CHANCELLOR'S PROFESSOR UCLA Los Angeles, California, United States
Introduction: : Immune cells are sensitive to mechanical cues in the microenvironment, but how to harvest this potential for cell engineering and disease therapy remains to be addressed. Chimeric antigen receptor (CAR)-T cells have tremendous potential for cancer therapy, yet the ex vivo expansion of CAR-T cells faces the challenges of donor-to-donor variability, inconsistent cell products, and the lack of control of expanded cell subpopulations.
Materials and
Methods: : Here we develop a scalable microfluidic platform to fabricate microspheres as synthetic viscoelastic activating cells (SynVACs) with programmable mechanical and chemical properties. The stiffness and viscoelasticity of artificial cells are engineered to mimic the mechanical property of antigen presenting cells. The surface of artificial cells are coated with CD3/CD28 antibodies as T cell activation signals. We demonstrate that the viscoelastic nature of SynVACs significantly impacts T cell functionality.
Results, Conclusions, and Discussions:: Compared to rigid or elastic microspheres, SynVACs induce superior T cell expansion with higher CD8+/CD4+ T cell ratio, enhanced tumor killing capability, and significant increase in T memory stem cells. These engineered CAR-T cells are more efficient in eliminating tumor cells, not only in a human lymphoma mouse model but also in an ovarian xenograft mouse model, and persist in vivo for longer time periods to suppress tumor growth and recurrence. These findings underscore the crucial role of mechanical signals in T cell engineering and highlight the potential of SynVACs in CAR-T therapy and immunoengineering applications. In addition, based on this platform, we have developed a biomimetic “charging station” that incorporates chemotactic and activation signals to facilitate the recruitment, activation, and expansion of CAR-iNKT cells, which significantly enhances tumor infiltration, strengthens long-term immune memory, and demonstrates superior efficacy over conventional CAR-iNKT therapies in solid tumor models.
