1450 Cytolytic T Cells in Adoptive Tumor Immunotherapy

Recent publications from this laboratory (1, 2) have shown that it is possible to cause the regression of established immunogenic murine tumors by the passive transfer of tumor-sensitized T cells from immunized donors, provided the tumor-bearing recipients have been made T cell-deficient by thymectomy and irradiation. The need for T cell-deficient tumor-bearing recipients to demonstrate successful adoptive immunotherapy suggested the existence in normal tumor bearers ofa T cell-dependent mechanism that prevents intravenously infused sensitized T cells from expressing their antitumor function. Evidence that this obstacle to adoptive immunotherapy is a tumor-induced, T cell-mediated mechanism of immunosuppression was supplied by the demonstration (3, 4) that the passive transfer of splenic T cells from normal tumor bearers prevents passively transferred tumor-sensitized T cells from causing tumors to regress in T cell-deficient recipients. It was hypothesized, on the basis of this and other evidence (5) that the growth of an immunogenic tumor results in the generation of a state of T cell-mediated immunosuppression that functions to "down-regulate" a preceding concomitant immune response. Hence, the explanation for the paradoxical growth of immunogenic tumors in their immunocompetent hosts, and the reason why these tumors develop refractoriness to active and adoptive immunotherapy. In designing experiments to investigate the mode of action of suppressor T cells, two aspects of this model of adoptive immunotherapy need to be considered. The first is that the sensitized T cells routinely used to passively transfer anti-tumor immunity are obtained from donor mice that are immunized by causing their tumor to regress 2-3 wk earlier by intralesional therapy with Corynebacterium parvum. The sensitized T cells are harvested, therefore, after the cytolytic T cell response to the immunizing tumor has decayed (6) and when the donors possess a state of immunological memory. Thus, the sensitized T cells infused intravenously have no detectable cytolytic activity of their own. The second important aspect of the model is that the passive transfer of tumor-sensitized T cells does not result in an immediate onset of tumor regression in T cell-deficient recipients. Instead, there is invariably a 6-8-d delay before regression commences. It can be postulated, therefore, that the intravenously infused sensitized T cells do not possess the capacity themselves to immediately destroy the tumor, but