Trackable Intratumor Microdosing and Spatial Profiling Provide Early Insights into Activity of Investigational Agents in the Intact Tumor Microenvironment
Purpose: Cancer drug development is currently limited by a paradigm of preclinical evaluation that does not adequately recapitulate the complexity of the intact human tumor microenvironment (TME). To overcome this, we combined trackable intratumor microdosing (CIVOTM) with spatial biology readouts to directly assess drug effects in patient tumors in situ. Patients and Methods: In a first-of-its-kind Phase 0 clinical trial, we explored the effects of an investigational stage SUMOylation Activating Enzyme (SAE) inhibitor, subasumstat (TAK-981) in 12 patients with head and neck carcinoma (HNC). Patients scheduled for tumor resection received percutaneous intratumor injections of subasumstat and vehicle control 1 to 4 days prior to surgery, resulting in spatially localized and graded regions of drug exposure (~1000-2000 microns in diameter). Drug-exposed (n=214) and unexposed regions (n=140) were compared 2 by GeoMx Digital Spatial Profiler, with evaluation at single cell resolution in a subset of these by CosMx Spatial Molecular Imager. Results: Localized regions of subasumstat exposure revealed SUMO pathway inhibition, elevation of Type I interferon (IFN-I) response, and inhibition of cell cycle across all tumor samples. Single cell analysis by CosMx demonstrated cell cycle inhibition specific to the tumor epithelium, and IFN pathway induction commensurate with a TME shift from immune- suppressive to immune-permissive. Conclusions: Pairing CIVO with spatial profiling enabled detailed investigation of response to subasumstat across a diverse sampling of native and intact TMEs. We demonstrate that drug mechanism of action can be directly evaluated in a spatially precise manner in the most translationally relevant setting: an in situ human tumor.
Overall design
Total 354 areas of interest (AOIs) from 9 Head and Neck Carcinomas were sequenced using Digital Spatial Profiling (DSP) using GeoMX Nanostring, with the Cancer Transcriptome Altas (1812 genes). AOIs were asssessed for drug (subasumstat) exposure using MIL113 staining allowing comparison of drug exposed to non exposed AOIs.
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