Coupling IL-2 with IL-10 to mitigate toxicity and enhance antitumor immunity
Julie Ahn, Steven Dudics, David Langan, Jeffrey D. Smith, Alice H. Hsu, Jacob McCright, Sawyer R. Smith, Alicia L Castleberry, Benjamin George, Javier A. Goitía Vázquez, Phillip N Kuri, Sri Sai Vivek Alla, Jennifer Garcia, Yusuf Haider, Fatima Hamdan, Jhonnatan Esquivel Juárez, Robert Reddy, Aranganathan Shanmuganathan, Yuanyuan Wang, Arielle Welch, David Boclair, Pavel A. Khrimian, Christopher H. Yaen, John B. Mumm
Abstract
Wild-type interleukin (IL)-2 induces anti-tumor immunity and toxicity, predominated by vascular leak syndrome (VLS) leading to edema, hypotension, organ toxicity, and regulatory T cell (Treg) expansion. Efforts to uncouple IL-2 toxicity from its potency have failed in the clinic. We hypothesize that IL-2 toxicity is driven by cytokine release syndrome (CRS) followed by VLS and that coupling IL-2 with IL-10 will ameliorate toxicity. Our data, generated using human primary cells , mouse models, and non-human primates, suggest that coupling of these cytokines prevents toxicity while retaining cytotoxic T cell activation and limiting Treg expansion. In syngeneic murine tumor models, DK2 10 epidermal growth factor receptor (EGFR), an IL-2/IL-10 fusion molecule targeted to EGFR via an anti-EGFR single-chain variable fragment (scFV), potently activates T cells and natural killer (NK) cells and elicits interferon (IFN)γ-dependent anti-tumor function without peripheral inflammatory toxicity or Treg accumulation. Therefore, combining IL-2 with IL-10 uncouples toxicity from immune activation, leading to a balanced and pleiotropic anti-tumor immune response.