Despite recent encouraging advances in the treatment of advanced ovarian cancer, this epithelial malignancy remains incurable for the vast majority of patients. Yet, since modern medical and surgical treatment can induce clinical remissions in most patients, the time is now to attempt innovative therapies for the treatment and eradication of minimal residual disease. Dr. Butler has chosen ovarian carcinoma as a model for the application of new concepts in tumor immunology in order to accomplish this goal. The applicant's overall hypothesis is that human epithelial adenocarcinomas can appropriately present unique tumor-associated antigens which are capable of inducing T cell responses and that these studies will form a foundation for the development of novel antigen specific therapies. In order to test this hypothesis the applicant and his co-principal investigators have developed a phase I clinical vaccine trial in an attempt to immunize ovarian cancer patients against their own tumor while they are in remission. This protocol is based on the extensive clinical experience of the applicant's institution in vaccinating cancer patients with autologous, lethally irradiated tumor cells engineered genetically engineered to secrete human GM-CSF (Granulocyte Macrophage-Colony Stimulating Factor). With this trial as a basis for his studies, Dr. Butler plans to accomplish the following aims: 1) Identify a finite set of candidate ovarian cancer-associated antigens which may be capable of eliciting an in vivo T cell response. 2) Determine which candidate antigens/peptide sequences are targets of T cells obtained from patients following vaccination. 3) Demonstrate that tumor cells appropriately process and present candidate antigens such that they can serve as targets of cytotoxic T lymphocytes. The team of clinicians and scientists of which Dr. Butler is an important member is committed to developing a program in the immunotherapy of ovarian cancer. The breadth of research methods entailed in this project will provide an outstanding training experience in tumor immunology. The guidance Dr. Butler will receive from his mentor, as well as his collaborators, will enable Dr. Butler to mature into a leading clinician-scientist interested in translating breakthroughs in immunotherapy to the care of patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA087720-04
Application #
6615702
Study Section
Subcommittee G - Education (NCI)
Program Officer
Lohrey, Nancy
Project Start
2000-08-10
Project End
2005-07-31
Budget Start
2003-02-01
Budget End
2004-01-31
Support Year
4
Fiscal Year
2003
Total Cost
$126,711
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
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
Butler, Marcus O; Lee, Jeng-Shin; Ansen, Sascha et al. (2007) Long-lived antitumor CD8+ lymphocytes for adoptive therapy generated using an artificial antigen-presenting cell. Clin Cancer Res 13:1857-67
Hirano, Naoto; Butler, Marcus O; Xia, Zhinan et al. (2006) Engagement of CD83 ligand induces prolonged expansion of CD8+ T cells and preferential enrichment for antigen specificity. Blood 107:1528-36
Hirano, Naoto; Butler, Marcus O; Xia, Zhinan et al. (2006) Identification of an immunogenic CD8+ T-cell epitope derived from gamma-globin, a putative tumor-associated antigen for juvenile myelomonocytic leukemia. Blood 108:2662-8
Hirano, Naoto; Butler, Marcus O; Xia, Zhinan et al. (2006) Efficient presentation of naturally processed HLA class I peptides by artificial antigen-presenting cells for the generation of effective antitumor responses. Clin Cancer Res 12:2967-75
Hirano, Naoto; Butler, Marcus O; Von Bergwelt-Baildon, Michael S et al. (2003) Autoantibodies frequently detected in patients with aplastic anemia. Blood 102:4567-75
Maecker, Britta; Sherr, David H; Vonderheide, Robert H et al. (2003) The shared tumor-associated antigen cytochrome P450 1B1 is recognized by specific cytotoxic T cells. Blood 102:3287-94
von Bergwelt-Baildon, Michael S; Vonderheide, Robert H; Maecker, Britta et al. (2002) Human primary and memory cytotoxic T lymphocyte responses are efficiently induced by means of CD40-activated B cells as antigen-presenting cells: potential for clinical application. Blood 99:3319-25
Vonderheide, R H; Butler, M O; Liu, J F et al. (2001) CD40 activation of carcinoma cells increases expression of adhesion and major histocompatibility molecules but fails to induce either CD80/CD86 expression or T cell alloreactivity. Int J Oncol 19:791-8