Monoclonal antibody therapy of T cell lymphoma: single agent trials of anti-CD2 (Siplizumab) and anti-CD4 (Humax-CD4)

Abstract

Although there has been significant progress in the management of B-cell non-Hodgkin’s lymphoma, the treatment of T-cell lymphomas remains unsatisfactory with less than 20% of patients experiencing long term disease control. In addition to their inherent resistance to chemotherapy, the complexity of treating T-cell lymphoma in part resides in the diverse clinical entities encompassed by this diagnosis as well as their less frequent occurrence compared with the more common B-cell lymphomas. The T cell has a wide array of cell-surface receptors that can serve as targets for treatment by monoclonal antibodies. These receptors include broadly expressed antigens, for example CD2 and CD52 present on almost all normal and malignant T cells or their expression may be restricted, such as CD4 or CD8 where only specific populations display the antigen. The advantage of using the broadly expressed antigens as targets for monoclonal antibodies is their applicability to a wide array of T cell neoplasms but the concomitant immunosuppression associated with their use is a major disadvantage. Restricted receptors limit the target cell population depleted by treatment and thus may be better tolerated but this limits the population eligible for treatment. Two monoclonal antibodies evaluated for the treatment of T cell lymphoproliferative disorders are siplizumab which binds to CD2 and zanolimumab which binds to CD4. Two phase I trials of siplizumab demonstrated promising activity in T cell malignancies with partial and complete responses observed in patients with peripheral T cell lymphoma (PTCL), adult T cell leukemia/ lymphoma and large granular lymphocyte leukemia but the development of Epstein-Barr virus-related lymphoproliferative disease (EBV-LPD) in five of 51 patients (10%) treated prompted closure of the single agent trials. Siplizumab is being evaluated in combination with rituximab in an attempt to prevent EBV-LPD. Zanolimumab has been evaluated in the treatment of cutaneous Tcell lymphoma (CTCL) and PTCL with responses observed in both groups. Fifty-six percent of patients with CTCL treated with high doses of zanolimumab (980 mg per treatment) responded with a median response duration of 81 weeks. In a separate trial in patients with aggressive T cell lymphomas, three of fourteen patients (21%) achieved objective responses to the same high dose treatment regimen used in the CTCL trial. Zanolimumab therapy was well tolerated with a limited increase in infectious complications; no cases of EBV-LPD were Monoclonal antibody therapy of T cell lymphoma: single agent trials of anti-CD2 (Siplizumab) and anti-CD4 (Humax-CD4) J.E. Janik D. O’Mahony T.A. Waldmann J.C. Morris Metabolism Branch, Center for Cancer Research, National Cancer Institute, Bethesda, USA SESSION IV reported. Zanolimumab is currently being evaluated in patients with CTCL who have progressive disease following bexarotene and at least one other systemic treatment in a licensing trial. Although responses occur with both siplizumab and zanolimumab alone, receptor modulation represents an obstacle to the effective use of these antibodies.