The adoptive transfer of sensitized T lymphocytes has been shown to effectively mediate the regression of established tumors. Using the weakly immunogenic MCA 105 sarcoma, we have developed an in vitro sensitization (IVS) procedure which allowed cellular expansion as well as augmentation of the therapeutic efficacy of immune spleen cells. With the IVS procedure, we were able to generate, from tumor-bearing mice, lymphocytes with therapeutic efficacy against established pulmonary metastases. Before culture these lymphoid cells did not exhibit antitumor reactivity. Since effective T lymphocytes could not be generated from normal mice, it became evident that progressive growth of the MCA 105 tumor elicited pre-effector cells from which antitumor effector cells could be induced by IVS. We have recently extended these observations to two nonimmunogenic murine sarcomas. The MCA 101 and MCA 102 tumors failed to elicit a systemic immunty in syngeneic hosts by a variety of immunization protocols including tumor growth and excision, immunization with irradiated tumor cells as well as with mixtures of various doses of tumor cells and a bacterial adjuvant, Corynebacterium parvum. However, preliminary experimental results demonstrated that immunization with tumor cells and adjuvant elicted pre-effector cells in the draining lymph node. IVS of these lymphoid cells resulted in the generation of effector cells capable of mediating the regression of established MCA 101 and MCA 102 tumors. The purpose of the proposed studies is to analyze further the optimal conditions and cellular mechanisms involved in eliciting therapeutic pre-effector cells in vivo and effector cells invitro which have therapeutic activity against these """"""""nonimmmunogenic tumors."""""""" The studies in this proposal seek to: 1) determine the immunization conditions necessary for eliciting pre-effector cells. 2) elucidate mechanisms of cellular interactions leading to the sensitization of pre-effector cells: 3) elucidate conditions of IVS for induction of therapeutic lymphocytes and to determine criteria for cellular expansion in culture: 4) determine the immunologic specificity of adoptive immunotherapy; 5) determine the effect of exogenous IL-2 on the function, distribution and proliferation of transferred IVS effector cells in vivo: and, 6) determine the therapeutic efficacy of IVS cells in the treatment of advanced metastases in various organs.
