Powerful synergistic effects of a STING agonist and an IL-2 superkine in cancer immunotherapy against MHC I-deficient and MHC I+ tumors

Cyclic dinucleotides (CDNs) and TLR ligands mobilize antitumor responses by NK cells and T cells, potentially serving as complementary therapies to immune checkpoint therapy. In the clinic thus far, however, CDN therapy has yielded mixed results, perhaps because it initiates responses potently, but does not provide signals to sustain activation and proliferation of activated cytotoxic lymphocytes. To improve efficacy, we combined CDNs with a half-life extended IL-2 superkine, H9-MSA. CDN/H9-MSA therapy induced dramatic long-term remissions of the most difficult-to-treat MHC I-deficient and MHC I+ tumor transplant models. H9-MSA combined with CpG oligonucleotide also induced potent responses. Mechanistically, tumor elimination required CD8 T cells and not NK cells in the case of MHC I+ tumors and NK cells but not CD8 T cells in the case of MHC-deficient tumors. Furthermore, combination therapy resulted in more prolonged and more intense NK cell activation, cytotoxicity and expression of cytotoxic effector molecules in comparison to monotherapy. Remarkably, in a primary autochthonous sarcoma model that is refractory to PD-1 checkpoint therapy, the combination of CDN/H9-MSA combined with checkpoint therapy yielded long-term remissions in the majority of animals, mediated by T cells and NK cells. This novel combination therapy has potential to activate responses in tumors resistant to current therapies and prevent MHC I-loss accompanying acquired resistance of tumors to checkpoint therapy. One sentence summary Powerful immunotherapy effects mediated by the combination of innate agonists and superkine. ### Competing Interest Statement C.O.N. and S.M.M. served in the past as paid employees of Aduro Biotech, are listed as inventors on Aduro Biotech patents and patent applications related to CDNs, and hold stock in Aduro Biotech. D.H.R. is a co-founder of Dragonfly Therapeutics and served or serves on the scientific advisory boards of Dragonfly Therapeutics, Aduro Biotech, Innate Pharma, and Ignite Immunotherapy; he has a financial interest in all four companies and could benefit from commercialization of the results of this research. KCG is an inventor of H9, which is patented (PCT/US2011/066911) and licensed by Medicenna Therapeutics. KCG is also the Founder of Synthekine Therapeutics. The other authors declare that they have no competing interests.