Biologic and therapeutic efficacy of mafosfamide in patients with metastatic renal cell carcinoma.

Abstract

It is well known that oxazaphosphorines [e.g., cyclophosphamide and 4-hydroperoxycyclophosphamide (mafosfamide)] are potent immunosuppressive agents. Under the proper conditions, they can potentiate immune responses as well. Immunomodulation represents a major breakthrough in the management of chemotherapy-resistant tumors. Thus, we evaluated the clinical and laboratory sequelae of low to intermediate doses (100-1000 mg/m2) of mafosfamide administered to 16 patients. Four weeks after therapy, one patient had a complete remission, eight patients presented with stable disease, and seven patients did not respond. Clinical and laboratory toxicity was mild and totally reversible, and therapy was well tolerated in all patients. Analyses of phenotypic cell surface antigens on circulating peripheral blood mononuclear cells showed inconsistent alterations of the CD4/CD8 ratio, initial depletion with later rebound of CD8+ cells, increase of CD20+ cells, and a mafosfamide dose-dependent regulation of natural killer-like cells as characterized by CD16 and CD56 positivity. Cell-mediated cytotoxicity against K562 target cells peaked 1 day after therapy and was most pronounced in patients who had received 300 mg/m2 mafosfamide, whereas cytotoxicity against Daudi targets was essentially unchanged, consistent with an increase in natural killing activity without augmentation of lymphokine activated killing. We conclude that mafosfamide administration at low to intermediate doses can be performed with good safety and tolerance; immunophenotypic analyses and cytotoxicity assays showed most pronounced alterations in patients receiving low doses of mafosfamide. These observations support the use of mafosfamide in the attempt to augment antitumor immune responses.