Clinical Instructor
Department of Medicine

Project title: Development of a novel platform for the discovery of antigen specific TCRs

Dr. Gay Crooks - UCLA
Dr. Owen Witte - UCLA

Multidisciplinary Expertise:
Immunology, stem cell biology, cancer immunotherapy, cellular therapy, clinical hematology/oncology.

Project Description:
Engineered T cell immunotherapies offer unprecedented potential in the treatment of cancer. Identification of high-affinity T cell receptors (TCRs) that recognize public tumor-associated antigens (TAAs) may facilitate the rapid development of new T cell therapies for cancer. Identification of these TCRs from patient samples however is difficult, as TAA-reactive T cells are typically deleted in the thymus through negative selection. We have developed a novel artificial thymic organoid (ATO) system that permits the efficient in vitro generation of T cells from human hematopoietic stem cells. We hypothesize that T cells generated in ATOs are not subject to conventional negative selection and are thus a unique source of high-affinity TAA-reactive TCRs. In this project, I will optimize an ATO-based platform for the discovery of TCRs specific for model public tumor antigens; characterize the binding affinity and anti-tumor efficacy of ATO-derived TCRs; and validate this system through the proof-of-concept capture of TCRs against clinically relevant TAAs for which the isolation of high-affinity TCRs has been challenging. A platform for the rapid identification of high-affinity TAA-reactive TCRs would be readily translatable to clinical applications in cancer immunotherapy.