Eradication of large established tumors by combination immunotherapy engaging innate and adaptive immunity
Kelly D. Moynihan1,5,6,*, Cary Opel3,6,*, Gregory Szeto1,5,6, Eric Zhu3,6, Kavya Rakhra6, Jesse Engreitz2,7, Alice Tzeng1,5, Byron Kwan1,5, Sudha Kumari6, Wuhbet Abraham6, Robert Williams4, Kevin Hu1, Dane Wittrup1,3,6, and Darrell J. Irvine1,4,5,6,8
1Dept. of Biological Eng., MIT; 2Broad Institute; 3Dept. of Chem. Eng., MIT; 4Dept. of Biology, MIT; 5Ragon Institute of MGH, MIT, & Harvard; 6Koch Inst., MIT; 7HST, MIT; 8HHMI
In the clinic, checkpoint blockade has demonstrated that an endogenous immune response can be stimulated to elicit objective tumor regressions in metastatic disease, but these dramatic responses presently remain confined to a minority of patients. This suboptimal outcome is likely due in part to the complex network of immunosuppressive pathways in advanced tumors, which are unlikely to be overcome by intervention at a single signaling checkpoint, and may require a counter-directed network of pro-immunity signals. Here we demonstrate a combination immunotherapy that invokes a synergistic innate and adaptive immune response, enabling elimination of large tumor burdens that to our knowledge have not previously been curable by endogenous immune responses. Maximal efficacy required four components: a tumor antigen targeting antibody, an extended half life IL-2 (Zhu et al., 2015), anti-PD-1, and a novel T-cell vaccine (Liu et al., 2014). Treatment led to durable cures in a majority of mice and the formation of protective memory in multiple murine cancer models. CD8+ T-cells and cross-presenting DCs were critical to therapy, and effective treatment was characterized by high levels of inflammatory cytokines and immune infiltrates in the tumor, enhanced antibody-mediated tumor antigen uptake, and antigen spreading. This powerful immunotherapy also induced regression in an autochthonous BrafV600E/Pten-/- melanoma model. These results demonstrate the capacity of the endogenous immune response to destroy large, established tumors and define characteristics of combination immunotherapies capable of curing a majority tumors in experimental settings typically viewed as intractable.
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