ].…”

Oncolytic Viruses in Tumor Therapy: The Russian Perspective

“…During the evolution, viruses have developed various mechanisms to control the immune response, which, in principle, can be redirected to destroy cancer cells through eliciting both antiviral and anti-tumor immune responses. Importantly, the infection of individual tumor cells stimulates the so called abscopal effect, the destruction of its uninfected areas, including metastases [36]. This effect is achieved by the release of a wide range of antigens upon cell death, i. e. death associated molecular patterns (DAMPs), which in turn trigger both innate and acquired anti-tumor immune responses [37,38].…”