Cd56-Specific T Cells: Using Genetically Engineered T Cells to Redirect Specificity to A T Cell Expressed Antigen

<p>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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2014

Author dc:creator

• Crossland, Denise L

Contributors dc:contributor

• Laurence J.N. Cooper, M.D., Ph.D.
• Dean A. Lee, M.D., Ph.D.
• Bradley McIntyre, Ph.D.

• Chimeric Antigen Receptor
• CAR
• Neural Cell Adhesion Molecule
• NCAM
• CD56
• Fratricide
• Autolysis
• T cell immunotherapy
• self-targeting
• CD56CAR
• Cancer Biology
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/493

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1532