This Program Project is organized along the common theme of increasing the immune response to human tumors by genetic engineering of tumor cells or immune effector cells. We propose to determine whether cytokine-transduced human tumors generate an immune response in vivo. To accomplish this, we propose a clinical vaccine trials for 2 solid tumors - melanoma, neuroblastoma - 4 different cytokines - IL-2, IL-7, gammaIFN, alphaIFN. Coordinated by a Vaccine Core and a Clinical Immunology Core, similar protocol design and clinical testing will allow a comparison of cytokines and tumors and allow us to refine gene therapy strategies. Using recombinant adenovirus vectors, we propose to develop improved strategies for cytokine-based vaccines. We will determine whether these high efficiency vectors can optimize ex vivo or in vivo gene delivery to tumors. Finally, we propose to develop a novel method for delivery of gene- engineered proteins to tumors by targeting proteins to granules of TIL. We will identify the """"""""targeting peptide motif"""""""" that can direct proteins to cytotoxic granules and determine whether gene-engineered TIL will release the introduced protein only when specifically triggered by interaction with tumor targets. In summary, a Program Project is proposed that quickly brings several vaccine protocols to clinical trial and provides for the testing of novel strategies of tumor and cytotoxic lymphocyte gene transfer.
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