Effect of Low Dose Cyclophosphamide on the Immune System of Cancer Patients: Reduction of T-Suppressor Function without Depletion of the CD8+ Subset1

Low dose cyclophosphamide (CY) can augment the development of delayed-type hypersensitivity to primary antigens in patients with ad vanced cancer. In this paper, we have considered the hypothesis that the immunopotentiation is related to reduction of T-suppressor activity. Peripheral blood lymphocytes were collected and cryopreserved from 45 patients with metastatic malignancy before and then 3, 7, and 19 days after administration of CY, 300 mg/mz i.v. The peripheral blood lympho cytes were tested for generation of concanavalin A-inducible suppressor activity, proliferative response to phytohemagglutinin, and phenotype using monoclonal antibodies to ( '1)4 and CDS. Concanavalin A-inducible suppression was significantly reduced by day 3 and declined progressively through day 19. The mean percentage changes in suppression were: day 3, -23.4 ±6.8 (SE) (P < 0.01); day 7, -33.1 ±143 (P = 0.052); day 19, -43.1 ±10.7 (P < 0.01). In contrast, CY caused no significant changes in phytohemagglutinin proliferation (mean percentage changes: day 3, -4.7 ±6.1; day 7, -15.6 ±7.5; day 19, -5.5 ±8.1), indicating that the reduction in concanavalin A-inducible suppression was not merely a reflection of a general reduction in peripheral blood lymphocyte func tion. The total number of circulating lymphocytes was not affected by low dose CY. Moreover, flow cytometric analysis showed no significant changes in the percentage of circulating CD8+ or CD4+ T-cells or in the CD4/CD8 ratio at any time point after CY. Thus, administration of low dose CY to these patients caused impairment of nonspecific T-suppressor function without selective depletion of the CD8+ subset that is generally associated with that function. Several immunoregulatory models that are consistent with these observations are discussed.