This is the third competitive renewal of our Program Project Grant. We have modified the name to reflect the refinement in focus, Antibody Targeted Radiation and Immunotherapy for the Treatment of Solid Tumors. There are three projects, 1) Radioimmunotherapy: clinical and radiobiologic studies, 2) pretargeting with anti-cea mabs for therapy, and 3) cea-targeted immunotherapeutics Project 1 exploits the most effective strategies we have developed for RIT of solid tumors, combining RIT with chemotherapy in the most appropriate clinical setting. Significant is the addition of a radiobiologic research component. Project 2 is a merger of our antibody engineering effort and the synthetic chemistry effort from the last PPG into a project which now clearly focuses on the development of clinically applicable pretargeting approaches. Project 3 represents a new project which has developed out of our previous work on engineering an anti-CEA-IL2 immunocytokine. The projects will be supported by the same six cores (Clinical Imaging, Radiopharmacy, Clinical Production, Animal Core, Biostatistics, and Administration) that have been the foundation for both the research and the clinical trials. There are a number of new key personnel on this application; Dr. Colcher, with over 25 years of experience with monoclonal antibodies, Dr. Yu with world renown expertise in molecular immunology, Dr. Radany with both clinical and research interests in radiobiology, Dr. Bading with over 25 years of imaging physics, Dr. Frankel providing excellent biostatistical support, Dr. Hudson for novel constructs, and our collaborator Dr. Conti providing expertise in clinical imaging. Our outside collaborators are outstanding and essential; Dr. Gillies for protein engineering, Dr. Meares for chelate chemistry and anti-chelate antibodies and Dr. Reisfeld for his tremendous expertise in immunology. This application is also notable for its use of cutting edge technologies; CEA transgenic mice for the immunotherapy projects, molecularly targeted immunotherapeutics, advanced imaging for both animal and clinical studies, nanoparticles for both radiosensitization and immunotherapy, high throughput screening to discover new constructs, a licensed cGMP compliant biologies production facility, and the newly established Clinical Immunology Correlates Support Laboratory headed by Dr. Kalos. This is all taking place in the setting of the newly established Division of Cancer Immunotherapeutics & Tumor Immunology, with a commitment from the City of Hope to build a new $60M facility by summer 2008 which will house most of the Program Project Team.