First-In-Human Study in Cancer Patients Establishing the Feasibility of Oxygen Measurements in Tumors Using Electron Paramagnetic Resonance With the OxyChip

Abstract

ObjectiveThe overall objective of this clinical study was to validate an implantable oxygen sensor, called the ‘OxyChip’, as a clinically feasible technology that would allow individualized tumor-oxygen assessments in cancer patients prior to and during hypoxia-modification interventions such as hyperoxygen breathing.MethodsPatients with any solid tumor at ≤3-cm depth from the skin-surface scheduled to undergo surgical resection (with or without neoadjuvant therapy) were considered eligible for the study. The OxyChip was implanted in the tumor and subsequently removed during standard-of-care surgery. Partial pressure of oxygen (pO2) at the implant location was assessed using electron paramagnetic resonance (EPR) oximetry.ResultsTwenty-three cancer patients underwent OxyChip implantation in their tumors. Six patients received neoadjuvant therapy while the OxyChip was implanted. Median implant duration was 30 days (range 4–128 days). Forty-five successful oxygen measurements were made in 15 patients. Baseline pO2 values were variable with overall median 15.7 mmHg (range 0.6–73.1 mmHg); 33% of the values were below 10 mmHg. After hyperoxygenation, the overall median pO2 was 31.8 mmHg (range 1.5–144.6 mmHg). In 83% of the measurements, there was a statistically significant (p ≤ 0.05) response to hyperoxygenation.ConclusionsMeasurement of baseline pO2 and response to hyperoxygenation using EPR oximetry with the OxyChip is clinically feasible in a variety of tumor types. Tumor oxygen at baseline differed significantly among patients. Although most tumors responded to a hyperoxygenation intervention, some were non-responders. These data demonstrated the need for individualized assessment of tumor oxygenation in the context of planned hyperoxygenation interventions to optimize clinical outcomes.

EPR and Related Magnetic Resonance Imaging Techniques in Cancer Research

“…Only a few groups in the world have used their own house-made instrument [ 7 , 129 ]. Therefore, no human application of EPRI has been reported, although several EPR spectroscopic application on human skin or other partial application has been reported from early stage of in vivo EPR studies [ 130 , 131 , 132 ]. Hyperpolarized 13 C-MRI is simply a chemical shift imaging of an infused/injected extracorporeally hyperpolarized 13 C-labeled compound and it’s in vivo metabolites [ 31 ].…”

The Role of Imaging Biomarkers to Guide Pharmacological Interventions Targeting Tumor Hypoxia

“…EPR oxygen imaging also demonstrated its predictive value for tumor control according to tumor oxygenation level and radiation dose (Elas et al, 2008;Elas et al, 2013;Epel et al, 2019). So far, a limited number of studies have been applied in humans to measure by EPR the oxygen level in superficial tumors (Swartz et al, 2014;Swartz et al, 2016;Flood et al, 2018;Jeong et al, 2019;Flood et al, 2020;Schaner et al, 2021).…”

Biocompatible Monophosphonated Trityl Spin Probe, HOPE71, for In Vivo Measurement of pO2, pH, and [Pi] by Electron Paramagnetic Resonance Spectroscopy

“…Low-field electron paramagnetic resonance with the use of paramagnetic spin probes allows for non-invasive measurement of critical biomarkers in preclinical 1−3 and, more recently, in clinical settings. 4 Two types of paramagnetic probes are used for in vivo EPR, namely, particulate probes such as chars, coals, lithium phthalocyanine, lithium naphthalocyanine, and soluble probes such as nitroxide and triarylmethyl (TAM or trityl) radicals. 5 To date, only particulate lithium octa-n-butoxynaphthalocyanine embedded inside a biocompatible polymer (polymeric dimethylsiloxane) named OxyChip has been used in clinical trials to assess tumor oxygenation.…”

“…5 To date, only particulate lithium octa-n-butoxynaphthalocyanine embedded inside a biocompatible polymer (polymeric dimethylsiloxane) named OxyChip has been used in clinical trials to assess tumor oxygenation. 4 Particulate spin probes are limited to oxygen measurement and have to be implanted at the site of measurement. The lack of particulate distribution throughout the tissue makes imaging applications very challenging.…”

“…Low-field electron paramagnetic resonance with the use of paramagnetic spin probes allows for non-invasive measurement of critical biomarkers in preclinical − and, more recently, in clinical settings . Two types of paramagnetic probes are used for in vivo EPR, namely, particulate probes such as chars, coals, lithium phthalocyanine, lithium naphthalocyanine, and soluble probes such as nitroxide and triarylmethyl (TAM or trityl) radicals .…”