the majority of non-Hodgkin's lymphomas (NHL) and chronic lymphocytic leukemias (CLL) are of B cell origin and many of these patients ultimately die from their disease despite standard therapy. Lym-1 is a monoclonal antibody that reacts with B cells specifically including malignant tissue from more than 80% of patients with NHL and 40% of patients with CLL of B cell origin. Durable clinical responses were observed in the majority of 58 patients with B cell malignancies, primarily NHL, that were treated with radiolabeled Lym-1. Toxicity was acceptable and thrombocytopenia was dose-limiting. Several patients developed inflammation over lesions that suggested a biologic response although Lym-1 alone has not proven therapeutic. The efficacy of radiolabeled Lym-1 in NHL is remarkable when one considers that it was used in isolation, and improvements could lead to cure of incurable disease. We examined a number of enhancement strategies to improve the therapeutic index including various radionuclides and radiochemistries for conjugation, effects of fractionation of therapy, agents to alter delivery to the tumor, and immunoabsorption to decrease radiation to normal tissues. While all of these strategies showed merit, we've chosen to focus on the radionuclide and radiochemistry, and Interleukin-2 (IL-2) during the proposed grant period because they were most promising. Observations on the pharmacokinetics and radiation dosimetry of 67 Cu or 90Y conjugated to Lym-1 with macrocyclic chelates specifically generated for these radionuclides in Project 3 indicated significant advantages for therapy. Because 67Cu-BAT-Lym-1 is retained in the malignancy, the radiation dose was several times greater than that from 131I-Lym-1 in patients. The MTD for 67Cu-BAT-Lym-1 was two doses each of 60 mCi/m2 given four weeks apart, and two of three patients responded to therapy. Studies in mice with human lymphoma showed that tumor uptake and radiation dose was increased two fold by IL-2 and suggested that response surface experimental designs were an efficient approach to studies of this type. Methods to be used include: 1) classical phase II clinical trial design for therapeutic agents in patients with malignant disease; 2) newer response surface designs for Il-2 enhancement; 3) quantitative imaging for pharmacokinetics and radiation dosimetry; and 4) tomographic imaging for tumor volume. Strengths of this project include an interdisciplinary group that has established their commitment and cohesiveness, and the clinical relevance of Lym-1 treatment. This project benefits from studies in Project 4 where new constructs and radiochemistry are generated and opportunities for comparisons of the biology and radiobiology with breast cancer in Project 2. Finally, Lym-1 or similar antibodies may be applicable to treatment of lymphomas associated with AIDS and other immunologic disorders.
Showing the most recent 10 out of 187 publications
