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.
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