Summary:
Researchers in the Department of Bioengineering at UCLA have developed a hydrogel platform that measures single T cell secretions, aiding in the definition of T cell receptor repertoires for functional immunotherapy applications.
Background:
T cell immunotherapies, namely T cell receptor (TCR) therapies, have emerged as promising candidates for next-generation cancer treatments. TCR therapies can reach intracellular targets that present early in the cancer’s progression; however, they must be personalized to each patient by matching the T cells to antigens on the targeted cell’s surface. T cells have an extremely diverse sequence repertoire, and therapeutic cell candidates need to have sufficient affinity and potency. Methods of identifying rare TCRs are nonspecific, resulting in many nonfunctional TCRs. There remains the critical yet challenging process of identifying and defining the rare and low-affinity cell populations with therapeutic potential. Current tools rely on surface-marker staining; however this method does not take into account the functional stages of the T cells and the presence of these surface complexes is not always correlated to therapeutic efficacy. To improve future TCR therapeutic applications, there remains an unmet need for a streamlined process of TCR identification and capture.
Innovation:
Researchers in UCLA’s Di Carlo lab have developed functionalized “nanovial” hydrogel particles to isolate T cells based on TCR binding and enable the measurement of their cytokine secretion. After the cells’ secretions are captured on the surface of the nanovials, millions of cells can be analyzed quickly using flow cytometry for their binding and function. By barcoding the nanovials, with oligonucleotides that correspond to the specific peptides, a TCR repertoire can be easily established at the single cell level. This method enables direct linkage of TCR binding and functional cytokine secretion with TCR sequences at the single-cell level. This method will expand TCR repertoires and reduce the false positives associated with TCR immunotherapies, ultimately enhancing their prospects as a clinical modality. In addition, beyond TCRs, the nanovial format is applicable to other cell screening processes for CAR-T cells or bispecific T cell engagers, more broadly opening functional screening methods for cell therapy development.
Potential Applications:
• T cell immunotherapy development
• TCR discovery
• Viral antigen identification
• Tolerance induction
• Transplantation
• Rejection reduction
• Improved donor matching
• Drug screening
Advantages:
• Precise TCR binding
• Analyze cell binding and function simultaneously
• Single-cell resolution
• Customizable nanovials
• Utilizes off-the-shelf cytometry tools
State of Development:
Nanovial efficacy has been extensively demonstrated and the particles are manufactured by a startup. The functionalized nanovials have been used to define TCR repertoires; subsequently published in a peer-reviewed academic journal.
Related Papers:
Koo, Doyeon, et al. "Defining T cell receptor repertoires using nanovial-based binding and functional screening." Proceedings of the National Academy of Sciences 121.14 (2024): e2320442121. https://www.pnas.org/doi/10.1073/pnas.2320442121
Reference:
UCLA Case No. 2024-042
Lead Inventor:
Dino Di Carlo, UCLA Professor and Chair of Bioengineering.