Deletion of immunomodulatory genes as a novel approach to oncolytic vaccinia virus development

Abstract

Vaccinia virus (VV) has emerged as a promising platform for oncolytic virotherapy. Many clinical VV candidates, such as the double-deleted VV, vvDD, are engineered with deletions that enhance viral tumor selectivity based on cellular proliferation rates. An alternative approach is to exploit the dampened interferon-based innate immune responses of tumor cells by deleting one of the many VV immunomodulatory genes expressed to dismantle the antiviral response. We hypothesized that such a VV mutant would be attenuated in non-tumor cells but retain the ability to effectively propagate in and kill tumor cells, yielding a tumor-selective oncolytic VV with significant anti-tumor potency. In this study, we demonstrated that VVs with a deletion in one of several VV immunomodulatory genes (N1L, K1L, K3L, A46R, or A52R) have similar or improved in vitro replication, spread, and cytotoxicity in colon and ovarian cancer cells compared to vvDD. These deletion mutants are tumor selective, and the best performing candidates (DK1L, DA46R, and DA52R VV) are associated with significant improvement in survival, as well as immunomodulation, within the tumor environment. Overall, we show that exploiting the diminished antiviral responses in tumors serves as an effective strategy for generating tumor-selective and potent oncolytic VVs, with important implications in future oncolytic virus (OV) design.

Disruption of the cGAS/STING axis does not impair sensing of MVA in BHK21 cells

“…Poxviruses are also employed as oncolytic viruses where the virus preferentially replicates and destroys tumour cells. There have been reports of increased efficacy upon deletion of immunomodulatory genes [59,60], further limiting the tropism of the modified viruses to tumour cells with disrupted innate sensing. The functional redundancy of poxviral immunomodulators makes studying attenuated strains or those with genomic deletions an attractive prospect.…”

Comprehensive assessment on the applications of oncolytic viruses for cancer immunotherapy

“…Expressing HSV-derived, truncated TK in oVV renders the virus susceptible to treatment with ganciclovir without affecting tumor selectivity, thereby strengthening the safety profile of oVV ( Islam et al, 2020 ). oVVs deleted for virus-encoded immune evasion genes also hold potential as agents for driving tumoral selectivity in future studies, leaving intact the viral TK gene ( Ho et al, 2021 ).…”

The employment of vaccinia virus for colorectal cancer treatment: A review of preclinical and clinical studies

“… i.p. 37 vA34 R Western reserve Mutated A34 R Improved spread and increased replication within the peritoneal cavity. i.p.…”

“… 72 A52 R also contains TIR domain and potently blocks NF-κB activation induced by IL-1 and TLR4. 73 Ho TY et al 37 tested a panel of VV with a deletion of immunomodulatory genes like N1 L, K1 L, K3 L, A46 R, or A52 R in treating colon and ovarian cancer. The mutation of K1 L, A46 R, and A52 R potentiated the ability of VV in prolonging survival and immunomodulation in animal models.…”

“…The mutation of K1 L, A46 R, and A52 R potentiated the ability of VV in prolonging survival and immunomodulation in animal models. 37 The deletion of some immunomodulatory genes in VV might be a promising way for the enhancement of VV potency in cancer therapy.…”