Recent advances in immunoncology have dramatically changed the treatment options available to cancer patients. However, the fundamental challenges with this therapeutic modality are not new and still persist with the current wave of immunoncology compounds. These challenges are centered on the activation and expansion, induction of intratumoral infiltration and persistence of highly activated, cytotoxic, tumor antigen specific CD8+ T cells. We have investigated the anti-tumor mechanism of action of pegylated recombinant interleukin-10, (PEG-rIL-10) both pre-clinically with murine (PEG-rMuIL-10) and now clinically (AM0010) with human pegylated interleukin-10. The preponderance of data suggest that IL-10's engagement of its receptor on CD8+ T cells enhances their activation status leading to antigen specific expansion. Quantitation of CD8+ T cell tumor infiltration reveals that treatment of both humans and mice with pegylated rIL-10 results in 3-4 fold increases of intratumoral, cytotoxic, CD8+ T cells. In addition, mice cured of their tumors with PEG-rMuIL-10 exhibit long term immunological protection from tumor re-challenge and long term treatment of cancer patients with AM0010 results in the persistence of highly activated CD8+ T cells. Cumulatively, these data suggest the IL-10 represents an emerging therapeutic that specifically addresses the fundamental challenges of the current wave of immunoncology assets.