In our Phase II trial of yttrium-labeled Zenapax we have treated 30 patients with Hodgkin's lymphoma. We describe developed a novel effective therapy for patients with refractory and relapsed Hodgkins lymphoma. We administered the anti-CD25 monoclonal antibody daclizumab armed with Yttrium-90, a radionuclide that provides a strong beta emission, to patients with refractory or relapsed Hodgkins lymphoma. Of the 30 patients treated there were 6 with progressive disease, 5 with stable disease, 7 partial responses and 12 patients with a complete response. The therapeutic strategy used in this clinical trial that involved repeated 90Y daclizumab infusions provided much more effective therapy for patients with Hodgkins lymphoma than was obtained in any previous trials with monoclonal antibodies armed with toxins or radionuclides. This increased efficacy reflects the fact that not only the tumor cells but also associated lymphomatous lesion polyclonal rosetting T-cells expressed the CD25 antigen thereby increasing the target that binds the radiolabeled antibody. Furthermore, the increased efficacy was related to the use of the beta-emitting radionuclide Yttrium-90 that does not have to come in contact with each tumor cell because it can act at a distance by crossfire that facilitates the killing of CD25 non-expressing malignant cells. Finally the repeated dosing permits an increased total dose of radiation to the tumor. Repeated 90Y infusions provided effective therapy for select patients with refractory and relapsed Hodgkins lymphoma. Accrual of patients with Hodgkin's lymphoma continues and futures studies are planned to move this treatment into an earlier point in the treatment of these patients. In particular we plan a study of yttrium-labeled Zenapax in combination with autologous stem cell transplantation for patients with relapsed Hodgkins lymphoma. This will bring access to a new patient population for study at the NCI. We will also evaluate methods of enhancing tumor targeting in small trials. First, we will use targretin in an attempt to increase CD25 expression on tumor cells to increase delivery of radiolabelled antibody and secondly, we will evaluate the ability of bevacizumab to improve tumor penetration of the monoclonal antibody with evaluation of this parameter by imaging in collaboration with Peter Choyke and the molecular imaging facility. Clinical trials evaluating a variety of agents in the management of patients with adult T-cell leukemia/lymphoma have continued. These trials include evaluations of agents that target CD2 (siplizumab), CD25 (daclizumab) and CD52 (alemtuzumab). The phase I trial of siplizumab completed accrual to its initially planned evaluation of a two- or three-day course of treatment administered on an every other week basis for up to 16 weeks. Seven cohorts of patients were treated with doses ranging from 0.4 to 4.8 mg/kg. There were no dose-limiting toxicities and both T cell and natural killer cell (NK cell) depletion were observed. In this cohort of patients there was one patient who developed Epstein Barr virus (EBV)lymphoproliferative disease nine months after her initial treatment with siplizumab. This was attributed to the agent that she was being treated with at the time. Down modulation of the siplizumab target, CD2, was observed within 24 hours of antibody administration in the peripheral blood and appeared to impair the activity of the administered antibody from producing further decreases in peripheral blood T cell numbers, particularly in patients with high white blood cell counts. The protocol was amended to permit accrual of several additional cohorts of patients with doses ranging from 0.8 to 15 mg/kg administered as a single infusion weekly. Three of the six patients entered in this cohort developed Epstein Barr virus lymphoma or lymphoproliferative disease. Although partial and complete responses were observed, the sponsor of this trial has elected to close the study. It is possible that Epstein Barr virus lymphoproliferative disease can be prevented by preemptive treatment with rituximab to deplete B cells. A follow-up study has been reviewed by the NCI IRB and we await a cross reference letter from MedImmune Oncology that will permit us to begin a study of siplizumab in combination with rituximab and dose-adjusted EPOCH chemotherapy in newly diagnosed patients with T or NK cell lymphoma. The phase II trial of daclizumab has shown that this agent is inactive in patients with lymphomatous and the acute leukemic form of adult T-cell leukemia/lymphoma; however, patients with the smoldering and chronic forms of adult T-cell leukemia/lymphoma are responsive to this treatment. It is thought that these earlier forms of adult T-cell leukemia remain dependent on interleukin-2 (IL-2) signaling and that the responses are due to apoptosis due to cytokine deprivation. Accrual continues in our phase II trial of alemtuzumab as responses were observed in patients during the first stage of this trial. Accrual to a total of 29 patients is planned. Responses have been confined to patients with the acute leukemic and chronic forms of the disease but not in the lymphomatous presentation. In an attempt to define the mechanisms responsible for response and resistance to treatment we have begun collaborations with Dr. John Brady and Dr. Jane Trepel to identify new targets for treatment of patients with adult T-cell leukemia/lymphoma. Dr. Brady has observed high levels of the anti-apoptotic protein, survivin, in patients with adult T-cell leukemia/lymphoma. Using cDNA microarrays, Dr. Brady has observed that responding patients treated with daclizumab have reduced levels of survivin message compared with pretreatment samples, whereas the malignant cells that are resistant to alemtuzumab have elevated levels of survivin compared with pretreatment samples. Clinical and preclinical animal model studies of survivin inhibitors are planned. Jane Trepel has observed that beta catenin plays an important role in proliferation of the malignant lymphocytes in patients with ATL. A phase I clinical trial of humanized MiK-beta-1, directed at the beta chain of the interleukin-2 receptor continues accrual in patients with large granular lymphocyte leukemia. No dose-limiting toxicity has been observed and patients are being treated with the highest dose level planned for the study. Reduction in the numbers of peripheral blood malignant cells has been observed.
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