Administration of the synthetic STING agonist ADU-S100 leads to durable anti-tumor immunity via promoting T-cell responses
Anthony Desbien, Meredith Leong, Laura Hix Glickman, Kelsey Sivick-Gauthier, Gabrielle Reiner, Thomas Hudson, Natalie Surh, Tammara Schroeder, David B. Kanne, Ed Lemmens, George E. Katibah, Leticia Corrales,Weiwen Deng,Justin J. Leong, Leonard Sung, Ken Metchette, Chudi Ndubaku,Thomas W. Dubensky, Jr., Sarah M. McWhirter
Aduro Biotech, Berkeley, CA
ADU-S100 is a rationally designed synthetic cyclic dinucleotide (CDN) derivative being evaluated as a cancer immunotherapeutic in patients with advanced, accessible cutaneous lesions (NCT02675439). ADU-S100 binds and activates all known alleles of the human cytosolic dsDNA sensor, STING (STimulator of INterferon Genes) and provides durable anti-tumor activity in multiple mouse-tumor models. To inform clinical development strategy we evaluated the mechanism of action of ADU-S100. Intratumoral injection of ADU-S100 induced the production of TNFa and type I interferons in diverse tumor immune cells including monocytes, macrophages and neutrophils. This was accompanied by maturation of APCs in the TDLN and activation/expansion of tumor-specific T cells. Importantly, the magnitude of the induced pro-inflammatory cytokine responses modulated priming efficiency of tumor-specific immunity. Bone marrow chimera studies showed that priming of tumor specific T cells required hematopoietic compartment expression of STING. Through depletion and adoptive transfer studies we found that CD8+ T cells were necessary to provide protection against autologous tumor challenge. Combination of ADU-S100 and immune checkpoint blockade targeting PD1 resulted CD8+ T cell-dependent distal tumor control. Together these results demonstrate the potential of CDN-tumor therapy to control primary and metastatic tumors via CD8+ T cells.
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