It has recently been demonstrated that human sarcomas express tumor-associated antigens potentially capable of being recognized by T cells. Despite these observations, it is evident that the weakness of these antigens and/or the presence of tumor-induced suppression results in an ineffective immune response in cancer patients. The applicants hypothesize that the immune response to sarcoma can be modulated to elicit T cell reactivity, and that this response may be useful for therapy. They propose to generate vaccine-primed T cells for the immunotherapy of stage IV sarcoma patients utilizing methods derived from extensive preclinical studies. These studies have demonstrated that lymphocytes from lymph nodes primed by tumor vaccination harbor T cells which can develop specific anti-tumor reactivity against poorly immunogenic tumors after in vitro activation. Furthermore, animal data suggest that using vaccines composed of tumor cells transfected with the GM-CSF gene are more therapeutically efficacious and may overcome systemic immunosuppression of T cells. The studies proposed herein may yield important insights into the requirements for eliciting T cell responses against sarcoma-associated tumor antigens, and will allow us to study whether tumor-induced suppression of the T cell signal transduction molecule TCR-z is present in sarcoma patients.
The specific aims of this application are: 1. To assess the in vivo immune response to lymph node lymphocytes primed with autologous tumor plus BCG and activated in vitro in the adoptive immunotherapy of metastatic sarcoma. To assess the in vivo immune response of lymph node lymphocytes primed with GM-CSF gene-modified tumor in the adoptive immunotherapy of metastatic sarcoma. 3. To examine the in vitro immunologic reactivity of in vitro activated vaccine-primed lymph node lymphocytes with respect to autologous tumor. 4. To examine the expression of TCR-z in the peripheral blood and vaccine-primed lymph node lymphocytes of sarcoma patients, and to determine whether TCR-z expression is upregulated after in vitro activation.
