Armed Oncolytic Myxoma Virus Induces Systemic Antitumor Immunity Against Solid Tumors in Immunocompetent Mice

Area of Science:

• Oncolytic virotherapy
• Immunooncology
• Viral vector engineering

Background:

• Oncolytic viruses (OVs) are promising cancer therapeutics.
• Engineering OVs with immunostimulatory transgenes can enhance antitumor immune responses.
• Myxoma virus (MYXV) is a potential oncolytic platform.

Purpose of the Study:

• To evaluate the oncolytic activity and therapeutic efficacy of MYXV recombinants expressing murine LIGHT (vMyx-mLIGHT), murine mIL-15, or IL-15Rα-IL-15 fusion protein (vMyx-IL15Rα).
• To assess the impact of these engineered MYXV variants on systemic antitumor immunity and the tumor microenvironment.

Main Methods:

• Construction and characterization of recombinant MYXV variants.
• Assessment of viral replication and cytotoxicity in cancer cell lines.
• Evaluation of therapeutic efficacy in a bilateral tumor model in immunocompetent mice.
• Analysis of tumor-infiltrating lymphocytes and serum cytokine profiles.

Main Results:

• All recombinant MYXVs exhibited similar replication and cytotoxic activity.
• Intratumoral treatment with vMyx-IL15Rα and vMyx-mLIGHT induced significant regression in both treated and untreated tumors, indicating systemic immunity.
• vMyx-IL15Rα treatment led to significantly longer survival and increased effector memory CD8+ T cells, NK cells, and NKT cells.
• vMyx-mLIGHT enhanced effector memory CD4+ T cells and dendritic cell infiltration.
• Both treatments modulated serum cytokine profiles, increasing antitumor cytokines and decreasing protumor inflammatory mediators.

Conclusions:

• Arming MYXV with immunostimulatory transgenes like IL-15Rα-IL-15 or mLIGHT enhances local and systemic antitumor activity.
• These engineered viruses remodel the tumor microenvironment to promote effective immune responses.
• vMyx-IL15Rα shows particular promise for enhancing systemic antitumor immunity and improving survival.