The candidate for this NCI Career Development Award is Marcela Valderrama Maus, MD, PhD, who is currently a hematology and medical oncology fellow at Memorial Sloan-Kettering Cancer Center (MSKCC). Dr. Maus has a long-standing interest in tumor immunology and gene and cell therapies. Her thesis work was on the activation and costimulation requirements of human CD4 and CD8 T cells, which was explored with the use of artificial antigen presenting cells bearing multiple costimulatory molecules, most notably 4-1BB. Dr. Maus also completed a brief post-doctoral fellowship where she identified capsid-specific memory T cells in patients who had undergone gene transfer in a clinical trial of hemophilia B. At MSKCC, Dr. Maus has joined the laboratory of Michel Sadelain, a worldwide leader in the field of T cell therapy and gene transfer. An immediate term goal of the candidate is to complete the Aims in this proposal, which center around designing and testing new forms of antigen receptors directed to a cytoplasmic tumor antigen, NY-ESO-1. The completion of these aims will provide the candidate with the candidate with new technical skills, intellectual advancement, and a substrate on which to build her laboratory-based career in immunotherapy and gene transfer. The long-term goal of the candidate is to become an academic medical oncologist who develops and uses cell-based therapies to treat solid tumors such as melanoma. Over the past decade, the adoptive transfer of T cells has emerged as an effective therapy in some patients with hematological malignancies or melanoma, but the process of generating these cells has been labor-intensive and not widely applicable due to the low frequency of tumor-specific T cells. The candidate's mentor is at the forefront in the development of adoptive T cell therapy with cells transduced with chimeric antigen receptors that re-direct them toward native surface antigens. Here, the candidate proposes to expand the concept of chimeric antigen receptors by targeting a cytoplasmic antigen with an antibody-based receptor (Aim 1) and a modified T cell receptor (Aim 2). These two new forms of designer antigen receptors will be characterized and compared in re-directed T cells with respect to affinity, co-receptor binding, immune synapse formation, and ex vivo and in vivo effector functions (Aim 3). MSKCC is an ideal site for this project because of the intellectual and technical resources available, and because of the institutional history and commitment to this line of research. The tumor antigen targeted here was initially described at MSKCC; the physician-scientist community and melanoma service are ideally suited to support and aid the candidate as she transitions to independent investigation, and there is evidence of their unconditional support for the candidate. The candidate has access to prior mentors, all highly respected physician scientists, and her current mentor has a track record of successfully training and launching other physician scientists; in addition, she has enlisted three leaders in the field of immunotherapy to serve on an advisory committee as she navigates the transition to independent investigation. This career development award will greatly enhance Dr. Marcela Valderrama Maus's research proposal and professional development.