Abstract
Twenty-five patients who had recently undergone complete resection of malignant melanoma, but who were at high risk of recurrence, were treated with 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (methyl-CCNV; meC) as adjuvant therapy. We studied the immunosuppressive effects of this drug by testing the immune response to four exogenous antigens, namely, keyhole limpet hemocyanin (KLH), Escherichia coli Vi, dinitrochlorobenzene (DNCB), and tetanus toxoid, before, simultaneous with, and 21 days after administration of the first course of meC (200 mg/sq m p.o.). Thirteen patients were pretested with Vi and DNCB and posttested (either same day as meC or 21 days later) with KLH, while the other 12 were pretested with KLH and posttested with Vi and DNCB. All patients were given tetanus toxoid as part of the pretesting phase so that the effect of meC on established antibody to this antigen could be determined.
Before meC, 24 of 25 patients made a primary antibody response to either Vi or KLH with antibody detectable by Day 7, maximal on Day 14 (median titers, log2, Day 14, Vi, 3.5; KLH, 4.5), and persisting through Day 35; 14 of 25 eventually made 2-mercaptoethanol-resistant antibody. When either Vi or KLH was given on the same day as or 21 days after meC, 23 of 25 made an antibody response that was of similar magnitude (median titers, Day 14, when antigen given same day or 21 days after meC were, respectively, Vi, 4.0, 5.0; KLH, 3.5, 4.5), with 19 of 25 eventually making 2-mercaptoethanol-resistant antibody. Challenge with either antigen on the same day as meC did result in a slight delay in the development of antibody as manifested by lower titers on Day 7, but the difference did not reach statistical significance.
All 12 pretested patients and 12 of 13 posttested patients also developed delayed hypersensitivity to KLH. However, sensitization with KLH 21 days after meC resulted in delayed hypersensitivity reactions that were smaller than in pretested patients (median diameter of induration, 14 mm versus 11 mm, p < 0.02). meC did not significantly impair delayed hypersensitivity to DNCB. Eleven of 13 pretested patients and 8 of 12 posttested patients reacted.
Thirteen of 25 patients made a typical secondary antibody response to tetanus toxoid, and meC did not cause a decrease in the established level of antibody (median titers before meC, 9.5; after meC, 10.5). Seven other patients who had no detectable antibody to tetanus toxoid on initial testing made a secondary antibody response after 3 doses of toxoid (median titer, 8.0) despite the periodic administration of meC.
We conclude that meC is minimally immunosuppressive in this relatively immunocompetent group of patients with malignant melanoma.
Supported by USPHS Grants CA-13456 and CA-06927 from the National Cancer Institute, Grant IM-193 from the American Cancer Society, and by an appropriation from the Commonwealth of Pennsylvania.
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