The overall goal of this revised project is to develop new strategies for the treatment of human colorectal cancer with radiolabeled monoclonal antibodies (MoAbs) in animal studies and ultimately clinically. Radiolabeled MoAbs offer the possibility that radiation can be targeted preferentially toward cancer cells, which could yield a higher therapeutic index than external beam radiation alone. The chief stumbling block is the low dose of radiation that can be delivered to the tumor without causing systemic toxicity. We propose the study of new fractionation schedules in animal models based on preliminary studies that showed a high percentage of complete tumor regressions with little animal lethality and to elucidate the therapeutic efficacy, toxicity, radiobiological and physiological effects of fractionated radioimmunotherapy. We hypothesize that the short time interval (3 days) that was used between injections is more effective than the same radionuclide dose administered in a single injection due to improved tumor uptake of the second dose of radiolabeled MoAb as a result of increased vascular permeability and a difference in the intratumor distribution of the radiolabeled MoAb. MoAbs B72.3, CC49 and 17-1A which are well characterized reagents reactive with human adenocarcinoma with affinities that vary by a factor of 200 will be utilized. These MoAbs have been used in clinical radioimmunodetection and radioimmunotherapy trials of human colorectal cancer.
The Specific Aims of this application are to evaluate the therapeutic efficacy of 131I- and 186Re-labeled MoAbs with reactivities against human gastrointestinal cancer associated antigens in an in vivo human colon cancer experimental tumor model, to optimize the therapeutic efficacy and minimize the toxicity by testing various fractionation schedules or administration by continuous infusion, and to determine the tumor uptake and distribution of radiolabeled MoAbs given in 1 or 2 injections. We will measure vascular permeability, antigen expression and tumor cell cycle status which are parameters that may affect therapeutic efficacy.
