The magnitude of cell-mediated immunity in vivo is, in part, a reflection of the number of antigen-reactive effector T cells present. Primary immunization in vivo results in an increase in the number of antigen-reactive T cells and an augmented cell- mediated response. Repeated immunization can further increase the number of antigen-reactive effector T cells, but eventually a plateau of responsiveness is reached--mediated by a complex network of specific and non-specific regulatory systems which limit the clonal expansion of antigen-reactive T cells. By selectivity expanding the number of antigen-reactive T cells in vitro and then adoptively transfering such cultured T cellls into the host, it has become possible to augment in vivo cell-mediated immunity to a variety of viral, tumor, transplantation and tissue antigens and to potentially achieve a higher degree of responsiveness than can be generated by active immunization in vivo. As an example, we have recently shown that T cells immune to murine leukemia can be grown to large numbers in vitro, and subsequently proliferate rapidly in vivo, distribute widely, eradicate disseminated leukemia and persist long-term as functional memory T cells. The experiments outlined in the current proposal will further define the principles necessary to utilize cultured T cells as reagents in vivo to augment specific anti-tumor T cell immunity and to utilize the augmented T cell immunity as a form of cancer therapy. Such studies should provide additional insights into how to exploit a weak autochthonous anti-tumor response by selectively growing and adoptively transferring large numbers of effector T cells of the desired specificity and function for therapy.
The specific aims of the proposed plan are: 1) to examine the efficacy of non-cytotoxic helper/inducer T cell clones and helper- independent cytotoxic T cell clones in tumor therapy; 2) to determine the principles for growing T cells clones in vivo with antigen as the stimulus for proliferation; 3) to determine whether a host anti-clonotype response prevents the survival and persistence of cultured T cells in vivo; 4) to determine whether selective host immunosuppression or the administration of exogenous growth factors can facilitate the adoptive transfer of cultured T cells; and, 5) to develop the use of anti-clonotype antibodies as reagents to identify, quantify and expand the number of tumor-reactive effector T cells.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Method to Extend Research in Time (MERIT) Award (R37)
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Experimental Immunology Study Section (EI)
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University of Washington
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Gaiger, A; Carter, L; Greinix, H et al. (2001) WT1-specific serum antibodies in patients with leukemia. Clin Cancer Res 7:761s-765s
Bernhard, H; Huseby, E S; Hand, S L et al. (2000) Dendritic cells lose ability to present protein antigen after stimulating antigen-specific T cell responses, despite upregulation of MHC class II expression. Immunobiology 201:568-82
Cignetti, A; Bryant, E; Allione, B et al. (1999) CD34(+) acute myeloid and lymphoid leukemic blasts can be induced to differentiate into dendritic cells. Blood 94:2048-55
Clark, J G; Madtes, D K; Hackman, R C et al. (1998) Lung injury induced by alloreactive Th1 cells is characterized by host-derived mononuclear cell inflammation and activation of alveolar macrophages. J Immunol 161:1913-20
Chen, W; Chatta, G S; Rubin, W D et al. (1998) T cells specific for a polymorphic segment of CD45 induce graft-versus-host disease with predominant pulmonary vasculitis. J Immunol 161:909-18
Disis, M L; Cheever, M A (1997) HER-2/neu protein: a target for antigen-specific immunotherapy of human cancer. Adv Cancer Res 71:343-71
Disis, M L; Pupa, S M; Gralow, J R et al. (1997) High-titer HER-2/neu protein-specific antibody can be detected in patients with early-stage breast cancer. J Clin Oncol 15:3363-7
Cheever, M A; Chen, W (1997) Therapy with cultured T cells: principles revisited. Immunol Rev 157:177-94
Liu, K J; Chatta, G S; Twardzik, D R et al. (1997) Identification of rat prostatic steroid-binding protein as a target antigen of experimental autoimmune prostatitis: implications for prostate cancer therapy. J Immunol 159:472-80
Disis, M L; Bernhard, H; Shiota, F M et al. (1996) Granulocyte-macrophage colony-stimulating factor: an effective adjuvant for protein and peptide-based vaccines. Blood 88:202-10

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