The Metabolism Branch is engaged in a broad program involving the use of monoclonal antibodies alone or armed with radionuclides for the treatment of cancer. The major focus of our studies is T cell non-Hodgkin's lymphoma more specifically adult T-cell leukemia/lymphoma. In contrast with the excellent results in the treatment of B cell large cell non-Hodgkin's lymphoma (over 80% of patients achieve durable complete remissions) less than 20% of patients with T cell large cell non-Hodgkin's lymphoma survive for more than five years. The outcome for patients with adult T-cell leukemia/lymphoma is even worse. New therapies are desperately needed. The definition of cell surface molecules expressed by the malignant T cells has identified a large array of potential targets for investigation. The viability of these cell surface molecules as targets has been verified in preclinical studies conducted in the laboratory of Dr. Thomas A. Waldmann. We are currently investigating humanized monoclonal antibodies directed at CD2, CD25 and CD52 in patients with T-cell non-Hodgkin's lymphoma as well as recombinant fusion proteins. In the case of CD25 targeting, we are evaluating daclizumab alone in an attempt to induce growth factor deprivation induced apoptosis, daclizumab armed with the radionuclide yttrium 90 and the recombinant fusion protein denileukin difitox. We have completed a phase I study of Zenapax, directed at CD25, and determined a dose of 8 mg/kg administered every three weeks as the phase II dose. Our initial phase II study demonstrated a response rate of less than 30% in patients with the acute leukemia or lymphomatous form of adult T cell leukemia/lymphoma. Accrual of patients with chronic or smoldering adult T cell leukemia/lymphoma is ongoing; patients with the earlier stages of disease are more likely to have malignant T cells that are dependent on IL-2 signaling for survival. Zenapax by binding to CD25 interferes with this signal and showed antitumor activity in our phase I trial in patients with the chronic form of ATL. The anti-CD25 antibody has also been armed with the beta emitter yttrium 90 for the therapy of adult T cell leukemia/lymphoma and other CD25 positive malignancies. Our phase I/II trial of yttrium labeled Zenapax has completed accrual and a dose of 25 mCi has been defined as the phase II dose. Dose-limiting myelosuppression was observed at the 30 mCi dose. Although almost half of the patients treated on the phase I portion of this study responded to treatment only one response was observed during the phase II portion of this study. In CD25 positive malignancies other than adult T cell leukemia/lymphoma yttrium labeled Zenapax is also being evaluated in a phase I/II study. The maximum tolerated dose in these patients was 15 mCi with dose limiting myelosuppression noted at the 20 mCi dose level. Antitumor activity was observed in two patients with Hodgkin's disease with one patient achieving a complete remission that lasted for about nine months. At relapse the patient was retreated and again achieved a complete remission. The study is actively accruing patients with Hodgkin's disease following a protocol amendment that permitted treatment of patients with a history of previous stem cell transplantation. We are evaluating siplizumab, directed at CD2, in a phase I trial for patients with CD2 positive lymphoproliferative disease. The major objectives of the study are to determine the safety, tolerability and maximum tolerated dose of the agent. Treatment produced infusional reactions in all patients that were largely confined to the first day of treatment. T cell depletion was prompt with reduction of both normal and malignant T cell populations and was associated with reactivation of cytomegalovirus infection in 26% of patients.
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