Abstract 3448: The IV STING agonist, TAK-676, enhances immune-mediated anti-tumor activity of radiation in syngeneic mouse models
Authors: Appleman Vicky A. , Berger Allison J. , Roberts Emily R. , Maldonado-Lopez Angel E. , Ganno Michelle L. , Christensen Camilla I. , Hatten Tiquella , Sato Yosuke , Shaw Michael H. , Malek Karim S. , Lineberry Neil B. , Abu-Yousif Adnan O. , Gregory Richard C. 
Published: June 2022

Abstract
Robust interferon (IFN) signaling is integral for productive immune-mediated anti-tumor responses; however, impaired IFN signaling has been linked to checkpoint inhibitor (CPI) resistance. The cyclic GMP-AMP Synthase (cGAS)-STimulator of InterferoN Genes (STING) pathway is an essential regulator of IFN signaling in response to aberrant cytosolic DNA, including from tumors, and has emerged as an attractive therapeutic target. TAK-676 is a systemically delivered novel synthetic STING agonist that binds to and activates STING along with downstream IFN signaling, which is currently being evaluated in a Phase 1 dose escalation study of patients with advanced tumors (NCT04420884). In addition, focal radiation treatment of tumors leads to cell death coupled with innate cell activation and antigen presentation, suggesting that combining STING activation with radiotherapy (+/- anti-PD1) could lead to improved tumor control. The combination of TAK-676 with radiation +/- anti-PD1 was explored in immunocompetent EMT6 tumor-bearing BALB/c mice. Fractionated focal radiation (8Gy X 3) followed by TAK-676 (1 mg/kg dosed Q3D X 3) resulted in complete regression (CR) of tumors in 6/8 mice, whereas no CRs were detected in groups treated with radiation alone or with TAK-676 as a single agent. These observations suggest that addition of TAK-676 to a radiation regimen leads to enhanced tumor growth control compared to either treatment alone. In contrast, adding anti-PD1 to TAK-676 + fractionated radiation did not further increase tumor growth inhibition in this anti-PD1 resistant tumor model, with 5/8 CRs detected. Rechallenge of mice achieving CRs with EMT6 tumors resulted in rejection of the tumors in 3/5 and 4/5 mice from the double and triple combinations regimens, respectively, suggesting establishment of immunologic memory following primary challenge and treatment. Pharmacodynamic studies found both TAK-676 (1mg/kg) and fractionated radiation (8Gy X 3) monotherapy led to increased T cell accumulation and activation in the lymph nodes. However, only TAK-676 with fractionated radiation enhanced local IFN-γ production within the tumor, suggesting an enhanced adaptive immune response to this combination that drives the increase in observed efficacy. These studies support the evaluation of TAK-676 in combination with pembrolizumab following fractionated stereotactic body radiation therapy (SBRT) in a dose escalation clinical trial in patients with select advanced tumors (NCT04879849).
Citation Format: Vicky A. Appleman, Allison J. Berger, Emily R. Roberts, Angel E. Maldonado-Lopez, Michelle L. Ganno, Camilla I. Christensen, Tiquella Hatten, Yosuke Sato, Michael H. Shaw, Karim S. Malek, Neil B. Lineberry, Adnan O. Abu-Yousif, Richard C. Gregory. The IV STING agonist, TAK-676, enhances immune-mediated anti-tumor activity of radiation in syngeneic mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3448.