Spatial Control of CAR T Cell Activation Using Tumor-Homing Polymers

Area of Science:

• Biotechnology
• Synthetic Biology
• Immunotherapy

Background:

• CAR T cell therapies face challenges with specificity, leading to insufficient tumor targeting and off-tumor toxicities.
• Developing strategies for precise anatomical control of CAR T cells is crucial for improving therapeutic efficacy and safety.

Purpose of the Study:

• To develop and demonstrate a novel framework, IMPACT (In situ Mobilization: Polymer Activated Cell Therapies), for polymer-mediated, anatomical control of CAR T cells.
• To engineer CAR T cells and a tumor-localizing polymer for conditional activation within the tumor microenvironment.

Main Methods:

• Designed a synthetic biology approach combining engineered CAR T cells with a tumor-localizing polymer.
• Developed an injectable polymer that binds to fibrin deposits in tumors and displays fluorescein.
• Engineered CAR T cells to express a payload only upon engagement with the fluorescein-displayed polymer within the tumor.

Main Results:

• Successfully developed the polymer and CAR T cell components of the IMPACT framework.
• Demonstrated tumor-localized CAR T cell activation in a murine tumor model following intravenous administration of the polymer and engineered T cells.
• Showcased conditional expression of a protein within tumors based on polymer-cell interaction.

Conclusions:

• The IMPACT framework enables precise, polymer-mediated anatomical control of CAR T cell therapies.
• This approach offers a potential strategy to enhance CAR T cell specificity and reduce off-tumor toxicities.
• IMPACT holds promise for advancing targeted cancer immunotherapies.