VSV strains with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents

Area of Science:

• Virology
• Oncology
• Gene Therapy

Background:

• Oncolytic viruses offer a promising strategy for cancer treatment by selectively targeting and destroying malignant cells.
• Ideal oncolytic viruses should replicate in tumors, combat metastases, and be cleared post-treatment.
• Vesicular stomatitis virus (VSV) is a potential candidate, but its widespread use is limited by safety concerns.

Purpose of the Study:

• To evaluate the efficacy and safety of two novel attenuated VSV strains, AV1 and AV2, as oncolytic agents.
• To elucidate the mechanism of selective attenuation of AV1 and AV2 in interferon-responsive cells.
• To assess the therapeutic potential of AV1 and AV2 in preclinical cancer models.

Main Methods:

• In vitro characterization of AV1 and AV2 replication in human tumor cell lines and normal cells.
• Investigation of the mechanism underlying selective viral attenuation.
• In vivo efficacy studies using xenograft models of human ovarian cancer and immunocompetent mouse models of metastatic colon cancer.

Main Results:

• AV1 and AV2 demonstrated selective replication in 80% of tested human tumor cell lines while being attenuated in interferon-responsive cells.
• Systemic administration of AV1 and AV2 resulted in complete and durable cures in the majority of animals across both ovarian and colon cancer models.
• The viruses were attenuated in normal mice, suggesting a favorable safety profile.

Conclusions:

• Attenuated VSV strains AV1 and AV2 possess the desired characteristics of an oncolytic virus, including tumor selectivity, anti-metastatic activity, and patient clearance.
• AV1 and AV2 represent a promising platform for systemic oncolytic virotherapy with potential for durable cancer cures.