Abstract

The purpose of the proposed study is to dissect the cellular vectors of adoptive immunotherapy utilizing tumor-infiltrating lymphocytes (TIL), in order to achieve insight into the nature and mechanisms of TIL-mediated tumor eradication. TIL will be studied in a murine model system utilizing methylcholanthrene-induced MCA105 sarcoma, the colon adenocarcinoma MC-38 and the melanoma B16. TIL,s are now generated from each of these tumors and expanded in IL-2 and used in adoptive transfer experiments. Study of the optimal conditions for growth of TIL in vitro and their effectiveness in vivo will be undertaken. TIL grown from each tumor will serve as specificity control for the other tumors. Clones will be generated by treating bulk populations with monoclonal antibody and complement and these clones or subpopulations will be compared to bulk TIL cultures and LAK cells for in vitro growth characteristics and in vivo efficacy. Activation of murine TIL's with anti-CD3 (2C-ll) will be studied in vitro and in vivo utilizing a subdermal tumor model and sequential sacrifice of mice during tumor rejection will be performed. Samples of tumor will be studied immunohistologically. These studies will document the cell populations involved in tumor rejection. The role of cytoxan in these adoptive immunotherapy models will be studied, specifically to separate the cytoreductive and immunosuppressive effect of this drug, and optimal dose and schedule will be determined. Parallel experiments will be performed utilizing human TIL's. Optimal conditions for growth of these cells will be defined. The role of anti-T3 and other antibodies such as WT31 which induce activation of human TIL's will be studied. The phenotype and function of TIL bulk cultures will be studied, paying particular attention to the T4/4B4 population as defined by 2-color immunofluorescence in conjunction with cell sorting, to isolate T4/4B4 positive T cells from TIL bulk culture. TIL phenotypic changes over time, and characterization of optimal conditions for growth and tumor specific cytotoxicity will be defined. Clones will be generated from human TIL's and studied in vitro for growth and function. At the completion of this grant, there should be a much better understanding of the underlying mechanisms and nuances of TIL in the mouse and human which will be applied toward the design of new immunotherapy trials in the human.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA045484-02
Application #
3188571
Study Section
Experimental Immunology Study Section (EI)
Project Start
1989-07-01
Project End
1992-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
2
Fiscal Year
1990
Total Cost
Indirect Cost

  Institution

Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115

  Publications

Matory, Y L; Dorfman, D M; Chen, M et al. (1999) T cells mediate treatment of six-day-old cytokine-gene-transfected mouse mammary tumor. Pathobiology 67:3-11
Linehan, D C; Goedegebuure, P S; Eberlein, T J (1996) Vaccine therapy for cancer. Ann Surg Oncol 3:219-28
Peoples, G E; Smith, R C; Linehan, D C et al. (1995) Shared T cell epitopes in epithelial tumors. Cell Immunol 164:279-86
Matory, Y L; Chen, M; Dorfman, D M et al. (1995) Antitumor activity of three mouse mammary cancer cell lines after interferon-gamma gene transfection. Surgery 118:251-5;discussion 255-6
Peoples, G E; Goedegebuure, P S; Smith, R et al. (1995) Breast and ovarian cancer-specific cytotoxic T lymphocytes recognize the same HER2/neu-derived peptide. Proc Natl Acad Sci U S A 92:432-6
Burger, U L; Chang, M P; Goedegebuure, P S et al. (1995) Recruitment of host CD8+ T cells by tumor-infiltrating lymphocytes and recombinant interleukin-2 during adoptive immunotherapy of cancer. Surgery 117:325-33
Peoples, G E; Blotnick, S; Takahashi, K et al. (1995) T lymphocytes that infiltrate tumors and atherosclerotic plaques produce heparin-binding epidermal growth factor-like growth factor and basic fibroblast growth factor: a potential pathologic role. Proc Natl Acad Sci U S A 92:6547-51
Matory, Y L; Chen, M; Goedegebuure, P S et al. (1995) Anti-tumor effects and tumor immunogenicity following IL2 or IL4 cytokine gene transfection of three mouse mammary tumors. Ann Surg Oncol 2:502-11
Linehan, D C; Goedegebuure, P S; Peoples, G E et al. (1995) Tumor-specific and HLA-A2-restricted cytolysis by tumor-associated lymphocytes in human metastatic breast cancer. J Immunol 155:4486-91
Lee, K Y; Goedegebuure, P S; Linehan, D C et al. (1995) Immunoregulatory effects of CD4+ T helper subsets in human melanoma. Surgery 117:365-72

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