Anti‐tumor and immunomodulatory activity of intraperitoneal IFN‐γ in ovarian carcinoma patients with minimal residual tumor after chemotherapy

Abstract

Eight patients with epithelial ovarian carcinoma persisting after chemotherapy, selected for having a residual tumor no larger than 1 cm in diameter, were treated intra-peritoneally (i.p.) with recombinant interferon-gamma twice weekly for 3 months. Toxicity consisted of fever and malaise in all patients and a transient rise in hepatic enzyme levels in 3 patients. The cytotoxic function of peripheral blood and peritoneal tumor-associated lymphocytes (TAL) and macrophages (TAM), was studied using cell lines as targets. I.p. IFN-gamma augmented the cytotoxic activity of lymphocytes and mononuclear phagocytes: stimulation was more marked and more frequently observed with TAL and occasionally TAM than with blood effectors, suggesting preferential modulation at the site of tumor growth and IFN administration. Surgical laparotomy revealed that 1 patient had a complete response, 2 a partial response and 2 had stable disease, while 3 patients had progressive disease. In this small series of patients there was no obvious, strict correlation between immunomodulation by IFN-gamma and clinical response. These results indicate that, in contrast to its lack of activity in advanced ovarian carcinoma, IFN-gamma has definite immunomodulatory and antitumor activity in the presence of limited tumor burden.

Interleukin (IL)‐18, a biomarker of human ovarian carcinoma, is predominantly released as biologically inactive precursor

“…40 Previous reports indicated that IFNc sensitizes ovarian carcinoma cells to the cytotoxic effect of TNFa and cisplatin 41 and has antitumor effects in ovarian carcinoma patients by intraperitoneal administration. 42,43 Altogether these previous data suggest that mat-IL-18-driven IFNc production by lymphoid cells present at the tumor site would inhibit ovarian tumor growth. In this report, we show that patients with high levels of IL-18 in the serum or in the ascites display low levels of IFNc, further suggesting that the IL-18 accumulating in patient's fluids is biologically inactive and unable to activate an immune response.…”

Eicosapentaenoic acid and docosahexaenoic acid inhibit macrophage-induced gastric cancer cell migration by attenuating the expression of matrix metalloproteinase 10

“…It has been reported that recruitment of TAMs is due to cancer-cell-mediated upregulation of host stromal cell production of colony-stimulating factor-1 [19]. TAMs stimulate tumor growth, produce angiogenic factors [20] and facilitate vascular invasion of tumor cells [21,22]. It has also been reported that the invasiveness of tumors co-cultured with macrophages is enhanced by tumor necrosis factor-α and MMPs released from macrophages [23][24][25][26].…”

Macrophages, innate immunity and cancer: balance, tolerance, and diversity

“…IFNg has been shown to re-educate TAM [64] and there is proof of principle evidence for antitumor activity of this molecule in minimal residual disease in humans [65][66][67]. Given the protumor function of TAM in many cancer, strategies have been directed at blocking recruitment (see above) targeting chemokines or CSF-1 or inhibiting TAM directly [68,69 ,70].…”