Because the immune system has the capacity to recognize and in many cases destroy tumor cells, significant efforts are being devoted to the development of immune-based therapies for cancer. Both cytotoxic T lymphocytes (CTL) and helper T lymphocytes (Th) have been shown to react with antigens expressed by tumor cells and as a result, establish protective and therapeutic effects. Since CTL and Th recognize antigens in the form of peptide complexes with major histocompatibility complex (MHC) surface molecules, it is necessary to identify the chemical nature of tumor-derived peptides that can elicit T-cell responses capable of inhibiting tumor-cell growth. The overall objective of the proposed study is to identify peptides derived from sequences of several known prostatic-associated antigens (PAA) that will be capable of stimulating CTL and Th against prostate tumor cells. We have selected several PAA which are preferentially expressed on cells of prostatic epithelial origin including transformed cells. The amino acid sequences of these PAA have been screened for the presence of peptides containing MHC binding motifs. Those peptides that display a high degree of probability of binding to MHC molecules will be synthesized and tested for their capacity to elicit in vitro T-cell responses to naturally processed PAA as final proof that they indeed represent T-cell epitopes. The ultimate goal of our work is to utilize these tumor-reactive T-cell epitopes to develop immunotherapeutic approaches to treat prostatic cancers. To accomplish this goal, we propose the following specific aims: 1.- Identify MHC class I-restricted CTL epitopes from PAA expressed on prostate cancers. 2.- Identify MHC class II-restricted helper T-cell epitopes from PAA commonly found on prostate cancers. 3.- Increase CTL and T helper immune responses to PAA's by epitope re-engineering. The completion of these aims should facilitate the development of novel broadly applicable T-cell based immune therapies such as epitope-based vaccines and adoptive T-cell therapy for the treatment of early and advanced prostate cancer respectively.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA082677-02
Application #
6174280
Study Section
Special Emphasis Panel (ZRG1-SSS-4 (03))
Program Officer
Mccarthy, Susan A
Project Start
1999-07-20
Project End
2002-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
2
Fiscal Year
2000
Total Cost
$200,290
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Kobayashi, Hiroya; Nagato, Toshihiro; Aoki, Naoko et al. (2006) Defining MHC class II T helper epitopes for WT1 tumor antigen. Cancer Immunol Immunother 55:850-60
Kobayashi, Hiroya; Nagato, Toshihiro; Oikawa, Kensuke et al. (2005) Recognition of prostate and breast tumor cells by helper T lymphocytes specific for a prostate and breast tumor-associated antigen, TARP. Clin Cancer Res 11:3869-78
Kobayashi, Hiroya; Nagato, Toshihiro; Yanai, Mitsuru et al. (2004) Recognition of adult T-cell leukemia/lymphoma cells by CD4+ helper T lymphocytes specific for human T-cell leukemia virus type I envelope protein. Clin Cancer Res 10:7053-62
Davila, Eduardo; Kennedy, Richard; Celis, Esteban (2003) Generation of antitumor immunity by cytotoxic T lymphocyte epitope peptide vaccination, CpG-oligodeoxynucleotide adjuvant, and CTLA-4 blockade. Cancer Res 63:3281-8
Kobayashi, Hiroya; Omiya, Ryusuke; Sodey, Benjamin et al. (2003) Identification of naturally processed helper T-cell epitopes from prostate-specific membrane antigen using peptide-based in vitro stimulation. Clin Cancer Res 9:5386-93
Giuntoli 2nd, Robert L; Lu, Jun; Kobayashi, Hiroya et al. (2002) Direct costimulation of tumor-reactive CTL by helper T cells potentiate their proliferation, survival, and effector function. Clin Cancer Res 8:922-31
Lu, Jun; Giuntoli 2nd, Robert L; Omiya, Ryusuke et al. (2002) Interleukin 15 promotes antigen-independent in vitro expansion and long-term survival of antitumor cytotoxic T lymphocytes. Clin Cancer Res 8:3877-84
Davila, Eduardo; Velez, Maria G; Heppelmann, Carrie J et al. (2002) Creating space: an antigen-independent, CpG-induced peripheral expansion of naive and memory T lymphocytes in a full T-cell compartment. Blood 100:2537-45
Kobayashi, Hiroya; Omiya, Ryusuke; Ruiz, Marta et al. (2002) Identification of an antigenic epitope for helper T lymphocytes from carcinoembryonic antigen. Clin Cancer Res 8:3219-25
Omiya, Ryusuke; Buteau, Chantal; Kobayashi, Hiroya et al. (2002) Inhibition of EBV-induced lymphoproliferation by CD4(+) T cells specific for an MHC class II promiscuous epitope. J Immunol 169:2172-9

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