Allogeneic Cell Therapy of Lung Cancer

Conventional therapeutic strategies for non-small cell lung carcinoma (NSCLC) include the use of surgery, chemotherapy and radiation. Many NSCLC patients present with advanced disease that is not treatable by surgery or does not respond to chemotherapy or radiation treatment. An alternative option would be the use of allogeneic stem cell therapy (ACT). This approach utilizes the responsiveness of T cells present in a donor lymphocyte graft to respond against allogeneic histocompatibility antigens present on lung cancer cells. It has been shown that a beneficial graft-versus-tumor (GVT) response is associated with the major complication of this procedure, graft-versus-host disease (GVHD). During GVHD, donor T cells attack recipient tissues resulting in significant morbidity and mortality including the development of idiopathic pneumonia syndrome in the lung. Allogeneic stem cell transplantation has been successfully utilized to treat a number of hematologic malignancies and more recently selected epithelial solid tumors, as well. Treatment with this procedure resulted in the regression of renal cell carcinoma lung metastases. Even more exciting is a recent report that demonstrated the elimination ofNSCLC following ACT. With this in mind, we will utilize a major histocompatibility antigenmatched murine transplantation model to test the central hypothesis that the allogeneic immune response that develops following ACT will be effective in controlling the growth of lung cancer. Experiments will utilize a reduced intensity conditioning regimen, bone marrow transplantation and delayed ACT with donor lymphocytes to reduce recipient regimen related toxicities including GVHD and idiopathic pneumonia syndrome in the lung. We will determine the effectiveness ofthe GVT response that develops after ACT against murine lung tumors. Finally, studies will be conducted that will evaluate the alloreactive immunity that mediates GVT responsiveness against lung tumors in the murine ACT model. These studies will provide the basis for future development of this procedure to enhance the allogeneic anti-tumor immune response and reduce regimen related toxicities.