Elimination of immune suppressor mechanisms in humans by oxazaphosphorines

The oxazaphosphorine drug cyclophosphamide (CY), has significant immunopotentiating effects. Maguire and Ettore (21) were the first workers to describe CY-mediated immunopotentiation: They reported that guinea pigs treated with CY and then contact-sensitized developed much more intense and prolonged allergic contact dermatitis reactions than did control guinea pigs that had received sensitizer alone. Subsequently, CY was shown to immunopotentiate the acquisition of delayed-type hypersensitivity (DTH) to a variety of antigens and even to syngeneic tissue. The critical factor determining whether CY depresses or potentiates an immune response in experimental animals is the timing of administration of CY and antigen. The dose of CY seems to be much less important. Since 1982, we have performed immunological studies of 74 cancer patients treated with CY. We have tested two doses--1000 mg/M2 and 300 mg/M2, given by rapid intravenous infusion. Using the animal data as a guide, we have elected to administer CY 3 days prior to sensitization with antigen. Our initial two studies were performed with the primary antigen keyhole limpet hemocyanin (KLH): patients with advanced cancer were either sensitized with KLH alone or with KLH 3 days after administration of CY, 1000 mg/M2 ("high dose") or 300 mg/M2 ("low dose"). We found that pretreatment of patients with CY, at either "high" or "low" dose, significantly augmented the development of DTH to KLH. In contrast, the antibody response to KLH was potentiated by pretreatment with "low" dose CY, but not with "high" dose CY. DTH responses to microbial recall antigens (trichophyton, mumps, candida) were not augmented by CY administration.(ABSTRACT TRUNCATED AT 250 WORDS)