Zhang, Li, and Ritter et al. showed that sustained STING signaling in TNBC cells enhanced STING agonist response and facilitated CXCL10- and CCL5-mediated T cell migration. STING agonist delivery to tumors was toxic to endogenous T cells, but the toxicity could be mitigated using polyethylene glycol (PEG) biopsy marker to deliver STING agonists locally in a controlled release fashion into the TME. Sustained STING activation in the TME primed CAR T cell recruitment. PEG-STING agonism followed by CAR T cell injection into the PEG hydrogel (sequential delivery) led to long-term, durable tumor control and effective suppression of distant TNBC growth.
Contributed by Shishir Pant
ABSTRACT: Stimulator of interferon genes (STING) has emerged as a critical cancer immunotherapy target. However, no STING agonist has advanced beyond phase I/II clinical trials, as obstacles center around applying STING agonism to the appropriate clinical context, retaining it in the tumor microenvironment (TME), and limiting its T cell toxicity. Using triple-negative breast cancer (TNBC), we identify defective STING turnover as a cancer state promoting hypersensitivity to STING agonism. We also repurpose a US Food and Drug Administration (FDA)-approved polyethylene glycol (PEG) biopsy marker to deliver STING agonists in a controlled release fashion into the TME. However, STING agonist-induced T cell toxicity limits robust endogenous clonal T cell response, which can be overcome by sequential co-delivery of the STING agonists with CAR T cell therapy using the same PEG marker, eradicating orthotopic TNBC in mouse models while also controlling distant disease. These findings identify a highly translatable platform to combine STING agonists with CAR T cell therapy locally for TNBC and potentially other solid cancers.
Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (2) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (3) Department
Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (2) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (3) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (4) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (5) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. (6) Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. (7) Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, MA, USA. (8) Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, MA, USA. (9) Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, MA, USA. (10) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (11) Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA. (12) Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA. (13) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (14) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (15) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (16) Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA. (17) Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA. (18) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (19) Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA. (20) Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA. (21) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (22) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Division of Breast Surgery, Department of Surgery, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, MA, USA; Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA. Electronic address: tbarbie@bwh.harvard.edu.
