In vivo anti‐tumor activity of combinations of interferon alpha and interleukin‐2 in a murine model. Correlation of efficacy with the induction of cytotoxic cells resembling natural killer cells

Abstract

The in vivo anti-tumor activity of 2 recombinant cytokines, interleukin-2 (rIL-2) and human hybrid interferon alpha (rHuIFN-alpha A/D), were tested using the murine reticulum cell sarcoma M5076. Experimental hepatic metastases, following i.v. injection of tumor cells, and tumor growth and spontaneous metastases, following s.c. injection of tumor cells, were inhibited to a greater extent in mice treated with a combination of these cytokines than in animals treated with either one alone. When used in conjunction with surgical removal of the s.c. tumor, treatment of mice with both cytokines significantly prolonged survival of tumor-bearing animals. Injection of normal mice with a combination of cytokines, but not with either cytokine alone, resulted in a marked increase in cytotoxic activity of hepatic effector cells. The effector cells in these mice appeared to be NK cells since this enhanced cytotoxicity was markedly reduced in animals treated in vivo with anti-asialo GM1 or in NK-deficient beige mice. Furthermore, no in vivo efficacy was observed in M5076-bearing beige mice treated with these cytokines. Thus, injection of mice with rIL-2 and rHuIFN-alpha A/D results in the induction of an NK-cell-like population in the liver with enhanced cytotoxic activity that correlates with the observed anti-tumor activity in vivo in this murine model. These results suggest that combinations of cytokines, in particular IFN-alpha and IL-2, can be effectively used in combination for the treatment of tumors and/or metastases.

Viral Infection Causes Rapid Sensitization to Lipopolysaccharide: Central Role of IFN-αβ

“…This rHuIFN-␣ has previously been tested in mice and found to exert the expected effect (31,32). Mice to be treated received 2 ϫ 10 6 U i.p.…”

“…Finally, to test whether IFN-␣␤ sufficed for an augmented response to LPS, wild-type (C57BL/6) mice were pretreated with rHuIFN-␣ to which murine cells are responsive (31,32,39); a matched control group received PBS only. Twenty-four hours later all mice were challenged with LPS and 1.5 h later TNF-␣ levels in serum were analyzed, and mortality over the next 48 h was registered.…”

In vivotreatment with interferon causes augmentation of IL-2 induced lymphokine-activated killer cells in the organs of mice

“…Combination therapy with both cytokines can mediate greater regression or cures of murine tumours (Brunda et al, 1987;Cameron et al, 1988) and recently this therapy has been shown to have significant anti-tumour effects on advanced human cancer as well . The mechanism of synergistic antitumour effects of these two cytokines is not known.…”

“…In a murine system IFN-a has been shown to synergize IL-2 in the regression or eradication ofa variety of tumours (Brunda et al, 1984(Brunda et al, , 1987Cameron et al, 1988;Iigo et al, 1988). IFN-y, when administered with IL-2, has also caused marked retardation of tumours 317 (Iigo etal, 1988), The mechanism ofthe synergistic anti-tumour effects of IFN-a and IL-2 is unclear, IFNs in general have demonstrated anti-proliferative activity against a variety of tumours in vitro and in vivo (Fidler et al, 1987;Gresser et al, 1972;Belardelli et al, 1982), In addition, interferons can promote a partial reversal ofthe malignant phenotype (Hicks et al, 1981) and enhance expression of surface molecules including a-2-microglobulin, Fc receptors, tumour antigens and histocompatibility antigens (Wan et al, 1987;Greiner et al, 1987), IFNs are also known to activate macrophages (Pace et al, 1983), augment NK cell activity (Oehler et al, 1978), and activate T cells (Lindahl et al, 1972),…”

Final report of a phase II study of interleukin 2 and interferon α in patients with metastatic melanoma

“…Based on the synergistic activity of IL-2 and IFN-a in preclinical experiments (Brunda et al, 1987;Cameron et al., 1988; ligo et al, 1988) and on the encouraging results of early clinical trials with this combination (Budd et al, 1989;Lee et al, 1989;Rosenberg et al, 1989b), we decided to perform a phase II study. Here, we report the final analysis after a median follow-up period of 10.5 months (range 1.1 -47+ months).…”