Description
Recent advances in our understanding about the mechanisms of antigen presentation, T-cell activation, and the design of tumor vaccines offer the opportunity to design more sophisticated immunotherapeutic strategies in the management of women with ovarian carcinoma. This project looks to develop both clinical strategies and preclinical assays for evaluating both dendritic cell base taxanes as well as viral based DNA vaccines.

We have developed a vaccine for patients with cancer by fusing their tumor cells with dendritic cells (DC). Fusion cell vaccines have been shown to be effective in the treatment of metastatic mouse tumor models and in reversing immunologic unresponsiveness to the human MUC1 carcinoma antigen in MUC1-transgenic mice. A Phase I clinical trial of the fusion cell vaccine has demonstrated the induction of immunologic and clinical responses. Our overall hypothesis is that ovarian cancer cells express antigens that can be exploited as targets for the induction of anti-tumor immunity. Certain ovarian carcinoma-associated antigens, such as the MUC1 glycoprotein, represent known targets. Given the genetic instability associated with progression of human tumors, there are conceivably many epitopes unique to ovarian cancer cells that, while unknown, represent additional targets for vaccine therapy.

Our objective is to develop a fusion cell vaccine that induces immunity against multiple antigens expressed by ovarian cancer cells, is associated with substantial clinical efficacy and is non-toxic. Our hypotheses are that we can generate an effective fusion cell vaccine for the treatment of ovarian cancer by: 1) using mature autologous DC; 2) combining the vaccine with recombinant human IL-12 (rhIL-12); and 3) vaccinating patients with metastatic disease earlier in their treatment course. Effectiveness of the fusion cell vaccine will be assessed in vitro and in a Phase I/II trial that monitors anti-tumor activity and induction of immunity in patients with advanced ovarian cancer. The findings from these studies will be used to design a Phase II study to compare the efficacy of the fusion approach and a vaccinia virus-based vaccine that targets the MUC1 antigen (rV-MUC1+rV-TRICOM) in patients who have achieved a minimal disease state. The development of vaccines that are non-toxic and effective against advanced ovarian cancer could provide alternative treatment options and potentially improve prognosis for patients with this disease.

The specific aims are:

1. To assess fusions of ovarian carcinoma cells with immature and mature autologous DC by evaluating cytokine production (IL-12, IL-10) and potency of the fusions in generating tumor specific immunity in vitro
2. To conduct a Phase I/II trial of the ovarian carcinoma-DC fusion vaccine generated with mature DC and administered with rhIL-12
3. To assess the induction of immunity against ovarian cancer cells and MUC1 in patients treated with the fusion cell vaccine alone and with rhIL-12
4. To perform a Phase II trial that will define the immunologic efficacy of the fusion cell vaccine and the rV-MUC1+rV-TRICOM vaccine in the treatment of patients with advanced ovarian cancer who have achieved a complete remission following primary chemotherapy.
   
   
   

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