INTRODUCTION:
UCLA researchers in the Department of Medicine have developed a novel method for the isolation of T cells reactive to specific antigens for use in cellular immunotherapy.
BACKGROUND:
T cell responses to proteins on antigen presenting cells is exceptionally antigen-specific. The identification of antigen-specific T cells, or the sequences of T cell receptors (TCRs) reactive to specific antigens, enables the development of cellular immunotherapies by adoptive transfer of these T cells into patients, to precisely target cells expressing disease-associated antigens. However, the isolation T cells reactive to a single antigen is challenging due to the rarity of endogenous T cells specific to any particular antigen, as well as technical challenges associated with current methods of antigen-specific T cell isolation. Existing strategies to cultivate antigen-specific T cells include, 1) labeling cells with peptide-MHC multimers, which requires predication of antigenic peptide sequences and an enriched source of antigen-specific T cells; 2) functional assays for T cell response to antigen presenting cells, that necessitates a functional T cell pool, suitably matched antigen presenting cells, and a specific activation marker; and, 3) antigen presenting cells/T cell doublet sorting, which is still in the experimental stage.
INNOVATION:
UCLA researchers have established an approach to label and expand antigen-specific T cells in one step, to virally target T cells to antigens based on their TCR specificity. Antigen-specific T cells are enriched by transduction of a selective advantage gene, and sorted for successful transduction using a marker. This method allows for the identification and expansion of antigen specific T cells for use in adoptive transfer immunotherapies to treat conditions such as cancer, infectious diseases, and autoimmune diseases. The approach does not require prediction of antigen peptide sequences, yet has improved specificity of viral targeting by abolishing endogenous viral T cell tropism. Additional features may be built upon this system for increased efficiency and throughput.
POTENTIAL APPLICATIONS:
• Cellular immunotherapy via adoptive transfer of primary antigen-specific T cells
• Cellular immunotherapy via adoptive transfer of T cells “redirected” with antigen-specific T cell receptors
• Labeling and enrichment of antigen-specific T cells
ADVANTAGES:
• Antigen-specific T cells may be labeled and enhanced in one step
• Cells may be sorted based on transduced marker expression
• Does not require prediction of antigen peptide sequences
• Improved efficiency and versatility by enhancing viral pMHC display
• Enveloped proteins may be engineered directly with pMHC or MHC domains for increased viral fusion and transduction over uncoupled envelope and pMHC expression
• Non-target MHC on the viral particles are abolished, to enhance specificity of viral binding
• May be adapted for high throughput applications, for use in downstream functional applications including adoptive transfer
DEVELOPMENT-TO-DATE:
This method has been successfully demonstrated and evaluated for transduction efficiency.