Human cancer therapy based on the adoptive transfer of T lymphocytes has relied on T cell populations with poorly defined functional characteristics and consequently, poor clinical results. Recent work in this laboratory has documented that CD4+ Th2 helper T cells account for the majority of infiltrating T cells in human renal cell carcinoma. We have demonstrated that these cells secrete virtually no IL-2 following TcR/CD3 stimulation. In contrast, TcR/CD3 stimulation causes the secretion of IL-4 which has been identified as a potent inhibitor of NK and CTL responses. The functional characteristics of Th2 may in part be responsible for the absence of effective CTL immunity and thus, disease progression. We began our preclinical studies on ovarian cancer by examining the biology of the host immune response to both solid tumor and malignant ascites. Our results indicate that T cells obtained from malignant ascites possess tumor-specific tumoricidal activity against tumor obtained from ascites. Likewise, T cells isolated from solid tumor possess tumor-specific tumoricidal activity against solid tumor. T cells from solid tumor also efficiently kill ascitic tumor. However, we have demonstrated that T cells from ascites do not efficiently kill solid tumor. Thus, metastatic ovarian cancer is not only characterized by two distinct clinical forms of disease but these two forms of disease are also immunologically distinguished by the tumor-bearing host. These results suggest that in the therapeutic setting, use of T cells obtained from ascites will not provide optimum therapeutic benefit to the patient with ovarian cancer since tumor will not effectively trigger ascitic T cell cytotoxic activity. The objective of this application are to establish the biological profile of T cells with therapeutic efficacy as well as those T cells with tumor- promoting characteristics.
The specific aims are (1) To determine the functional characteristics of tumor-specific CD8+ CTL isolated from malignant ascites and solid tumor. (2) To correlate specific CTL functional traits with specific TcR variable (V) genes. (3) To determine the functional characteristics of tumor-specific CD4+ helper T cells isolated from malignant ascites and solid tumor. (4) To correlate specific helper cell functional characteristics with specific TcR variable (V) genes. (5) To identify tumor-derived peptides as targets of CTL immunity.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA060662-02
Application #
2101409
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1994-05-16
Project End
1998-02-28
Budget Start
1995-03-01
Budget End
1996-02-29
Support Year
2
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Peiper, Matthias; Goedegebuure, Peter S; Alldinger, Ingo et al. (2002) Comparison of various sources of antigen-presenting cells for the generation of GP2-tumor peptide specific cytotoxic T-lymphocytes. Anticancer Res 22:3357-63
Bernstorff, Wolfram V; Glickman, Jonathan N; Odze, Robert D et al. (2002) Fas (CD95/APO-1) and Fas ligand expression in normal pancreas and pancreatic tumors. Implications for immune privilege and immune escape. Cancer 94:2552-60
Joo, H G; Goedegebuure, P S; Sadanaga, N et al. (2001) Expression and function of galectin-3, a beta-galactoside-binding protein in activated T lymphocytes. J Leukoc Biol 69:555-64
Lockhart, D C; Chan, A K; Mak, S et al. (2001) Loss of T-cell receptor-CD3zeta and T-cell function in tumor-infiltrating lymphocytes but not in tumor-associated lymphocytes in ovarian carcinoma. Surgery 129:749-56
Chan, A K; Goedegebuure, P S; von Bernstorff, W et al. (2000) B7.1 costimulation increases T-cell proliferation and cytotoxicity via selective expansion of specific variable alpha and beta genes of the T-cell receptor. Surgery 127:342-50
Chan, A K; Lockhart, D C; von Bernstorff, W et al. (1999) Soluble MUC1 secreted by human epithelial cancer cells mediates immune suppression by blocking T-cell activation. Int J Cancer 82:721-6
Sadanaga, N; Nagoshi, M; Lederer, J A et al. (1999) Local secretion of IFN-gamma induces an antitumor response: comparison between T cells plus IL-2 and IFN-gamma transfected tumor cells. J Immunother 22:315-23
Nagoshi, M; Sadanaga, N; Joo, H G et al. (1999) Tumor-specific cytokine release by donor T cells induces an effective host anti-tumor response through recruitment of host naive antigen presenting cells. Int J Cancer 80:308-14
Burger, U L; Chang, M P; Nagoshi, M et al. (1996) Improved in vivo efficacy of tumor-infiltrating lymphocytes after restimulation with irradiated tumor cells in vitro. Ann Surg Oncol 3:580-7
Linehan, D C; Goedegebuure, P S; Eberlein, T J (1996) Vaccine therapy for cancer. Ann Surg Oncol 3:219-28