Generation of a Novel Oncolytic Vaccinia Virus Using the IHD-W Strain

Abstract

Oncolytic viruses are promising cancer therapies due to their selective killing of tumor cells and ability to stimulate the host immune system. As an oncolytic virus platform, vaccinia virus has unique advantages, including rapid replication, a broad range of host targets, and a large capacity for transgene incorporation. In this study, we developed a novel oncolytic vaccinia virus with high potency and a favorable safety profile. We began with the International Health Department-White (IHD-W) strain, which had the strongest cytotoxicity against tumor cells among the four vaccinia virus strains tested. Next, several candidate viruses were constructed by deleting three viral genes (C11R, K3L, and J2R) in various combinations, and their efficacy and safety were compared. The virus ultimately selected, named KLS-3010, exhibited strong antitumor activity against broad targets in vitro and in vivo. Furthermore, KLS-3010 showed a favorable safety profile in mice, as determined by the biodistribution and body weight change. More promisingly, KLS-3010 was able to shift the tumor microenvironment to a proinflammatory state, as evidenced by an increase in activated lymphocytes after KLS-3010 administration, suggesting that this strain may elicit an oncolytic virus-mediated immune response. The KLS-3010 strain thus represents a promising platform for the further development of oncolytic virus-based cancer therapies.

Transgenic viral expression of PH-20, IL-12, and sPD1-Fc enhances immune cell infiltration and anti-tumor efficacy of an oncolytic virus

“…In a previous study, we generated the novel oncolytic virus KLS-3010 by deletion of three viral genes (C11R, K3L, and J2R) from the vaccinia virus IHD-W strain. 10 KLS-3010 has robust anti-tumor activity and activates the immune response in the tumor microenvironment. To enhance its efficacy, we developed the KLS-3020 virus by inserting human PH-20, murine IL-12, and murine sPD1-Fc into KLS-3010 ( Figure 1 A).…”

“…K3L and J2R shuttle plasmids were described in the previous report. 10 Briefly, K3L shuttle plasmid 1 contains the left and right flanking regions of the K3L gene on each side of the dsRedII gene under the regulation of the p7.5 promoter, and K3L shuttle plasmid 2 contains the GusA gene instead of dsRedII. Similar to K3L shuttle plasmids, the J2R shuttle plasmid carries an EGFP gene regulated by a synthetic early/late (pE/L) promoter and left and right flanking regions of the J2R gene.…”

“… 9 In our previous study, we generated a novel OV, KLS-3010, by deleting three viral genes (C11R, J2R, and K3L) from the vaccinia virus International Health Department-White (IHD-W) strain. 10 In the present study, KLS-3010 was used as a viral backbone, and three transgenes were selected to overcome the current limitations of OV approaches and increase the therapeutic efficacy of KLS-3010. The therapeutic efficacy of KLS-3020, the recombinant virus containing the three transgenes, was evaluated, as were the effects of each transgene expressed singly.…”

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.…”

Oncolytic Bacterial and Viral Therapies as Cancer Prevention and Treatment Options: A Comprehensive Review

“…This virus has been demonstrated to be effective in the treatment of tumors in melanoma animal models (90). VV is a prospective oncolytic agent for cancer therapy owing to a number of benefits, including its capacity to infect a broad range of cancer cells, a good safety profile in persons with a history of smallpox vaccination, and the ability to contain transgenes in their genome (91). Additional advantages of VV include rapid replication, a high level of gene expression, the capacity to pass cell to cell, and the fact that the virus's activity is unaffected by hypoxia or therapeutic irradiation (92).…”