LAUSR

Solid tumors evade destruction by the immune system through many parallel pathways of immunosuppression. Combination immunotherapies that act synergistically to recruit the breadth of the immune system9s armamentarium against solid tumors provide the opportunity to counter this immunosuppressive network with a similarly complex immune attack. Many existing immunotherapeutic approaches may contain key elements to overcome the barriers presented by solid tumors, but are limited by issues of toxicity (e.g., agonist immunocytokines) or potency (e.g., therapeutic vaccines). Using both established and engineered immunotherapy reagents, we recently discovered a combination immunotherapy that recruits a diverse set of innate and adaptive immune effectors, enabling robust elimination of tumor burdens that to our knowledge have not previously been curable by treatments relying on endogenous immunity. Maximal anti-tumor efficacy required four components: a tumor antigen targeting antibody, an extended-pharmacokinetics IL-2 molecule, anti-PD-1, and a lymph node targeting peptide vaccine. This combination elicited durable cures of large established tumors in a majority of animals in multiple transplanted tumor models, and induced sustained tumor regression in an autochthonous BRrafV600E/Pten-/- melanoma model. Multiple innate immune cell subsets, CD8+ T-cells, and cross-presenting DCs were critical to successful therapy. Treatment induced high levels of intratumoral inflammatory cytokines and immune cell infiltration, enhanced antibody-mediated tumor antigen uptake, and promoted antigen spreading. These results demonstrate the capacity of the endogenous immune response to destroy large, established tumors and suggest essential characteristics of an integrated immune response capable of overcoming immunosuppressive tumors. Citation Format: Darrell J. Irvine. Engineering combination immunotherapy agents for synergistic innate and adaptive immune attack on solid tumors. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr IA15.