Low-dose IFN-gamma induces tumor MHC expression in metastatic malignant melanoma

Specific antitumor immune responses require expression of MHC class I or II molecules on tumor cells, and MHC antigen down-regulation is a presumed tumor growth promoting mechanism. Because IFN-gamma up-regulates tumor MHC antigen expression in vitro, in this Phase II trial of an immunologically active dose and schedule we evaluated whether this was the case in vivo. Twenty-three patients with metastatic melanoma were treated with IFN-gamma 100 microg/m(2) s.c. once weekly for a maximum of 6 months. There were three complete responses, now maintained for 53, 36, and 25 months. The remainder had progressive disease. The treatment was well tolerated, with no toxicity exceeding National Cancer Institute Common Toxicity Criteria grade II. Immunohistochemical analysis of tumor biopsies during treatment was performed using monoclonal antibodies to HLA class I (W/632) and class II (CR3/43) monomorphic determinants. HLA class I was down-regulated in 2 of 19 patients pretreatment and up-regulated by IFN-gamma in both. HLA class II was down-regulated pretreatment in 14 of 18 patients and up-regulated by IFN-gamma in 6 (43%). The HLA up-regulation persisted throughout the study. IFN-gamma induced significant but short-lived up-regulation of surrogate markers of monocyte activation (serum neopterin) and class I up-regulation (serum beta-2-microglobulin) in most patients. There was no consistent relationship between surrogate marker up-regulation, tumor antigen up-regulation, and responses. The study shows that the significant immune modulation induced by IFN-gamma does not correlate with tumor responses and that the serum surrogate marker changes do not reflect tumor events. The durable and long-lived responses, clear demonstration of tumor MHC up-regulation, and low toxicity suggest that weekly IFN-gamma 100 microg/m(2) would be a useful addition to chemoimmunotherapeutic regimens.