Synapse-tuned CARs enhance immune cell anti-tumor activity

Area of Science:

• Immunology
• Cancer Therapy
• Cellular Engineering

Background:

• Chimeric antigen receptor (CAR) therapies are effective against blood cancers but struggle with solid tumors.
• Natural killer (NK) cells offer inherent anti-tumor capabilities, making them promising for CAR-based treatments.
• Optimizing CAR T and CAR NK cell interactions at the immune synapse is crucial for enhancing anti-tumor responses.

Purpose of the Study:

• To engineer CARs with an intracellular PDZ binding motif (PDZbm) to enhance immune synapse formation and function.
• To evaluate the impact of this synapse tuning on CAR T and CAR NK cell efficacy against solid tumors.
• To assess improvements in effector cell functionality, cytokine secretion, tumor cell killing, and survival.

Main Methods:

• Engineered CARs incorporating a PDZ binding motif (PDZbm) for enhanced intracellular scaffolding.
• Utilized both Natural Killer (NK) cells and T cells expressing the modified CARs.
• In vitro and in vivo experiments to assess CAR immune cell function, including synapse formation, cytokine release, tumor cell killing, and survival in various solid tumor models.

Main Results:

• The PDZbm-engineered CARs significantly enhanced immune synapse formation and NK CAR cell polarization.
• Synapse-tuned CAR T and CAR NK cells demonstrated amplified synaptic strength and increased abundance of secreted cytokines.
• Demonstrated enhanced killing of tumor cells and prolonged survival across multiple solid tumor models.

Conclusions:

• Incorporating a PDZ binding motif into CARs effectively tunes the immune synapse, boosting CAR T and CAR NK cell anti-tumor activity.
• This novel CAR design shows significant potential for overcoming the limitations of current CAR therapies in treating solid tumors.
• Synapse-tuned CARs represent a promising advancement in cellular immunotherapy for a broader range of cancers.