Enhancement of Oncolytic Activity of oHSV Expressing IL-12 and Anti PD-1 Antibody by Concurrent Administration of Exosomes Carrying CTLA-4 miRNA

Abstract

Systemic administration of checkpoint inhibitors alone and especially concurrent with intratumoral administration of oncolytic herpesviruses (oHSV) has a major impact on cancer therapy marred by rare failures of healthy organs.Furthermore, tumors vary with respect to susceptibility to oncolytic effects of oHSV. Here we report the construction and properties of 3 families of oncolytic herpes simplex viruses expressing no immunomodulatory genes (T1 series), murine IL-12 (T2 series) or murine or human IL-12 and anti PD-1 antibody (T3 series). We report that insertion of the gene encoding PD-1 Ab significantly augmented the oncolytic activity of oHSV bereft of immunostimulatory genes (T1 series) or expressing IL-12 alone (T2 series). The T3 oHSV expressed IL-12, PD-1 Ab were restricted to the tumor bed whereas the induced IFN-γ accumulated to high levels both in tumor bed and in blood. Furthermore, the T3 oHSV was superior to systemic administration of IL-12 and antibody to PD-1. This report also shows that the oncolytic activity of T3 oHSV in a relatively resistant tumor was enhanced by concurrent intratumoral administration of genetically engineered exosomes carrying miRNA targeting CTLA-4 checkpoint.

β-Adrenergic Receptor Inhibitor and Oncolytic Herpesvirus Combination Therapy Shows Enhanced Antitumoral and Antiangiogenic Effects on Colorectal Cancer

“…In addition to CT26WT cell line (cultured in RPMI 1640 medium (Gibco, Life Technologies, China) supplemented with 10% FBS), the other cell lines were cultured in DMEM medium (Gibco, Life Technologies, China) supplemented with 10% FBS (HCT116 and MC38) or 5% newborn calf serum (Vero cell) (Gibco, Life Technologies, Australia) at 37 °C and 5% CO 2 in tissue culture incubator. The virus T1012G was obtained by single knocking γ34.5 on the basis of wild type F strain (Yan et al, 2019). Phase II clinical trials evaluating NV1020, an oncolytic herpesvirus (oHSV), have been completed in the US and showed safety and effectiveness in patients with colon cancer or liver cancer (Geevarghese et al, 2010).…”

β-adrenergic Receptor Inhibition Enhances Oncolytic Herpes Virus Propagation Through STAT3 Activation in Gastric Cancer

“…All cell lines were cultured in DMEM medium (Gibco,Life Technologies, China) supplemented with 10% FBS (HGC-27,AGS and MFC) or 5% newborn calf serum (vero) (Gibco, Life Technologies Australia) at 37°C and 5% CO 2 in tissue culture incubator. The virus T1012G was obtained by single knocking γ34.5 on the basis of wild type F strain (30). All experiments were performed with mycoplasma-free cells.…”

Delivery of cancer therapies by synthetic and bio-inspired nanovectors

“…trimerized CD137L, IL-12) that are toxic or even lethal when used systematically without proper vectorization. It also facilitates combinations, for example by inserting into large DNA virus genomes multiple immunotherapeutic transgenes (e.g IL-12 + anti-PD-L1) targeting different immune mechanisms for synergistic effects with no additional toxicity [296][297][298].…”

“…OV infection also promotes T cell infiltration in the infected tumors and could improve the efficacy of immune checkpoint inhibitors [ 293 ]. The vectorization of immunomodulating transgenes with OVs or VLPs turns cancer cells into therapeutic factories within the TME [ 86 , 294 ] as shown with immune checkpoint inhibitors encoded from engineered viruses [ 295 , 296 ]. This changes the pharmacokinetics of immunotherapies and enables the use of potent immune activators (e.g.…”