18F-FMISO PET Imaging Identifies Hypoxia and Immunosuppressive Tumor Microenvironments and Guides Targeted Evofosfamide Therapy in Tumors Refractory to PD-1 and CTLA-4 Inhibition

Abstract

Hypoxia is a well-known component of many tumors and acts in an immunosuppressive manner through multiple distinct pathways. 18 F-FMISO PET imaging has been demonstrated to accurately quantify hypoxia in a clinical setting, although it has not been investigated for immunotherapy. Our work demonstrates that effective immunotherapy prevents tumor hypoxia and that uptake of 18 F-FMISO was predictive of subsequent changes in anatomical tumor size. We further demonstrate that PET imaging of hypoxia is correlated with phenotypic characteristics of inflammation through transcriptomics, immune cell spatial correlation, and direct measurement of secreted inflammatory proteins. The upregulation of damage associated molecular pattern signaling in responding tumors warranted investigation of the addition of the hypoxia targeted pro-drug to non-responding tumors in order to enhance checkpoint blockade efficacy. The addition of evofosfamide improved tumor oxygenation and response, providing rationale for immediate clinical investigation of both 18 F-FMISO PET imaging and combination evofosfamide therapy for improved cancer immunotherapy.Research.

Identification of ISG15 and ZFP36 as novel hypoxia- and immune-related gene signatures contributing to a new perspective for the treatment of prostate cancer by bioinformatics and experimental verification

“…In addition, 18F-FMISO PET imaging was also applied in preclinical models of breast and colon cancer to probe the tumor and its surrounding microenvironment before and during PD-1 and CTLA-4 checkpoint blockade to quantify tumor hypoxia. Hypoxic signals from PET imaging are used to add hypoxia-targeted therapy to unresponsive tumor, which ultimately provides therapeutic synergy [ 53 ].…”

Detection of Hypoxia in Cancer Models: Significance, Challenges, and Advances

“…PET agents are radioactive compounds quantitatively measurable through their beta-decay, which is converted into a 3D image. Intratumoral hypoxia has been detected via PET by utilizing nitroimidazole isotopes, such as 18 F-fluoromisonidazole 18 F-FMISO and 18 F-EF5, which irreversibly bind to thiol groups on metabolic proteins at rates inversely proportional to O 2 concentrations [ 107 ]. Hirata et al recently reported that 18 F-FMISO provides valuable prognostic data on survival and treatment response for patients with glioma and information on necrosis, vascularization, and permeability of the tumor [ 108 ].…”

Tracers progress for positron emission tomography imaging of glial-related disease

“…18 F-fluoromisonidazole ( 18 F-FMISO) is a PET tracer that selectively binds to hypoxic tissues and can be used to measure the hypoxia in glioma and provide information for prognosis [ 90 ] . As it is retained by irreversible binding to the thiol-rich metabolic proteins at rates that are inversely proportional to oxygen concentration, 18 F-FMISO provides quantitative measurements of hypoxia level [ 91 ] .…”