Augmentation of the human immune response by cyclophosphamide.

Pretreatment of experimental animals with cyclophosphamide (CY) markedly potentiates the acquisition of T-cell-mediated immunity to an antigen given 1 to 4 days later. We have examined the primary induction of delayed-type hypersensitivity (DTH) and antibody to keyhole limpet hemocyanin (KLH) and DTH to 1-chloro-2,4-dinitrobenzene (DNCB) in 22 patients receiving CY for metastatic cancer, 12 with melanoma and 10 with colorectal carcinoma. Sixteen days before CY, one-half of the patients received KLH and one-half received DNCB; 3 days after CY, they received KLH or DNCB, whichever they had not received initially. Blood was drawn for antibody titer and/or skin testing was performed 14 days after administration of antigen. For each antigen, the responses of pre-CY patients were compared with those of post-CY patients. We found that pretreatment of patients with CY significantly augmented the development of DTH to KLH. The DTH reactions of the group of patients given KLH 3 days after CY were significantly greater than those of the group of patients given KLH without CY (medians: KLH alone, 0; KLH after CY, 18 mm; p = 0.025). With CY pretreatment, 11 of 11 patients developed a DTH response of greater than 5 mm compared with 4 of 11 patients without CY (p = 0.002). No patient developed DTH to DNCB when it was given without CY whereas 3 of 11 patients developed DTH when DNCB was given 3 days after CY (p = 0.082). CY pretreatment neither augmented nor suppressed the antibody response to KLH; the proportion of patients with antibody 14 days after antigen was 2 of 11 without CY and 4 of 11 with CY pretreatment (p = 0.24). It appears that CY pretreatment resulted in the development of DTH responses in otherwise unreactive patients. Reversal of the T-cell anergy of advanced cancer could lead to augmen tation of the immune response to tumor-associated antigens.