Methioninase Inducing Virus for Anti-Cancer Therapy

Application

A set of viral constructs that induce regulatable expression of methionine degrading enzyme for treatment of brain tumors.

Key Benefits

• Built-in Tet-responsive element ensures precise regulation, preventing unwanted enzyme activity.
• IL-2 signal directs the enzyme for secretion, optimizing its therapeutic impact.
• Specific delivery to cancer cells, minimizing off-target effects.
• Can potentially be introduced into macrophages ex vivo and re-injected in vivo, allowing them to naturally migrate to the tumor environment.

Market Summary

Medulloblastoma (MB), a tumor of the cerebellum, is the most frequent brain cancer in childhood and a major cause of pediatric mortality. There are over 400 new cases diagnosed each year in the United States, with over 70% of them being in children. The 5-year survival rate is approximately 80%, though survival rates can vary greatly depending on age, spread, recurrence, and subtype. The first treatment for MB is surgery to remove as much of the tumor as possible without creating additional symptoms for the patient. This is typically followed by radiation and/or chemotherapy. Methionine is an essential amino acid and plays a crucial role in modulating health, but many tumors are addicted to methionine. MB depends on a robust supply of methionine. Dietary methionine deprivation was shown to impair tumor growth, but stronger, targeted, and controlled methionine deprivation in the local environment is needed.

Technical Summary

Emory researchers have designed recombinant viral constructs that can transduce cells to express and secrete bacterial METase. They induce tumor cells or cells in the tumor microenvironment to express METase, depleting the tumor environment of methionine. The DNA coding sequence of bacterial methioninase was optimized and placed into a Cre-conditional viruses, including the MSCV virus and the RCAS virus. Secretion signal sequences were added to the construct to promote extracellular secretion of the enzyme. The requirement for Cre expression provides a safety switch to prevent widespread methioninase expression, which is helpful because normal cells in the brain need methionine. Intratumoral injection of drugs into the brain evades the blood-brain-barrier and reduces systemic side effects. Engineering macrophages to deliver drugs to tumor sites in a targeted manner could yield a promising strategy for cancer treatment. This approach can potentially enhance the effectiveness of current therapies and reduce side effects.

Development Stage

• Pilot studies show METase expression in glioblastoma-bearing mice significantly extended survival compared to saline controls.
• METase was stably expressed in tumor cells for weeks post-virus injection without causing brain injury, neurologic issues, or autoimmune reactions.
• Ongoing work focuses on optimizing METase delivery to further improve anti-tumor efficacy.