In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. CT139-CT139
Abstract:
Purpose/Objectives: The human tumor microenvironment (TME) has a dramatic impact on cancer prognosis and therapeutic response, but accurate models of the native TME do not exist. The Comparative In Vivo Oncology (CIVO) platform was developed as a means to assess the effect of investigational agents on the native TME in a Phase 0 microdosing study. CIVO was clinically validated using approved agents and is used for the first time here to assess the impact of an investigational agent - the SUMOylation inhibitor TAK-981 - on the native human TME in HNSCC. Materials/Methods: Eligible subjects have a confirmed HNSCC diagnosis, ECOG 0-2, and planned surgical resection. Injectable tumors were at the primary site or within cervical lymph nodes but had to be surface-accessible and ≥ 2cm. TAK-981 or control microdoses were simultaneously administered via a CIVO device and co-injected with a fluorescent tracking marker for injection site identification and visualization. Tumors were resected 24 or 72 hours after injection, processed, and then analyzed at a central site. Multiplexed biomarker staining and molecular profiling via GeoMx Digital Spatial Profiling were performed to capture pharmacodynamic responses in the native TME. Results: As of January 2022, 8 subjects provided informed consent and were enrolled, and no adverse events associated with the injection procedure or microdoses have been reported. Biomarker analysis demonstrated TAK-981 distribution around the injection site accompanied by reduction of SUMOylation. Dose-dependent elevation of IFN1 signaling was also observed in TAK-981-exposed areas within the TME. Elevated IFN1 signaling was accompanied by TME reconfiguration, with increased macrophage M1 polarization and activation of dendritic cells, NK cells, and CD8+ T cells. TAK-981 exposure was also associated with upregulation of CXCL10, PD-L1, and an IFNγ gene expression signature predictive of response to immune checkpoint blockade. Conclusion: IT microdosing with CIVO provided early insights into complex functional responses induced by the investigational agent TAK-981 that can only be accurately evaluated in the intact, native TME of a patient’s tumor. SUMO pathway inhibition in HNSCC tumors following TAK-981 exposure led to functional activation of multiple immune cell types, effectively shifting the local TME toward an inflamed “hot” state, highlighting TAK-981’s potential as an immune stimulating agent for treating patients with solid tumors. These data were generated while TAK-981 was still in Phase I dose escalation trials (via IV administration), highlighting CIVO’s ability to safely study investigational agents. Further evaluation of TAK-981 alone and in combination with other agents is ongoing in this Phase 0 CIVO microdosing trial. Citation Format: Jeffrey Houlton, Harrison Cash, Haodong Xu, Paul L. Swiecicki, Keith Casper, Steven B. Chinn, Daniel R. Clayburgh, Ryan J. Li, Robert J. Christian, Aaron Halfpenny, Annemieke van Zante, Beryl A. Hatton, Kimberly Sottero, Marc O. Grenley, Connor Burns, Jason Frazier, Jonathan Derry, Gloria Kung, Emily Beirne, Nathan J. Schauer, Atticus Turner, Wendy Jenkins, Kirsten Anderson, Richard A. Klinghoffer, Dennis Huszar, Allison Berger, Karuppiah Kannan. Intratumoral (IT) microdosing of the investigational SUMOylation Inhibitor TAK-981 in a phase 0 CIVO trial demonstrates the reactivation of type I Interferon (IFN1) signaling in head and neck squamous cell carcinoma (HNSCC) [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 CT139.
Type of Medium:
Online Resource
ISSN:
1538-7445
DOI:
10.1158/1538-7445.AM2022-CT139
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2022
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2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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