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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Career Transition Award (K22)
Project #
5K22CA129240-03
Application #
7629153
Study Section
Subcommittee G - Education (NCI)
Program Officer
Jakowlew, Sonia B
Project Start
2007-07-27
Project End
2010-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
3
Fiscal Year
2009
Total Cost
$162,135
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
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Imataki, Osamu; Ansén, Sascha; Tanaka, Makito et al. (2012) IL-21 can supplement suboptimal Lck-independent MAPK activation in a STAT-3-dependent manner in human CD8(+) T cells. J Immunol 188:1609-19
Tanaka, Makito; Butler, Marcus O; Ansén, Sascha et al. (2011) Induction of HLA-DP4-restricted anti-survivin Th1 and Th2 responses using an artificial antigen-presenting cell. Clin Cancer Res 17:5392-401
Butler, Marcus O; Friedlander, Philip; Milstein, Matthew I et al. (2011) Establishment of antitumor memory in humans using in vitro-educated CD8+ T cells. Sci Transl Med 3:80ra34
Butler, Marcus O; Ansen, Sascha; Tanaka, Makito et al. (2010) A panel of human cell-based artificial APC enables the expansion of long-lived antigen-specific CD4+ T cells restricted by prevalent HLA-DR alleles. Int Immunol 22:863-73
Ansen, Sascha; Butler, Marcus O; Berezovskaya, Alla et al. (2008) Dissociation of its opposing immunologic effects is critical for the optimization of antitumor CD8+ T-cell responses induced by interleukin 21. Clin Cancer Res 14:6125-36