The goal of the proposed research is to obtain an experimental basis for the rational design of immunotherapeutic modalities capable of causing the regression of established immunogenic tumors. The results obtained will be applicable to immunotherapy against other replicating antigens. The proposed studies are based on the knowledge that progressive immunogenic tumors evoke the generation of a T cell-mediated concomitant immune response that is down-regulated by CD4+ suppressor T cells after the tumor grows beyond a certain critical size. It is intended to cause the regression of established tumors at a relatively late stage of their growth by preferentially depleting the host of suppressor T cells, and if necessary augmenting the immunity released from suppression by treating the host with IL-2, IL-1, or with bacterial superantigens (enterotoxins) that stimulate T cells via the variable region of the beta chain (Vbeta) of their T cell receptor (TCR). With a view to causing the regression of larger tumors, immunity released from suppression will be supplemented by adoptive immunization with T cells from immunized donors. The idea here is to show that adoptive immunotherapy can be more effective and made capable of causing regression of much larger tumors if steps are taken to preserve or augment the recipients own immune response. Preferential removal of suppressor T cells for the proposed studies will be achieved by treating tumor bearers with anti-Vbeta mAbs that destroy Vbeta T cell populations that contain suppressor T cells, but not effector/helper T cells. Preferential depletion of suppressor T cells will also be achieved later in tumor growth by taking advantage of the knowledge that suppressor T cells, but not effector/helper T cells, are actively replicating. Hence, suppressor T cells will be depleted by giving the tumor bearer antimitotic drugs. The released immunity will be analyzed in terms of the identity and physiology of the T cells that mediate it.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA027794-13
Application #
2087643
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1980-12-01
Project End
1996-03-31
Budget Start
1994-04-01
Budget End
1995-03-31
Support Year
13
Fiscal Year
1994
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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