Newer Immunotherapeutic Approaches in Managing Metastatic Pancreatic Cancer

Pancreas Cancer remains one of the more difficult lesions to manage whether at the time of diagnosis or when seen for recurrent disease. When the tumor is operable by one of several surgical procedures depending on site of origin, survival rarely exceeds 10% at the 2 year level post op. When initially diagnosed with a metastatic lesion, survival of the patient rarely reaches 1 year. Chemotherapy becomes the standard method of treatment. When Gemcitabine is utilized the survival is found to be in the range of 5 months and when this is followed by Abraxane, an additional 7-10 wks can be expected. In order to improve survival beyond that achieved by chemotherapy alone, immunotherapeutic agents are being introduced, with the hope of enhancing the overall survival rate. Many immunogenic targets have been defined, but those offering the best opportunity for accomplishing the needed response are proteins (TAA's) expressed by the tumor that are immunogenic and specifically characterize that lesion without cross reactivity to normal tissue. We have found in our studies of colorectal carcinoma that several tumor associated antigens are present and that one in particular, the post translational modification of MUC5ac is highly expressed in many cases of pancreatic cancer. This protein is present mainly tumors of the colon and pancreas but at levels too low to be recognized by the host immune system. After isolating this TAA and measuring levels of its expression by the tumor, few lesions contain more than 25-50 ugms. A detailed study of levels necessary to induce the proper immune response has been shown to be between 500 and 1000 ugms. We have also looked at mechanisms by which TAA, when delivered at proper levels produce immune suppression of the lesion. The mechanism has been shown to primarily be IgG1 expression by the B cells and that the cytotoxic T cells do not play a major role. The monoclonals do not directly affect the tumor by rather function through ADCC (antibody dependent cell cytotoxicity). In the present paper discussing our clinical trials, patients entered have failed all therapeutic approaches, have been shown to express the proper target antigen and as such receive 400 mg. antibody IV q 2 wks. The nature of the tumor antigen, development of the monoclonal system employed and status of the ongoing FDA trial is described.