Abstract B065: TANK-Binding Kinase 1 (TBK1) as a novel cancer immunotherapy target

Despite the unprecedented success of immune checkpoint blockade (ICB) in melanoma and other cancers, tackling innate (primary) resistance remains a major challenge and robust biomarkers to guide treatment are lacking. Clinical trials are already underway evaluating novel immune modulatory agents in combination with anti-PD-1/PD-L1 therapies in an effort to overcome innate resistance. Despite increasing reports of ‘rational’ combination strategies, these therapies remain “one size fits all”, due the lack of robust biomarkers to guide clinical decision-making. There is an unmet need for novel approaches, tools, techniques, and methods for pre-clinical and clinical use to better understand mechanisms of response and resistance to immune checkpoint inhibitors and next-generation anti-tumor immune modulatory drugs. We have adapted a 3D microfluidic device to the short-term culture of murine- and patient-derived organotypic tumor spheroids (MDOTS/PDOTS)for functional ex vivo profiling of PD-1 blockade in a model tumor immune microenvironment (TIME) to facilitate identification of mediators of response and resistance to ICB and to guide development of next-generation immunotherapy combinations. The MDOTS/PDOTS platform provides a window into the complex and dynamic events of the TIME during response (and resistance) to ICB and is an ideal model system for pre-clinical evaluation of novel cancer immunotherapy targets. Focused evaluation of novel treatment combinations using MDOTS identified TANK-binding kinase 1 (TBK1) as a novel cancer immunotherapy target, mirroring in vivoefficacy of this treatment approach. TBK1 is a Ser/Thr kinase involved in innate immune signaling and is an emerging target for anti-cancer therapy. Importantly, independent orthogonal data from two different laboratories has also identified TBK1 as a cancer immunotherapy target.We have confirmed that Tbk1 deletion and/or TBK1 pharmacologic inhibition enhances response to in vivo anti-PD-1 therapy, and have characterized the impact of deletion of Tbk1 (CRISPR) or pharmacologic inhibition of TBK1 (Cmpd1) on the tumor-immune microenvironment.Lastly, we confirmed that resistance to PD-1 blockade can be overcome with pharmacologic TBK1 inhibition using murine- and patient-derived organotypic tumor spheroids in 3D microfluidic culture. These findings confirm TBK1 as a target to overcome resistance to PD-1 blockade, further supporting the pre-clinical and clinical development of this novel combination strategy. REFERENCES 1. Jenkins RW, Barbie DA, Flaherty KT. Mechanisms of resistance to immune checkpoint inhibitors. Br J Cancer. 2018;118(1):9-16. doi: 10.1038/bjc.2017.434. PubMed PMID: 29319049; PMCID: PMC5765236. 2. Manguso RT, Pope HW, Zimmer MD, Brown FD, Yates KB, Miller BC, Collins NB, Bi K, LaFleur MW, Juneja VR, Weiss SA, Lo J, Fisher DE, Miao D, Van Allen E, Root DE, Sharpe AH, Doench JG, Haining WN. In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Nature. 2017. doi: 10.1038/nature23270. PubMed PMID: 28723893. 3. Pan D, Kobayashi A, Jiang P, Ferrari de Andrade L, Tay RE, Luoma AM, Tsoucas D, Qiu X, Lim K, Rao P, Long HW, Yuan GC, Doench J, Brown M, Liu XS, Wucherpfennig KW. A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing. Science. 2018;359(6377):770-5. doi: 10.1126/science.aao1710. PubMed PMID: 29301958. Citation Format: Ajaykumar Vishwakarma, Yi Sun, Amina Fu, Emily Robitschek, Arvin Iracheta-Vellve, Susanna Stinson, Aliasger Salem, Robert Manguso, Russell Jenkins. TANK-Binding Kinase 1 (TBK1) as a novel cancer immunotherapy target [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B065. doi:10.1158/1535-7163.TARG-19-B065