Combination therapy to enhance NK cell anti-tumor responses

Abstract Current cancer immunotherapies are targeted at mobilizing CD8 T cells, although numerous tumors have few or no antigens for CD8 T cells, or have lost MHC I, thereby evading CD8 T cells. There is therefore a need for improved therapies that mobilize other immune cells, such as NK cells, to the tumor microenvironment. A recent therapy candidate, cyclic dinucleotide (CDN), activates the cGAS-STING pathway of the innate immune system. Intratumoral CDN injections induce type I IFNs and other mediators that amplify the CD8 T cell response and induce regressions of primary tumors. MHC I-deficient tumors are not susceptible to CD8 T cell-mediated rejection, but data from our lab demonstrates that STING activation still leads to long-term tumor regressions, mediated by NK cells and in some cases CD4 T cells, in 30–100% of animals in 5/6 transplant models tested. In order to improve upon CDN monotherapy, we are testing combinations of CDN therapy with other therapies to target and activate NK cells in the tumor microenvironment and prevent or delay the onset of desensitization. Our results show that engineered IL-2 family cytokines synergize with CDN therapy to mobilize anti-tumor responses by NK cells and in some cases CD4 T cells. These anti-tumor responses are due to increased recruitment of NK cells to the tumor and sustained activation of these recruited NK cells. Our combination therapy regimen shows enhanced systemic effects, both in vivo in abscopal tumor models, and ex vivo by cytolysis of target cells mediated by splenocytes. Overall, our work demonstrates the impact of a novel combination therapy in mobilizing powerful NK cell-mediated anti-tumor activity, providing evidence for the potential of NK cell-targeted immunotherapeutics for cancer.