Delivery of Cytokines by Liposomes. II. Interleukin-2 Encapsulated in Long-Circulating Sterically Stabilized Liposomes: Immunomodulatory and Anti-Tumor Activity in Mice

We have recently demonstrated that recombinant human interleukin-2 (IL-2) can be successfully encapsulated in small (mean size, 65 nm), unilamellar, long-circulating, sterically stabilized liposomes (SSL, also known as Stealth liposomes). The present study was undertaken to assess in mice the immunomodulatory and anti-tumor effects of SSL-IL-2 in comparison with soluble, unmodified IL-2 and pegilated IL-2 (PEG-IL-2). The main findings were as follows: (a) SSL-IL-2 was significantly more effective than IL-2 in increasing leukocyte number in the blood and spleen (p < 0.05) and triggering spleen lymphokine-activated killer cell activity (p < 0.01; t test), (b) In mice with advanced metastatic carcinoma previously treated with chemotherapy (cyclophosphamide), the survival was two to six times greater following administration of SSL-IL-2 as compared with IL-2 (p < 0.05; log-rank test). Moreover, successful treatment with SSL-IL-2 required lower cumulative doses (1.25 ± 10⁵vs. 2.5 ± 10⁵CU) and fewer (two versus five) administrations, (c) PEG-IL-2 was a more potent immunostimulator than SSL-IL-2 in normal mice and as effective therapeutically as SSL-IL-2 in tumor-bearing mice. The former agent, however, often caused marked toxicity (up to 40% mortality in some experiments), including severe thrombocytopenia. These findings suggest that SSL-IL-2 is an immunopotentiating agent superior to IL-2 in both normal mice and in tumor-bearing mice pretreated with chemotherapy.