Abstract 4136: Direct intratumoral microdosing via the CIVO® platform reveals anti-tumor immune responses induced by the SUMO inhibitor TAK-981
Authors: Hatton Beryl A. , Grenley Marc , Garnsey James , Shinde Vaishali , Huszar Dennis , Burns Connor , Ditzler Sally , Merrell Angela , Dey Joyoti , Beirne Emily , Klinghoffer Richard A. 
Published: August 2019

Abstract
The complex interplay between a drug, the tumor and the surrounding microenvironment is a critical determinant in how a patient will respond to their selected cancer therapy. Yet to date, this complex response has been difficult to evaluate prior to late stage clinical investigation. To enable a means for testing investigational agents earlier in the development process but still directly in human patients, in a way that limits the risk of adverse effects and provides an indication of efficacy, Presage Biosciences developed a technology called CIVO. This platform allows for simultaneous assessment of multiple drugs or drug combinations directly in a single solid tumor, in the context where the drugs are ultimately intended to be used, directly in the patient. Here we demonstrate the potential for using the CIVO platform in Phase 0 microdosing studies to detect complex responses to investigational agents. In this study, we used the CIVO platform to assess the impact of TAK-981 on the native tumor immune microenvironment of animal models. TAK-981 is a novel and selective small molecule inhibitor of the SUMOylation enzymatic cascade currently in Phase I clinical trials. SUMOylation is a reversible post-translational modification that regulates protein function by covalent attachment of a small ubiquitin-like modifier (SUMO) protein to protein substrates. TAK-981 was microinjected into tumors from a syngeneic mouse model of B cell lymphoma and responses assessed via immunohistochemistry and in situ hybridization following tumor resection. An early inflammatory response was evident by 24 hours, including the accumulation of neutrophils, inflammatory macrophages and a Type I interferon response. The chemokine IP10 was secreted around TAK-981 injection sites and was accompanied by the accumulation of cytotoxic T lymphocytes, likely recruited from the local tumor microenvironment. A localized cell death response was observed proximal to TAK-981 injection sites by 72 hours and was likely induced by the granzyme B-bearing cytotoxic T cells enriched at TAK-981 sites. Abscopal studies demonstrated that the local immune modulation induced by TAK-981 translated into an adaptive immune response. The results from this study were consistent with findings from systemically dosed in vivomouse efficacy studies carried out at Takeda, demonstrating that the local responses to agents microdosed intratumorally via CIVO are predictive of responses induced by systemic drug exposure. These studies highlight the unique capability of TAK-981 to promote antitumor immunity, which may be further evaluated using the CIVO platform in a Phase 0 trial in human solid tumor patients.
Citation Format: Beryl A. Hatton, Marc Grenley, James Garnsey, Vaishali Shinde, Dennis Huszar, Connor Burns, Sally Ditzler, Angela Merrell, Joyoti Dey, Emily Beirne, Richard A. Klinghoffer. Direct intratumoral microdosing via the CIVO® platform reveals anti-tumor immune responses induced by the SUMO inhibitor TAK-981 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4136.