Radioimmunotherapy (RIT) demonstrates promise in laboratory models. This promise has been realized in the clinic for hematologic malignancies. For the more radioresistant solid tumors, results have been less successful, but remain encouraging. Dosimetry estimates and anti-tumor effects observed on current trials with the first generation of engineered agents indicate that clinically meaningfully results are close to being realized for solid tumors. To build on this promising base will require application of strategies that have proven successful in optimizing other systemic therapies; namely dose-intensification, to increase tumor dose, and multi-modality approaches, to increase the biologic effect of that targeted dose. The proposed therapy trials will evaluate these strategies in patients with CEA-producing malignancies. Upon completion of Phase I and Phase II studies evaluating 90Y-DOTA-anti-CEA chimeric T84.66, subsequent trials will evaluate 90Y anti-CEA RIT combined with 5- fluorouracil (5-FU) in colorectal cancer, combined with 5- FU/leucovorin/cis-platinum and stem cell support in chemo-responsive metastatic breast cancer, and combined with IP iododeoxyuridine in patients with peritoneal carcinomatosis. Combined modality trials will evolve towards therapy in patients which have been less heavily pre- treated, are chemo-responsive, and have lower tumor burden. These trials will provide an opportunity to further increase tumor responses by taking advantage of the radiation enhancing properties of these chemotherapy agents in a more favorable group of patients. Further improvements in radioimmunotherapy and radioimmunodetection will also require refinements of the antibody. Three intermediate molecular weight engineered constructs derived from T84.66 (F(ab')2 (110 kD), minibody (80 kD), and diabody, (55 kD)) will be evaluated in imaging and biodistribution trials radiolabeled with I-123. Due to faster clearance, their tumor/blood rations are superior to that of the intact, making them promising for further evaluation as imaging agents. The minibody, which demonstrates the highest tumor uptake and tumor/marrow dose rations, and a humanized version of T84.66 will also be evaluated as potential therapy agents initially in biodistribution trials labeled with In-111. These trials will provide the necessary foundation for future evaluation of improved constructs and chelates for therapy and imaging developed in project 2 (Bioengineered Antibodies) and Project B (Antibody Chelates and Conjugates).
Showing the most recent 10 out of 112 publications
