1. How did this get started? The inspiration for this project stemmed from the challenges we encountered in current CAR T-cell therapies. While CAR-T therapies have revolutionized the treatment of blood cancers, solid tumors remain difficult to target effectively due to the immunosuppressive tumor microenvironment and suboptimal manufacturing process for CAR-T cells. In particular, we observed that existing tools for T-cell activation, such as Dynabeads, lack the mechanical properties that mimic natural antigen-presenting cells (APCs). This discrepancy led us to ask: how does the mechanical presentation of the activation signals affect CAR T-cell expansion and functionality?

2. Is there room for improvement? Yes, definitely. The primary issue with current T-cell activation methods is that they often lead to insufficient T-cell expansion, a low percentage of CAR+ cells, a lack of stemness, and a reduced capacity for long-term immune surveillance. For example, Dynabeads, which are widely used for T-cell activation, are rigid and do not emulate the mechanical cues provided by APCs. These mechanical properties may be crucial for effective T-cell receptor engagement and downstream signaling, which ultimately determine the quality of the activated T cells. Our challenge was to understand the mechanical regulation of T cells and develop a system that could better mimic the natural environment of T cells, improving the functionality and persistence of CAR-T cells following expansion.

3. How did we get the SynVACs idea? The idea for SynVACs emerged from the intersection of bioengineering and immunotherapy. We knew that T cells are highly responsive to their mechanical environment, which led us to explore materials that could replicate the viscoelastic nature of APCs. By designing synthetic antigen-presenting cells (SynVACs) with tunable viscoelasticity and stiffness, we aimed to create a platform that not only mimicked the mechanical properties of native APCs but also provided optimal signals for T-cell activation. Our team developed a high-throughput microfluidic system to produce SynVACs, allowing us to fine-tune these mechanical properties and conjugate activating molecules like anti-CD3/CD28 for optimal T-cell engagement.

4. What were the results? The results exceeded our expectations. SynVACs significantly boost the expansion of human CD8+ T cells compared to rigid or purely elastic microspheres, and increased the CAR+ T cells from 50% to 90%. We also observed an increase in the generation of memory stem-like T cells, which are critical for long-term immunity. In mouse models, CAR T cells activated and expanded with SynVACs showed enhanced tumor-killing efficiency, reduced tumor recurrence, and prolonged survival. These findings underscore the crucial role of viscoelasticity in T-cell activation and highlight SynVACs as a promising tool for improving the efficacy of cancer immunotherapies.

5. What is next? Moving forward, we plan to optimize SynVACs further by exploring their potential in different cancer types and in various immunosuppressive environments. We are particularly interested in understanding how the viscoelastic properties of SynVACs can be tuned for personalized immunotherapies, tailored to the specific needs of individual patients. Additionally, we aim to scale up the production of SynVACs for potential clinical applications, collaborating with industry partners to translate this technology into a therapeutic reality.

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You can read the paper at:

Liu, Z., Li, YR., Yang, Y. et al. Viscoelastic synthetic antigen-presenting cells for augmenting the potency of cancer therapies. Nat. Biomed. Eng (2024). https://doi.org/10.1038/s41551-024-01272-w