In our Phase II trial of yttrium-labeled Zenapax we have treated an original group of 30 patients with Hodgkin's lymphoma. We 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. 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 2- or 3-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 9 months after her initial treatment with siplizumab. This was attributed to the agent that she was being treated with at the time. Downmodulation 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 EBV 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 of siplizumab in combination with rituximab and dose-adjusted EPOCH chemotherapy in newly diagnosed patients with T or NK cell lymphoma has been initiated and the first two dose levels have been successfully completed. Depletion of T cells has not been as great as anticipated in the first two cohort of patients. The trial continues to accrue. The phase II trial of daclizumab has shown that this agent is inactive in patients with the lymphomatous and acute leukemic forms 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. The discontinuation of manufacture of daclizumab by Roche has led to the closure of this study to patient accrual. Laboratory studies on samples from the study show that smoldering/chronic ATL PBMC spontaneously proliferated ex vivo in a cytokine (IL-2/IL-9/IL-15)-dependent manner while acute type ATL did not proliferate or proliferated independent of these cytokines. Smoldering/chronic ATL cells produced IL-2 and IL-9 in 6-day ex vivo cultures. Interestingly, addition of an anti-IL-2Ralpha monoclonal antibody profoundly inhibited IL-9 expression, suggesting optimal expression of IL-9 was dependent on IL-2 signaling in these patients. Accrual has been completed in our phase II trial of alemtuzumab. Responses of significant duration 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 collaborations with Dr. Jane Trepel and had collaborations with Dr. John Brady to identify new targets for treatment of patients with adult T-cell leukemia/lymphoma. Dr. Brady 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. We have recently obtained YM155, a survivin inhibitor, and intiated animal model studies of the agent in the MET1 model. These studies, if promising, will be used provide support for a clinical trial of YM155 and alemtuzumab in patients with ATLL. Dr. 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.
