Newly developed radiolabelled molecule enables real-time imaging of innate immune activity
Study suggests molecule offers improved specificity to monitor inflammation across many potential clinical applications
Researchers at The University of Texas MD Anderson Cancer Center have developed a new radio-labelled molecule capable of selectively reacting with certain high-energy radicals that are characteristic of innate immune activity, which may allow a non-invasive approach to monitor inflammation in real time by positron emission tomography (PET) imaging.
The preclinical study, published in Nature Biotechnology [1], takes advantage of new chemistry techniques to synthesize 4-[18F]Fluoro-1-Naphthol ([18F]4FN) as a novel reporter of myeloperoxidase (MPO) activity – a key enzyme active in the innate immune response. The molecule may be able to pinpoint areas of inflammation in a variety of clinical settings, such as inflammatory diseases, infections and immunotherapy-related side effects.
“There has been a long-standing interest in imaging inflammation and redox in general, but most current approaches generate high levels of background noise from biological processes that generate lower-energy radicals,” said corresponding author David Piwnica-Worms, M.D., Ph.D., chair of Cancer Systems Imaging. “Our molecule is tuned toward inflammation mediated by high-energy radicals, offering the potential to selectively monitor activation of innate immunity.”
The innate immune response is the body’s first line of defence against invading pathogens. In contrast to the adaptive immune response, innate immunity is nonspecific and acts broadly against infections or foreign agents. Innate immunity is largely driven by myeloid cells, including neutrophils, macrophages and natural killer cells.
Myeloperoxidase (MPO) is a highly conserved feature of the innate immune response across myeloid cells. This proinflammatory enzyme is activated by hydrogen peroxide to produce a variety of high-energy radicals that are used to eliminate pathogens.
Co-led by Federica Pisaneschi, Ph.D., assistant professor, and Seth T. Gammon, Ph.D., associate professor of Cancer Systems Imaging, the research team focused on MPO activity to develop a redox-tuned reporter specific to innate immune activity. Using newly developed chemistry techniques, the team was able to synthesize [18F]4FN as a labelled molecule to selectively bind nearby proteins and cells when [18F]4FN has been oxidized by MPO plus hydrogen peroxide, but not hydrogen peroxide alone.
The researchers evaluated the potential uses of [18F]4FN as an in vivo PET imaging tool in several laboratory models of inflammation. The molecule was able to successfully highlight inflammation from acute toxic shock, arthritis and contact dermatitis, ailments known to be mediated by activation of innate immunity. In addition, their results suggest [18F]4FN is a more specific and robust reporter of inflammation than other clinically utilized PET imaging agents, such as fluorodeoxyglucose ([18F]FDG).
“We need to verify this PET imaging agent in clinical studies, but it certainly has the potential for broad applications that could benefit patients across all kinds of diseases and clinical scenarios,” Piwnica-Worms said. “A tool like this could be used to identify multi-focal hotspots of inflammation, allowing physicians to intervene before disease progression or to follow the resolution of symptoms during therapy.”
The research team is in discussions with clinical collaborators to test specific applications of [18F]4FN. An initial study, now under US FDA review for Investigational New Drug registration and Institutional Review Board approval, will evaluate [18F]4FN as an early biomarker of immune-related adverse events in patients being treated with immune checkpoint inhibitors.
References
1. Federica Pisaneschi, Seth T. Gammon, Vincenzo Paolillo, et al. Imaging of innate immunity activation in vivo with a redox-tuned PET reporter. Nature Biotechnology, 2022; doi: https://doi.org/10.1038/s41587-021-01169-y
David Piwnica-Worms, M.D., Ph.D., Federica Pisaneschi, Ph.D., and Seth T. Gammon, Ph.D.
MedUni Wien researchers develop new imaging method for the detection of gastric lymphomas
A new imaging technique for the detection of MALT lymphomas, malignant tumours of the lymphatic system, could probably save patients numerous gastroscopies. A study group of MedUni Wien achieved a high imaging accuracy by way of PET/MR and by using a PET Tracer directed against a certain cell receptor. The results are published in Blood [1].
The stomach is a frequent place of origin for lymphoid cancers (lymphomas). Among the most common variants is the so-called MALT lymphoma which, in most cases, is caused by a previous infection of the stomach with the bacterium Helicobacter pylori. The first therapy is therefore generally directed against this bacterium. In order to examine the response to therapy of MALT lymphomas of the stomach and to exclude a recurrence of the lymphoma even after complete regression in the further course, repeated gastroscopies with multiple tissue sampling (biopsies) at intervals of several months are necessary.
The research team of MedUni Vienna around Marius Mayerhöfer (Dept. of Biomedical Imaging and Image-guided Therapy), Markus Raderer (Dept. of Medicine I) and Alexander Haug (Dept. of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine) has investigated a new imaging technique as an alternative to these repeated tissue extractions: The combination of positron emission tomography in combination with magnetic resonance imaging (PET/MR) using [68Ga]Pentixafor, a new radiolabelled molecule directed against the cell receptor CXCR4 (PET-Tracer). As most MALT lymphomas show a high CXCR4 expression, the researchers already expected a corresponding accumulation of [68Ga]Pentixafor.
Results show that [68Ga]Pentixafor PET/MR has a very high accuracy. For example, it demonstrated 97% accuracy in detecting the tumour compared to gastroscopy in patients with MALT lymphoma of the stomach after H. pylori treatment.
“If a sufficiently high CXCR4 expression is detected at the initial diagnosis of MALT lymphoma, the new imaging could replace repeated gastroscopies in the course of the disease in the future or at least increase the time intervals between gastroscopies,” says study first author Mayerhöfer, explaining the advantages for those affected.
The findings support an earlier publication by the research team, which indicated high sensitivity of [68Ga]Pentixafor PET/MR for the detection of MALT lymphomas in various organs and tissues.
Reference:
Marius Mayerhoefer, Markus Raderer, Wolfgang Lamm, et. al. CXCR4 PET/MRI for follow-up of gastric mucosa-associated lymphoid tissue lymphoma after first-line H. pylori eradication. Blood (2022) 139 (2): 240–244. doi: https://doi.org/10.1182/blood.2021013239
