STING Activators as Therapy for Cancer

PROJECT SUMMARY The ability of dying cells to activate antigen presenting cells (APCs) is carefully controlled to avoid unwarranted inflammatory responses. Thus, tumor cells avoid aggravating APCs by efficiently simulating regular dying cells which following phagocytosis do not trigger inflammatory responses required for efficient cytotoxic T lymphocyte (CTL) priming. However, dying tumor cells containing exogenous innate immune agonists such as cytosolic DNA, potently activate APCs in trans through extrinsic innate immune, STING- dependent signaling to generate potent CTL activity. In the absence of STING agonists, dying cells were ineffectual in the stimulation of APCs in trans. Indeed, cytosolic STING activators, including cytosolic DNA and cyclic dinucleotides (CDNs), constitute cellular danger associated molecular patterns (DAMPs) usually only generated by viral infection or following DNA- damage events, that can render tumor cells highly immunogenic (make a `coldandapos; tumor `hotandapos;). Taking advantage of our mechanistic insight and discoveries, we have now developed a new generation of innate immune activators that trigger STING signaling (referred to as STAVs: STING activators). Tumor cells transfected with STAVs activated APCs in trans and can generate potent anti-tumor T cell activity. Immunocompetent mice bearing metastatic syngeneic tumors could be `curedandapos; following inoculation with STAV `loadedandapos; tumor cells. Our strategy provides a new, simple, inexpensive therapeutic approach for the treatment of cancer. We have recently published our findings in the journal Cancer CELL (31) and patented our intellectual property through the University of Miamiandapos;s Office of Technology Transfer (OTT). This technology has been licensed to STINGINN LLC, to acquire sufficient pre-clinical data to warrant the consideration of clinical trials. For this study, we aim to evaluate whether our STAV strategy could be useful for the treatment of leukemia (focusing on adult T cell leukemia/lymphoma [ATLL] and Acute Myeloid Leukemia [AML]). ATLL is a clonal disease, invariably lethal and there is no cure or vaccine. AML is among the most aggressive of leukemias and only 5-10% of patients over 60 survive up to 5 years using standard treatments. We have developed a murine tumor model for the study of these diseases. The objective is to procure sufficient data to consider the development of pre-clinical trials for the treatment of this and ultimately other types of leukemia and lymphoma related cancers.PROJECT NARRATIVE Tumor cells are notoriously non-immunogenic through their ability to mimic the properties of normal cells which have naturally evolved to avoid activating the immune system following cell death and phagocytosis. We have thus developed a new approach to overcome this obstacle and make previously immuno-evasive, inert tumor cells highly immunogenic. This has been achieved through developing activators of the STING-dependent innate immune signaling pathway, a strategy which holds considerable promise for the therapeutic treatment of cancer.