Recent encouraging results of adoptive immunotherapy in some melanoma patients suggest that tumor-specific T cells may induce clinically relevant tumor responses. Although anti-tumor CD8+ T cells have been shown to directly mediate tumor rejection, CD4+ T cells also play a pivotal role in the persistence and the functional enhancement of CD8+ T cells. The applicant's overall hypothesis is that potent anti-tumor immunity requires the development of both CD8+ and CD4+ anti-tumor immune responses. To test this, Dr. Hirano has chosen to target the tumor-associated antigen, Survivin, which is expressed by virtually all malignant cells. The fact that high Survivin expression negatively impacts the survival of cancer patients suggests that Survivin is an ideal therapeutic target. Survivin is also a promising immune target since it is immunogenic in vivo as demonstrated by the presence of an anti-Survivin immune response in some patients. Although Survivin-derived CD8+ T cell epitopes have previously been identified, very little is known about its CD4+ T cell epitopes. The process of identifying HLA class II restricted CD4+ T-cell epitopes has been hampered by promiscuous binding to class II molecules and the lack of a panel of APC that express single HLA class II alleles. With his successful production of artificial APC (aAPC) engineered to express a single HLA class I and/or class II allele and other immunoaccessory molecules, Dr. Hirano is poised to begin generating and analyzing CD4+ T cells capable of recognizing Survivin. He has therefore designed the following three aims: 1) Generate aAPC that express a single allele of HLA class II, take up exogenous protein, and process and present CD4+ T cell epitopes via the HLA class II pathway. 2) Immunologically and biochemically identify Survivin-derived HLA class II restricted T cell epitopes using HLA class II aAPC and generate Survivin-specific CD4+ T cells. 3) Evaluate the impact of Survivin-specific CD4+ T cells on the generation and function of anti-Survivin CD8+ CTL. Dr. Hirano is an M.D., Ph.D. with comprehensive training in molecular biology, tumor immunology, and clinical oncology. This proposal will help him to capitalize on this unique background, foster his development as an independent translational investigator, and provide him with the support which he requires for the development of breakthrough, novel therapies for cancer.
