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 investigated humanized monoclonal antibodies directed at CD2, CD25 and CD52 in patients with T cell non-Hodgkin's lymphoma. In the case of CD25 targeting, we are evaluating the antibody alone and armed with the radionuclide yttrium 90. 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. We are evaluating MEDI507, 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 50% of patients. Improvement in granulocytopenia was observed in two patients with T-cell large granular lymphocyte leukemia that was in association with reduction in the leukemic T cells in peripheral blood. This trial is ongoing and patients are being entered in the third dose level on the study. We are evaluating Campath (directed at CD52) in a phase II study in patients with adult T cell leukemia/lymphoma. A response pattern of response similar to that of patients with chronic lymphocytic leukemia was seen; responses were observed in patients with leukemia but not in bulky masses at nodal or extra-nodal sites. As with MEDI507, T cell depletion is prompt and has been associated with cytomegalovirus reactivation in all patients treated. CMV reactivation has not been associated with pathologic organ involvement and has not interfered with continued treatment. This trial is ongoing and will accrue 29 patients as one response was seen among the first nine patients treated. Both Campath and MEDI507 have been shown in the MET1 animal model to be dependent on Fc receptor function for antitumor activity. In contrast antibodies directed at CD30 appear to be able to induce apoptosis in the absence of Fc receptor I and III function. We are investigating in a phase I study the toxicity and determining the maximum tolerated dose of HeFi-1, a murine monoclonal antibody directed at CD30, in patients with Hodgkin's disease and anaplastic large cell lymphoma. This antibody is capable of signaling apoptosis induction in CD30 positive tumors and in contrast with the Campath and MEDI507 retains antitumor activity in the Fc receptor knockout mouse. Three patients have been treated and accrual continues. In addition we are about to begin accrual to a phase I study of a humanized monoclonal antibody directed at CD122, the beta chain of the IL2 receptor, in patients with T cell large granular lymphocyte leukemia. The malignant cells in patients with large granular lymphocyte leukemia express CD122 and this antibody could act by inhibiting IL15 signaling or may act as a means of directing antibody dependent cell mediated cytotoxicity.
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