CD56-SPECIFIC T CELLS: USING GENETICALLY ENGINEERED T CELLS TO REDIRECT SPECIFICITY TO A T CELL EXPRESSED ANTIGEN

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