VG161 activates systemic antitumor immunity in pancreatic cancer models as a novel oncolytic herpesvirus expressing multiple immunomodulatory transgenes

Abstract

The VG161 represents the first recombinant oncolytic herpes simplex virus type 1 carrying multiple synergistic antitumor immuno‐modulating factors. Here, we report its antitumor mechanisms and thus provide firm theoretical foundation for the upcoming clinical application in pancreatic cancer. Generally, the VG161‐mediated antitumor outcomes were analyzed by a collaboration of techniques, namely the single‐cell sequencing, airflow‐assisted desorption electrospray ionization‐mass spectrometry imaging (AFADSI‐MSI) and nanostring techniques. In vitro, the efficacy of VG161 together with immune checkpoint inhibitors (ICIs) has been successfully shown to grant a long‐term antitumor effect by altering tumor immunity and remodeling tumor microenvironment (TME) metabolisms. Cellular functional pathways and cell subtypes detected from patient samples before and after the treatment had undergone distinctive changes including upregulated CD8+ T and natural killer cells. More importantly, significant antitumor signals have emerged since the administration of VG161 injection. In conclusion, VG161 can systematically activate acquired and innate immunity in pancreatic models, as well as improve the tumor immune microenvironment, indicative of strong antitumor potential. The more robusting antitumor outcome for VG161 monotherapy or in combination with other therapies on pancreatic cancer is worth of being explored in further clinical trials.

HSV-1 Oncolytic Virus Targeting CEACAM6-Expressing Tumors Using a Bispecific T-Cell Engager

“…Oncolytic viruses (OVs) are a powerful tool for fighting cancer. Besides their ability to directly attack and lyse cancer cells, they have also demonstrated an impressive ability to induce a potent and lasting memory immune response against tumors [30][28]. Oncolytic virotherapy relies on tumor cell-specific changes associated with the hallmarks of cancer, including increased receptor expression, impaired antiviral response, and altered metabolism [32].…”

“…Viral infection in the tumor microenvironment may also provide a danger signal that partially counteracts the immunosuppressive tumor microenvironment. On the other hand, the BiTE will take advantage of the increased infiltration of T cells into the tumor induced by the OV treatment, which we have demonstrated in previous work [28], [29], promoting T-cell activation and tumor-cell killing in the presence of cells displaying a selected TAA on the cell surface.…”

“…Oncolytic viruses (OVs) have been engineered to express and deliver multiple payloads to tumors [11]. In particular, HSV-1-based OVs are known to have high capacity to accommodate multiple payloads [12] [13]. The virus may be engineered to express a variety of immunomodulators-such as IL-12, IL-15, and IL-15RA1-and it may be modified to enable tumor-specific virus replication and/or tumor-specific payload expression.…”

Oncolytic virotherapy: basic principles, recent advances and future directions

“…Our previous results demonstrated that VG161, together with anti-PD-1 monoclonal antibody (mAb), provided better therapeutic performance in PDAC humanized mouse model, and that a significant growth of CD8 + T cells and NK cells were observed in the combination group. 270 A combination of CF-33 and anti-PD-L1 therapy showed durable antigenspecific antitumor immunity and long-term survival against colon cancer in a syngeneic mouse model. 271 Interestingly, Nguyen et al addressed the significance of the timing of anti-PD-1 mAb to be administered in the combination treatment with OV.…”

Clinical diagnosis and management of pancreatic cancer: Markers, molecular mechanisms, and treatment options

“…For example, arginine glycine peptide-human serum albumin-mediated drug nanoparticles show tumor-targeting effects and increase the cytotoxicity of gemcitabine and curcumin[ 160 ]. Administration of VG161, the first recombinant oncolytic herpes simplex virus type 1 that delivers multiple synergistic antitumor immunomodulatory factors, can systematically activate both innate and adaptive immunity and improve the anti-tumor function of the tumor immune microenvironment[ 161 ]. Another study showed that using gold nanoparticles could enhance the intracellular delivery of oncolytic adenoviruses into PC cell lines[ 162 ].…”