Bioengineered Phages for Precision TME Targeting and Therapy Delivery

Jeya Chelliah B.VSc Ph.D.

This innovative research proposal introduces the use of bioengineered bacteriophages (phages) as a novel strategy to breach the TME barriers and enhance the delivery and efficacy of immunotherapies and other cancer treatments. Bacteriophages, viruses that infect bacteria, have been recognized for their specificity and ability to be genetically modified. By leveraging these properties, we propose to engineer bacteriophages to target specific components of the TME, deliver therapeutic agents directly into the tumor, and modulate the immune microenvironment to promote anti-tumor immunity.

Research Objectives:

1. Bioengineering Phages to Target the TME: Develop bacteriophages engineered with surface proteins that specifically bind to markers unique to the TME, such as cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), or specific ECM components.
2. Delivery of Therapeutic Agents: Incorporate genetic payloads into the phages that encode for therapeutic agents, such as cytokines (e.g., IL-12, IFN-γ) to activate immune responses, checkpoint inhibitors to block immune suppression, or enzymes that degrade the ECM to improve tissue penetration.
3. Modulation of the Immune Microenvironment: Engineer phages to express surface molecules or release factors that recruit and activate immune cells within the TME, converting an immunosuppressive environment into an immunostimulatory one.

Methodology:

• Phage Engineering: Utilize genetic engineering techniques to modify bacteriophages with targeting ligands and therapeutic payloads.
• In Vitro Testing: Assess the specificity of engineered phages for TME components, their ability to deliver therapeutic payloads, and their impact on cultured cancer cells and immune cells.
• In Vivo Efficacy: Evaluate the therapeutic potential of the engineered phages in mouse models of cancer, focusing on their ability to penetrate the TME, deliver therapies, and elicit anti-tumor immune responses.
• Safety and Specificity: Conduct studies to ensure that the engineered phages are safe, do not infect human cells, and are cleared by the body after delivering their therapeutic payload.

Expected Outcomes:

• Enhanced Delivery of Therapies: Direct delivery of therapeutic agents into the TME, overcoming physical and biochemical barriers that limit the efficacy of current treatments.
• Modulation of the TME: Transformation of the immunosuppressive TME into an environment that supports robust anti-tumor immunity.
• Precision Targeting: Minimized off-target effects and reduced toxicity compared to systemic therapies, due to the specificity of phage targeting.

Significance:

This novel approach has the potential to revolutionize cancer treatment by overcoming one of the major hurdles in oncology—the effective penetration and modulation of the TME. By harnessing the unique properties of bacteriophages for targeted delivery and TME modulation, this research could pave the way for more effective and less toxic cancer therapies, opening new avenues for the treatment of solid tumors.

Future Directions:

Future research could explore the combination of bioengineered phages with other treatment modalities, such as chemotherapy and radiation, to synergize and enhance overall treatment efficacy. Additionally, investigating the use of phages to target metastatic niches could offer new strategies for preventing and treating metastatic disease.