Twenty-seven patients with advanced gastrointestinal malignancies received recombinant γ-interferon (rIFN-γ, Biogen) prior to treatment with the murine monoclonal antibody 17-1A (Centocor), which mediates human monocyte antibody-dependent cellular cytotoxicity (ADCC). rIFN-γ was used because it enhances human monocyte Fc receptor expression, nonspecific monocyte cytotoxicity (NSMC) and ADCC in vitro. The study was designed to identify a rIFN-γ dose with acceptable toxicities which enhanced NSMC and ADCC. Patients received one course of therapy consisting of rIFN-γ by 4-h infusions daily for 4 days at doses ranging from 0.001 to 80.0 × 106 units/m2/d, followed by 400 mg of 17-1A on day 5. The maximally tolerated dose of rIFN-γ in this study was 40 × 106 units/d. Significant toxicity was seen at the high (>1 × 106 units) but not low (≤1 × 106 units) dose levels. Monocytes were isolated from patients' peripheral blood at baseline and on Days 3 and 5 for cytotoxicity studies which measured 111-In release from SW1116 cells which bear the target antigen of 17-1A. Low dose rIFN-γ enhanced NSMC by Day 5 as well as did high dose therapy. ADCC enhancement was seen with low dose therapy (% specific lysis on Day 5 = 23.5 ± 6.4 SEM versus baseline of 9.6 ± 3.3, P = 0.03), but not with high dose rIFN-γ treatment. Total (i.e., NSMC + ADCC) monocyte cytotoxicity was equivalent in the low and high dose treatment groups, although ADCC contributed more to total values in the low dose group. These findings were particularly striking if monocytes were exposed to additional rIFN-γ in vitro prior to incubation with labeled target cells. We conclude that low dose rIFN-γ therapy is at least equivalent, and possibly superior to high doses in this setting. Furthermore, low dose therapy, supplemented by ex vivo incubation of purified monocytes with rIFN-γ, may be an optimal treatment strategy for this cytokine.

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