Deletion of Apoptosis Inhibitor F1L in Vaccinia Virus Increases Safety and Oncolysis for Cancer Therapy

Abstract

Vaccinia virus (VACV) possesses a great safety record as a smallpox vaccine and has been intensively used as an oncolytic virus against various types of cancer over the past decade. Different strategies were developed to make VACV safe and selective to cancer cells. Leading clinical candidates, such as Pexa-Vec, are attenuated through deletion of the viral thymidine kinase (TK) gene, which limits virus growth to replicate in cancer tissue. However, tumors are not the only tissues whose metabolic activity can overcome the lack of viral TK. In this study, we sought to further increase the tumor-specific replication and oncolytic potential of Copenhagen strain VACV ΔTK. We show that deletion of the anti-apoptosis viral gene F1L not only increases the safety of the Copenhagen ΔTK virus but also improves its oncolytic activity in an aggressive glioblastoma model. The additional loss of F1L does not affect VACV replication capacity, yet its ability to induce cancer cell death is significantly increased. Our results also indicate that cell death induced by the Copenhagen ΔTK/F1L mutant releases more immunogenic signals, as indicated by increased levels of IL-1β production. A cytotoxicity screen in an NCI-60 panel shows that the ΔTK/F1L virus induces faster tumor cell death in different cancer types. Most importantly, we show that, compared to the TK-deleted virus, the ΔTK/F1L virus is attenuated in human normal cells and causes fewer pox lesions in murine models. Collectively, our findings describe a new oncolytic vaccinia deletion strain that improves safety and increases tumor cell killing.

Single-dose replicating poxvirus vector-based RBD vaccine drives robust humoral and T cell immune response against SARS-CoV-2 infection

“…Since then, many attenuations have been discovered that reduce the health risks of VACV strains even further. [36][37][38][39][40][41] In our lab, we have engineered oncolytic VACV variants used to treat immunocompromised cancer patients without safety concerns. [36][37][38]42 In this study, we evaluated the use of a replication-competent attenuated Tiantan (TT) strain of VACV as vector for a COVID-19 vaccine.…”

In situ cancer vaccination using lipidoid nanoparticles

“…Activation of the tumor immunological response via delivery of the oncolytic virus has been the most common method for in situ vaccination and has reached the stage of clinical trials for the treatment of metastatic melanoma (8,9). However, the excessive systemic activation of the immune system by the oncolytic virus, which might lead to severe side effects such as the cytokine release syndrome (CRS), has become a major concern about the application of this strategy in humans (10). To date, some other in situ vaccination strategies, including photothermal therapy (PTT), radiation therapy (RT), agonist immunotherapy, and even in situ chemotherapy, were also shown to induce effective immune response (11)(12)(13)(14)(15).…”

Deciphering the Immunomodulatory Capacity of Oncolytic Vaccinia Virus to Enhance the Immune Response to Breast Cancer

“…It also did not impart a survival benefit in the 4T1 tumor model compared with DJ2R, whereas the rest of our immunogenic knockout viruses did improve this response. It can be noted, however, that a DF1LDJ2R virus is more effective than DJ2R alone in treating subcutaneous colon tumors in mice (38). Similarly, DF4LDJ2R VACV, which demonstrated superior safety and equal treatment efficacy in bladder tumor models compared with a DJ2R VACV (20), was not therapeutically superior in 4T1 or TuBo breast tumor models.…”