This grant proposed the conduct of pre-clinical work to support the use of stem cells to regenerate a cancer-fighting immune system in mice and humans, and bedside-to-bench work to analyze populations of cells with potential ability to function as long term repopulating T lymphocytes obtained from patients treated within a phase 1 clinical trial. During this past year we have made progress to continue our study the biology of T cells with characteristics of long term memory immune cells, termed T memory stem cells (TMSC). We have recently studied the ability to use specific small molecule targeted inhibitors to increase the fraction of mature T cells with TMSC characgteristics, which will improve our ability to characterize them. We have also advanced our studies to test the transplantation of hematopoietic stem cells (HSC) genetically engineered to express T cell receptors (TCR) and provide a continuous progeny of TCR transgenic mature T cells in humanized mouse models. This work provides the rationale to allow us advancing our plans to conduct a clinical trial based on the transplantation of HSC genetically engineered to express TCR to regenerate a cancer-fighting immune system. We have successfully competed for a CIRM disease team award and have gone through a pre-IND meeting with the FDA to adequately plan for such a clinical trial to be started in approximately two years.