Systemic armed oncolytic and immunologic therapy for cancer with JX-594, a targeted poxvirus expressing GM-CSF

Area of Science:

• Oncolytic virotherapy
• Cancer immunotherapy
• Gene therapy

Background:

• Targeted oncolytic viruses and immunostimulatory therapeutics are emerging cancer treatments.
• Combining these approaches involves expressing cytokines from viruses like adenoviruses and herpesviruses.
• Intratumoral injection shows tumor inhibition but not metastasis eradication, limited by inefficient delivery and lack of predictive models.

Purpose of the Study:

• To develop a novel oncolytic virus for intravenous delivery to overcome limitations of current approaches.
• To evaluate the efficacy of JX-594, a targeted vaccinia virus expressing human GM-CSF, in immunocompetent preclinical cancer models.

Main Methods:

• Developed JX-594, a thymidine kinase-negative vaccinia virus engineered to express human granulocyte-macrophage colony-stimulating factor (hGM-CSF).
• Administered JX-594 intravenously (i.v.) in two immunocompetent liver tumor models: a rabbit model with lung metastases and a rat liver cancer model.
• Assessed tumor growth inhibition, metastasis prevention, virus replication, gene expression, systemic cytokine levels, and tumor-infiltrating cytotoxic T lymphocytes (CTLs).

Main Results:

• Intravenous JX-594 demonstrated significant efficacy and tolerability in both models, achieving complete responses against primary liver tumors.
• JX-594 treatment completely prevented the development of lung metastases in rabbits, unlike in control groups.
• Evidence of tumor-specific viral replication, hGM-CSF expression, and increased tumor-infiltrating CTLs confirmed the therapeutic mechanism.

Conclusions:

• JX-594 is a promising candidate for intravenous delivery as a targeted oncolytic virotherapy.
• The developed immunocompetent preclinical models are valuable for optimizing this novel cancer treatment strategy.