The candidate's career goal is to become a principal investigator (PI) of a translational immunology laboratory that will develop immunotherapeutic approaches towards the treatment of patients with advanced sarcoma. In the immediate term, the candidate aims to gain experience as a translational researcher by performing the studies outlined in this proposal. Central to this effort, the candidate will serve as the PI of the phaseI trial examining the use of autologous NY-ESO-1 specific CD8+ T cells for patient with advanced NY-ESO-1 expressing sarcomas in the context of a novel conditioning regimen which incorporates IFN?. This is a trial that the candidate has written, designed and developed much of the preclinical foundation for. By serving as PI for this trial, the candidate will gain experiece in conducting an adoptive immunotherapy trial, and gain experience collecting and analyzing data from this trial. Additionally, the trial will serve as the platform to initiate multiple labortory-based translational studies investigating mechanisms of immune escape for patients on the trial and strategies to improve successor trials. The trial will be conducted at the Fred Hutchinson Cancer Research Center, an ideal environment for clinical and translational research and a leader in the field of T-cell immunotherapy trials. Dr. Stanley Riddell, an internationally renowned expert in cancer immunology and adoptive T cell therapy trials who is also an experienced and successful mentor, will serve as the primary to mentor the candidate. The candidate has also assembled a mentoring team comprised of senior faculty each with internationally renowned expertise in their particular field of research: Robin Jones (expertise in sarcoma clinical care and clinical trials), Martin (Mac) Cheever (expertise in solid tumor immunotherapy trials) and Cassian Yee (expertise in antigen specific T cell therapy trials).
The specific aims of the proposal are as follows:
Aim 1 : To evaluate in a Phase I trial, the toxicity, persistence and antitumor activity of autologous NY- ESO-1 specific CD8+ cells administered with a novel conditioning regimen incorporating IFN?, Cyclophosphamide (CY) and low dose IL-2 for patients with advanced MRCL and SS.
Aim 2 : To evaluate the emergence of antigen loss variants and strategies to broaden the applicability and enhance antigenicity of SS and MRCL patients receiving adoptive T cell therapy.
Aim 3 : To evaluate strategies to isolate NY-ESO-1 specific CD4+ T-cells for adoptive therapy to enhance or maintain CD8+ T cell function.
/Relevance This project will provide the opportunity for a clinical researcher-in-training to gain experience running a phase I T cell therapy trial for patients with advanced sarcoma and performing critical patient oriented translational laboratory studies in order to improve future trials. This particular trial will be completely novel in that it will be the first trial ever using autologous NY-ESO-1 specific CD8+ T cells for patients with advanced sarcomas and the first T cell therapy trial to incorporate the drug, interferon gamma.
