The antitumor action of intravenous endotoxin, intratumor C. parvum, and intravenous cyclophosphamide will be studied in order to illustrate how three different types of immunomodulators can be employed to augment host antitumor defenses sufficiently to cause regression of relatively large established tumors. Experimental design will be based on published evidence showing that progressive growth of immunogenic tumors can evoke the generation of an underlying T cell-mediated concomitant immune response that is down-regulated by suppressor T cells before it develops sufficiently in magnitude to cause tumor regression. 1. The prediction will be tested that successful immunotherapy with intralesional C. parvum is only achievable with very small tumors, because with larger tumors the time required for C. parvum to exert its adjuvant effect overlaps with the time of onset of production of tumor-induced suppressor T cells. It will be determined whether passive transfer of suppressor T cells can inhibit the C. parvum-potentiated production of tumor-sensitixed effector T cells. It also will be determined whether elimination of suppressor T cells by sublethal radiation will allow C. parvum to cause regression of relatively large tumors. 2. Endotoxin will be studied to determine, by passive transfer procedures, whether its ability to cause tumor regression is dependent on the existence in the host of an adequate number of Ly-1+2- T cells that mediate DTH. The possibility also will be investigated as to whether the final effector cell in endotoxin-induced regression is not a lymphocyte but a macrophage that is primed by tumor-sensitized T cells via the secretion of lymphokines to be activated to a tumoricidal state by endotoxin. 3. The immunotherapeutic action of cyclophosphamide will be investigated by employing a cyclophosphamide-resistant tumor to test the prediction that cyclophosphamide-induced regression depends on the ability of the drug to eliminate suppressor T cells and to thereby enable an underlying population of cyclophosphamide-resistant memory T cells to generate a secondary immune response. This will involve showing that the drug cannot cause tumor regression until the host has generated cyclophosphamide sensitive supressor T cells, and cyclophosphamide-resistant menory T cells that are capable of passively transferring immunity to suitable recipients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA027794-08
Application #
3167828
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1980-12-01
Project End
1991-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
8
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Trudeau Institute, Inc.
Department
Type
DUNS #
City
Saranac Lake
State
NY
Country
United States
Zip Code
12983
Rakhmilevich, A L (1994) Failure of anti-T cell monoclonal antibodies to prevent acute tumor allograft rejection is associated with their inability to deplete or inactivate T cells at the site of rejection. Transplantation 58:72-80
Rakhmilevich, A L; North, R J (1994) Elimination of CD4+ T cells in mice bearing an advanced sarcoma augments the antitumor action of interleukin-2. Cancer Immunol Immunother 38:107-12
Rakhmilevich, A L; North, R J; Dye, E S (1993) Evidence inconsistent with a role for tumor necrosis factor in tumor allograft rejection. Transplantation 55:182-6
Rakhmilevich, A L; North, R J; Dye, E S (1993) Presence of CD4+ T suppressor cells in mice rendered unresponsive to tumor antigens by intravenous injection of irradiated tumor cells. Int J Cancer 55:338-43
North, R J; Dunn, P L; Havell, E A (1991) A role for tumor necrosis factor in poly(I:C)-induced hemorrhagic necrosis and T-cell-dependent regression of a murine sarcoma. J Interferon Res 11:333-40
Rakhmilevich, A L; North, R J (1991) Rapid acquisition of an enhanced capacity to produce tumor necrosis factor, alpha/beta interferon, and interleukin 6 after implantation of tumor cells. Cytokine 3:398-406
Dunn, P L; North, R J (1991) Effect of advanced ageing on the ability of mice to cause tumour regression in response to immunotherapy. Immunology 74:355-9
Dunn, P L; North, R J (1991) Effect of advanced aging on ability of mice to cause regression of an immunogenic lymphoma in response to immunotherapy based on depletion of suppressor T cells. Cancer Immunol Immunother 33:421-3
Dunn, P L; North, R J (1991) Selective radiation resistance of immunologically induced T cells as the basis for irradiation-induced T-cell-mediated regression of immunogenic tumor. J Leukoc Biol 49:388-96
North, R J; Awwad, M (1990) Elimination of cycling CD4+ suppressor T cells with an anti-mitotic drug releases non-cycling CD8+ T cells to cause regression of an advanced lymphoma. Immunology 71:90-5

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