In Situ Proinflammatory Effects of Dazostinag Alone or with Chemotherapy on the Tumor Microenvironment of Patients with Head and Neck Squamous Cell Carcinoma.

PURPOSE: The tumor microenvironment (TME) is difficult to model in an in vivo cancer research setting. This study leveraged intratumor microdosing using comparative in vivo oncology (CIVO) with spatial profiling to evaluate the effects of the stimulator of interferon genes agonist dazostinag, alone or with chemotherapy, on cellular responses within the native TME of intact human tumors.

PATIENTS AND

METHODS

This phase 0 study enrolled adult patients with head and neck squamous cell carcinoma (HNSCC) planned for surgical intervention. Intratumoral microdose injections of dazostinag (maximum dose: 1.68 μg in a 0.05 mg/mL solution), alone or combined with various chemotherapies, were delivered via CIVO to tumors 24, 48, 72, or 96 hours prior to resection. Each tumor sample was prepared for analysis using IHC and ISH. Analysis of the microdosed tumors using the GeoMx Digital Spatial Profiler and CosMx Spatial Molecular Imager was performed in one patient.

RESULTS

Type 1 IFN signaling was induced with dazostinag alone and in combination with chemotherapy from multiple cell types within the TME, including immune cells. Dazostinag also shifted the polarization of macrophages from an immune-suppressive phenotype to a proinflammatory phenotype at 24 hours after injection. Enrichment of cytotoxic T cells was observed in regions of localized dazostinag exposure, coinciding with increased chemokine (CXCL9) expression. Based on cleaved caspase-3, an apoptosis marker, dazostinag plus chemotherapy increased cellular apoptosis relative to either drug alone.

CONCLUSIONS

Utilizing CIVO and spatial profiling technology, dazostinag alone and combined with chemotherapy promoted an early proinflammatory response and enhanced chemotherapy-mediated cell death in the native TME of intact human HNSCC tumors.

SIGNIFICANCE: The CIVO approach demonstrates that dazostinag alone and combined with chemotherapy promotes both proapoptotic and early proinflammatory responses in the native TME of intact human HNSCC tumors, providing clinical evidence for an on-target mechanism of action and rationale for further clinical investigation.