Interleukin-10: An Immune-Activating Cytokine in Cancer Immunotherapy.

In the accompanying article, Naing et al report encouraging clinical results from a phase I trial of single-agent pegylated recombinant human interleukin-10 (IL-10) in the treatment of advanced refractory solid tumors. IL-10 has often been considered an immunosuppressive cytokine because of its association with multiple regulatory or suppressive immune-cell populations, such as regulatory CD4 and CD8 T cells, B10 cells, myeloid-derived suppressive cells, and tolerogenic dendritic cells, as well as its powerful inhibition on antigen presentation and immune-cell activation. Further supporting this notion is the observed strong correlation between circulating IL-10 levels and poor prognosis of various patients with cancer. However, there is also abundant preclinical and clinical evidence supporting an antitumor activity of IL-10. For example, it was found that mice lacking IL-10 or IL-10 receptor are susceptible to tumor development, and exogenous IL-10 can boost antitumor immunity in mice. The antitumor effect of IL-10 is likely a result of its stimulating activity on CD8 T cells as it promotes the differentiation and expansion of effector CD8 T cells. Several studies from tumor animal models have suggested that IL-10 directly expands CD8 tumor-infiltrating T cells (TILs) to kill tumor cells in vivo. Indeed, contrary to the reported correlation between circulating IL-10 levels and poor prognosis among patients with cancer, CD8 T cells expressing IL-10 are associated with a favorable prognosis in patients with lung cancer. These seemingly contradictory results raise a major question: Is systemic use of IL-10 immune suppressive or activating in patients with cancer? Because systemic IL-10 would act on all assessable IL-10 receptor–positive cells, the overall effect of pegylated recombinant human IL-10 on parenteral administration could be either proor antitumor. The Naing et al study provides strong evidence that IL-10 is an immune-activating cytokine in patients with advanced solid tumors. In all 24 patients treated with active dose of AM0010 at 20 to 40 mg/kg, the serum levels of proinflammatory cytokines IL-18 and interferon gamma (IFN-g as well as the Th2 cytokine IL-4 were dramatically increased. In contrast, the serum level of the immune-suppressive cytokine transforming growth factor beta was decreased in these patients (Fig 1A). Most importantly, the patients treated with the active dose had an overall response rate of 21%, a strong indication of clinical antitumor activity of recombinant IL-10 in vivo. Given the pleotropic effects of IL-10 on many types of cells, a major concern with systemic IL-10 application is its toxicity and tolerability. Clinical use of anticancer cytokines such as IL-2 and IFNs has been limited by their toxicity. The Naing et al study shows an acceptable safety profile of pegylated recombinant human IL-10 with prolonged clinical use. Although patients treated with AM0010 experienced grade 3 to 4 treatment-related adverse events (AEs), all treatment-related AEs seemed to be manageable and were reversed on temporary dose interruption or reduction. Even more encouraging is that no immune-related AEs were observed in any treated patients, paving the way for combinatorial therapy with other immune-targeting agents, such as immune checkpoint inhibitors anti–programmed death-1 (PD-1)/ PD-1 ligand (PD-L1) and anti–cytotoxic T-cell lymphocyte-4 (CTLA-4). The results from this phase I trial provide a solid foundation for future phase II to III trials to address several important questions. First, what types of cancers and subpopulations of patients will respond to systemic IL-10 treatment? Among 15 patients with advanced renal cell cancer (RCC) with a median of three prior therapies, there was an impressive 27% objective response rate, compared with a similar 25% objective response rate achieved in patients with RCC treated with anti–PD-1 nivolumab. The fact that one of five patients with non– small-cell lung cancer and one of four patients with melanoma also achieved partial response suggests broad suitability of IL-10 treatment, although the small sample sizes require that these data be interpreted with caution. As with all other cancer therapies, careful selection of patients responding to IL-10 treatment will be critical for precision therapy. Elevated serum levels of IL-18, IFN-g and IL-4 may serve as a useful readout for IL-10–induced immune activation in patients, but they are not sufficient for preselection of responding patients on the basis of the presented data. Notably, several patients showed mixed responses, with substantial reduction in some lesions and increase in others. On the basis of the evidence showing direct effect of IL-10 on CD8 TILs in situ, one may wonder whether the mixed responses in those patients resulted from different infiltrating levels of antitumor CD8 TILs in the various lesions within the same patients. We speculate that the degree of tumor tissue