Potentiation of human cell-mediated and humoral immunity by low-dose cyclophosphamide

Although cyclophosphamide (CY) is a potent immunosuppressive drug, under the proper conditions, it can potentiate immune responses as well. In past work, we have shown that administration of a commonly used oncostatic dose of CY (1000 mg/sq m) to patients with advanced cancer 3 days before sensitization with the primary antigen, keyhole limpet hemocyanin (KLH), resulted in augmentation of delayed-type hypersensitivity (DTH) but not antibody response to that antigen. The present study was performed to test the immunopotentiation of a lower dose of CY (300 mg/sq m); animal studies and studies of human lymphocytes in vitro suggested that the lower dose might be more effective. Eighteen patients with advanced metastatic cancer were alternately assigned to one of two groups. Sixteen days before CY, one group received KLH and the other group received 1-chloro-2,4-dinitrobenzene (DNCB). CY 300 mg/sq m was given as an i.v. bolus on Day 0. Three days after CY, the patients received KLH or DNCB, whichever they had not received initially. Blood was drawn for antibody titer, and skin testing was performed 14 days after administration of KLH or DNCB. In addition, skin tests to microbial recall antigens were made 2 days before and 17 days after CY. Pretreatment with low-dose CY resulted in significant augmentation of DTH to KLH; thus, the median DTH responses were: KLH alone, 10 mm; and KLH after CY, 27 mm (p less than 0.01). CY pretreatment also resulted in augmentation of the antibody response to KLH. The median total antibody titers (log2 of reciprocal of dilution) were as follows: KLH alone, less than 1; and KLH after CY, 3 (p less than 0.01). All nine CY-pretreated subjects but only 4 of 9 controls developed measurable anti-KLH antibody titers. CY pretreatment neither augmented nor suppressed the 48-hr challenge reaction to DNCB. Moreover, CY had no effect on DTH responses to the recall antigens, dermatophytin, Candida, and mumps.