CD56-SPECIFIC T CELLS: USING GENETICALLY ENGINEERED T CELLS TO REDIRECT SPECIFICITY TO A T CELL EXPRESSED ANTIGEN
Date of Graduation
Doctor of Philosophy (PhD)
Laurence J.N. Cooper, M.D., Ph.D.
Dean A. Lee, M.D., Ph.D.
Bradley McIntyre, Ph.D.
Stephen Ullrich, Ph.D.
Stephanie Watowich, Ph.D.
The CD56 antigen is expressed on several deadly malignancies currently lacking long-term efficacious therapies. Chimeric antigen receptor (CAR) based immunotherapies have shown both safety and efficacy and even a curative ability in clinical trials, laying the foundation for applying CARs to new targets. Using T cells to target a T cell expressed antigen, such as CD56, seems counterintuitive in that the T cells would be susceptible to self-targeting a.k.a. fratricide. However, we expand CD56-specific CAR+ T cells that co-express the CD56 antigen. Since other CARs targeting T cell expressed antigens are hypothesized to be undergoing fratricide, such as the CD38-specific CAR, this unexpected observation of CD56+CD56CAR+ T cells infers that these cells are unique in their survival capacity in a self-targeting scenario. CD56CAR+ T cells have redirected specificity to CD56+ tumor cells and generate anti-tumor responses in neuroblastoma xenograft studies in mice. These CD56CAR+ T cells expand similarly to CAR+ T cells that do not target self-antigen, CD19-specific CAR+ T cells, and do not undergo fratricide. The CD56 antigen co-expressed by CD56CAR+ T cells has diminished ability to stain with the CD56 monoclonal antibody clone N901, which is the epitope where the CAR binds, while the CD56 antigen on CD19CAR+ T cells retains staining. Our data strongly suggest that this epitope loss is not a result of epitope escape of the CD56 antigen. Significant differences in the protein expression profiles of CD19CAR+ and CD56CAR+ T cells, which may be responsible for fratricide evasion of CD56+CD56CAR+ T cells, were observed. Further investigation into these protein differences could delineate a key pathway or responsible for fratricide evasion and be applied in the generation of other CAR based immunotherapies targeting T cell expressed tumor associated antigens. Targeting T cell expressed antigens not only has implications for cancer therapies, but also for treating autoimmune diseases, for the manipulation of transplants or to ablate existing immune cells in a patient as an alternative to chemotherapy.
Chimeric Antigen Receptor, CAR, Neural Cell Adhesion Molecule, NCAM, CD56, Fratricide, Autolysis, T cell immunotherapy, self-targeting, CD56CAR