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Clinical Cancer Research : An Official... Jan 2022Hypoxia is a common characteristic of many tumor microenvironments, and it has been shown to promote suppression of antitumor immunity. Despite strong biological...
F-FMISO PET Imaging Identifies Hypoxia and Immunosuppressive Tumor Microenvironments and Guides Targeted Evofosfamide Therapy in Tumors Refractory to PD-1 and CTLA-4 Inhibition.
PURPOSE
Hypoxia is a common characteristic of many tumor microenvironments, and it has been shown to promote suppression of antitumor immunity. Despite strong biological rationale, longitudinal correlation of hypoxia and response to immunotherapy has not been investigated.
EXPERIMENTAL DESIGN
In this study, we probed the tumor and its surrounding microenvironment with F-FMISO PET imaging to noninvasively quantify tumor hypoxia prior to and during PD-1 and CTLA-4 checkpoint blockade in preclinical models of breast and colon cancer.
RESULTS
Longitudinal imaging identified hypoxia as an early predictive biomarker of therapeutic response (prior to anatomic changes in tumor volume) with a decreasing standard uptake value (SUV) ratio in tumors that effectively respond to therapy. PET signal correlated with markers of tumor immune response including cytokines (IFNγ, GZMB, and TNF), damage-associated molecular pattern receptors (TLR2/4), and immune cell populations (macrophages, dendritic cells, and cytotoxic T cells). Responding tumors were marked by increased inflammation that were spatially distinct from hypoxic regions, providing a mechanistic understanding of the immune signaling pathways activated. To exploit image-guided combination therapy, hypoxia signal from PET imaging was used to guide the addition of a hypoxia targeted treatment to nonresponsive tumors, which ultimately provided therapeutic synergy and rescued response as determined by longitudinal changes in tumor volume.
CONCLUSIONS
The results generated from this work provide an immediately translatable paradigm for measuring and targeting hypoxia to increase response to immune checkpoint therapy and using hypoxia imaging to guide combinatory therapies.
Topics: CTLA-4 Antigen; Cell Hypoxia; Humans; Hypoxia; Misonidazole; Neoplasms; Nitroimidazoles; Phosphoramide Mustards; Positron-Emission Tomography; Programmed Cell Death 1 Receptor; Tumor Microenvironment
PubMed: 34615724
DOI: 10.1158/1078-0432.CCR-21-2394 -
Journal of Nuclear Medicine : Official... Apr 2021Tumor hypoxia in head-and-neck squamous cell carcinoma (HNSCC) leads to an immunosuppressive microenvironment and reduces the response to radiotherapy. In this... (Clinical Trial)
Clinical Trial
Tumor hypoxia in head-and-neck squamous cell carcinoma (HNSCC) leads to an immunosuppressive microenvironment and reduces the response to radiotherapy. In this prospective imaging trial, we investigated potential interactions between functional hypoxia imaging and infiltrating lymphocyte levels as a potential predictor for treatment response in HNSCC patients. In total, 49 patients receiving definitive chemoradiation for locally advanced HNSCCs underwent pretherapeutic biopsies and peritherapeutic hypoxia imaging using F-misonidazole PET at weeks 0, 2, and 5 during chemoradiation. Hematoxylin-eosin and immunohistochemical stainings for tumor-infiltrating lymphocytes, tissue-based hypoxia, and microvascular markers were analyzed and correlated with the longitudinal hypoxia dynamics and patient outcomes. High levels of tumor-infiltrating total lymphocytes correlated with superior locoregional control (LRC) (hazard ratio [HR], 0.279; = 0.011) and progression-free survival (PFS) (HR, 0.276; = 0.006). Similarly, early resolution of F-misonidazole PET-detected tumor hypoxia quantified by F-misonidazole dynamics between weeks 0 and 2 of chemoradiation was associated with improved LRC (HR, 0.321; = 0.015) and PFS (HR, 0.402; = 0.043). Outcomes in the favorable early hypoxia resolution subgroup significantly depended on infiltrating lymphocyte counts, with patients who showed both an early hypoxia response and high lymphocyte infiltration levels exhibiting significantly improved LRC (HR, 0.259; = 0.036) and PFS (HR, 0.242; = 0.017) compared with patients with an early hypoxia response but low lymphocyte counts. These patients exhibited oncologic results comparable to those of patients with no hypoxia response within the first 2 wk of chemoradiation. This analysis established a clinical hypoxia-immune score that predicted treatment responses and outcomes in HNSCC patients undergoing chemoradiation and may help to devise novel concepts for biology-driven personalization of chemoradiation.
Topics: Adult; Female; Head and Neck Neoplasms; Humans; Lymphocytes; Male; Middle Aged; Neoadjuvant Therapy; Positron-Emission Tomography; Progression-Free Survival; Prospective Studies; Tumor Hypoxia
PubMed: 32859699
DOI: 10.2967/jnumed.120.248633 -
Radiation Oncology (London, England) Oct 2018Concomitant chemo-radiotherapy is the reference treatment for non-resectable locally-advanced Non-Small Cell Lung Cancer (NSCLC). Increasing radiotherapy total dose in...
BACKGROUND
Concomitant chemo-radiotherapy is the reference treatment for non-resectable locally-advanced Non-Small Cell Lung Cancer (NSCLC). Increasing radiotherapy total dose in the whole tumour volume has been shown to be deleterious. Functional imaging with positron emission tomography (PET/CT) offers the potential to identify smaller and biologically meaningful target volumes that could be irradiated with larger doses without compromising Organs At Risk (OAR) tolerance. This study investigated four scenarios, based on FDG and F-miso PET/CT, to delineate the target volumes and derive radiotherapy plans delivering up to 74Gy.
METHOD
Twenty-one NSCLC patients, selected from a prospective phase II trial, had FDG- and F-miso PET/CT before the start of radiotherapy and FDG PET/CT during the radiotherapy (42Gy). The plans were based planned on a standard plan delivering 66 Gy (plan 1) and on three different boost strategies to deliver 74Gy total dose in pre-treatment FDG hotspot (70% of SUV) (plan 2), pre-treatment F-miso target (SUV > 1.4) (plan 3) and per-treatment FDG residual (40% of SUV). (plan 4).
RESULTS
The mean target volumes were 4.8 cc (± 1.1) for FDG hotspot, 38.9 cc (± 14.5) for F-miso and 36.0 cc (± 10.1) for per-treatment FDG. In standard plan (66 Gy), the mean dose covering 95% of the PTV (D95%) were 66.5 (± 0.33), 66.1 (± 0.32) and 66.1 (± 0.32) Gy for FDG hotspot, F-miso and per-treatment FDG. In scenario 2, the mean D95% was 72.5 (± 0.25) Gy in FDG hotspot versus 67.9 (± 0.49) and 67.9 Gy (± 0.52) in F-miso and per-treatment FDG, respectively. In scenario 3, the mean D95% was 72.2 (± 0.27) Gy to F-miso versus 70.4 (± 0.74) and 69.5Gy (± 0.74) for FDG hotspot and per-treatment FDG, respectively. In scenario 4, the mean D95% was 73.1 (± 0.3) Gy to FDG per-treatment versus 71.9 (± 0.61) and 69.8 (± 0.61) Gy for FDG hotspot and F-miso, respectively. The dose/volume constraints to OARs were matched in all scenarios.
CONCLUSION
Escalated doses can be selectively planned in NSCLC target volumes delineated on FDG and F-miso PET/CT functional images. The most relevant strategy should be investigated in clinical trials.
TRIAL REGISTRATION
(RTEP5, NCT01576796 , registered 15 june 2012).
Topics: Adenocarcinoma; Adult; Aged; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Female; Fluorodeoxyglucose F18; Follow-Up Studies; Humans; Lung Neoplasms; Male; Middle Aged; Misonidazole; Organs at Risk; Positron-Emission Tomography; Prognosis; Prospective Studies; Radiopharmaceuticals; Radiotherapy Dosage; Radiotherapy, Image-Guided; Radiotherapy, Intensity-Modulated; Tumor Burden
PubMed: 30352608
DOI: 10.1186/s13014-018-1147-2 -
British Journal of Cancer May 1979A combination of misonidazole and MTDQ (6,6'-methylene-bis-2,2,4 trimethyl-1,2-dihydroquinoline) has been tested for its radiation-sensitizing properties and...
A combination of misonidazole and MTDQ (6,6'-methylene-bis-2,2,4 trimethyl-1,2-dihydroquinoline) has been tested for its radiation-sensitizing properties and cytotoxicity, using Chinese hamster V79 cells cultured in vitro. Both compounds sensitize hypoxic cells to the effects of X-rays, and when used in combination their sensitizing properties are additive. By contrast, the presence of MTDQ completely inhibits the cytotoxicity that misonidazole exhibits towards hypoxic cells. These experiments shed some light on the mechanism of action of electron-affinic hypoxic cell sensitizers, and the combination of radiosensitizers suggested may have an application in human cancer radiotherapy by eliminating the neurotoxicity experienced by patients receiving misonidazole during radiotherapy.
Topics: Animals; Cell Survival; Cells, Cultured; Cricetinae; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Drug Combinations; Misonidazole; Nitroimidazoles; Oxygen; Quinolines; Radiation-Sensitizing Agents
PubMed: 486306
DOI: 10.1038/bjc.1979.94 -
Seminars in Nuclear Medicine Oct 1999Direct "hot spot" imaging of myocardial tissue hypoxia is potentially of great clinical importance because available noninvasive approaches for the detection of... (Review)
Review
Direct "hot spot" imaging of myocardial tissue hypoxia is potentially of great clinical importance because available noninvasive approaches for the detection of myocardial ischemia have generally been based on the detection of flow heterogeneity or identification of regional alterations of myocardial metabolism. These existing approaches provide only an indirect assessment of regional myocardial ischemia, and may be affected by either sympathetic activation or substrate availability. The assessment of tissue oxygenation with hypoxic compounds may be the best indicator of the balance of flow and oxygen consumption. These compounds may provide a means of identifying dysfunctional chronically ischemic but viable "hibernating" myocardium and find a critical place in the assessment of angiogenesis. Nitroimidazole compounds hold promise for positive imaging of hypoxia in the heart. However, refinement of these compounds is needed to improve target specificity. The potential of technetium-99m (Tc99m) complexes derived from removal of the nitroimidazole moiety from a nitroimidazole-containing ligand is interesting and warrants further investigation. Experimental studies support the possibility of identifying myocardial hypoxia with the positron-emitting compound F18-fluoromisonidazole noninvasively. The potential of a Tc99m labeled nitroimidazole for positive imaging of myocardial ischemia is tremendous because single-photon imaging is more widely available. The true clinical potential of these nitroimidazole compounds can only be defined with future experimental and clinical studies. Ideally, these studies should include comparisons of tracer uptake with independent measures of regional ischemia or measures of oxygen tension, potentially using magnetic resonance imaging.
Topics: Animals; Cell Hypoxia; Heart; Humans; Misonidazole; Myocardial Stunning; Nitroimidazoles; Organotechnetium Compounds; Radionuclide Imaging; Radiopharmaceuticals
PubMed: 10534235
DOI: 10.1016/s0001-2998(99)80020-8 -
PloS One 2019Hypoxia can induce radiation resistance and is an independent prognostic marker for outcome in head and neck cancer. As 18F-FMISO (FMISO), a hypoxia tracer for PET, is... (Comparative Study)
Comparative Study
BACKGROUND
Hypoxia can induce radiation resistance and is an independent prognostic marker for outcome in head and neck cancer. As 18F-FMISO (FMISO), a hypoxia tracer for PET, is far less common than 18F-FDG (FDG) and two separate PET scans result in doubled cost and radiation exposure to the patient, we aimed to predict hypoxia from FDG PET with new techniques of voxel based analysis and texture analysis.
METHODS
Thirty-eight patients with head-and-neck cancer underwent consecutive FDG and FMISO PET scans before any treatment. ROIs enclosing the primary cancer were compared in a voxel-by-voxel manner between FDG and FMISO PET. Tumour hypoxia was defined as the volume with a tumour-to-muscle ratio (TMR) > 1.25 in the FMISO PET and hypermetabolic volume was defined as >50% SUVmax in the FDG PET. The concordance rate was defined as percentage of voxels within the tumour which were both hypermetabolic and hypoxic. 38 different texture analysis (TA) parameters were computed based on the ROIs and correlated with presence of hypoxia.
RESULTS
Within the hypoxic tumour regions, the FDG uptake was twice as high as in the non-hypoxic tumour regions (SUVmean 10.9 vs. 5.4; p<0.001). A moderate correlation between FDG and FMISO uptake was found by a voxel-by-voxel comparison (r = 0.664 p<0.001). The average concordance rate was 25% (± 22%). Entropy was the TA parameter showing the highest correlation with hypoxia (r = 0.524 p<0.001).
CONCLUSION
FDG uptake was higher in hypoxic tumour regions than in non-hypoxic regions as expected by tumour biology. A moderate correlation between FDG and FMISO PET was found by voxel-based analysis. TA yielded similar results in FDG and FMISO PET. However, it may not be possible to predict tumour hypoxia even with the help of texture analysis.
Topics: Adult; Aged; Aged, 80 and over; Female; Fluorine Radioisotopes; Fluorodeoxyglucose F18; Head and Neck Neoplasms; Humans; Male; Middle Aged; Misonidazole; Positron-Emission Tomography; Predictive Value of Tests; Prognosis; Radiation Tolerance; Radiopharmaceuticals; Tumor Hypoxia
PubMed: 30818360
DOI: 10.1371/journal.pone.0213111 -
Journal of Nuclear Medicine : Official... Jan 1987Misonidazole is a known hypoxic cell sensitizer that binds covalently in hypoxic cells. Its congeners labeled with 77Br, 75Br, or 18F, are likely candidates for imaging...
Misonidazole is a known hypoxic cell sensitizer that binds covalently in hypoxic cells. Its congeners labeled with 77Br, 75Br, or 18F, are likely candidates for imaging hypoxia. We have synthesized and tested [82Br]-4-bromomisonidazole, [3H]-4-bromomisonidazole, [3H]fluoromisonidazole and [3H]misonidazole as prototype radiopharmaceuticals and have compared their uptake in normal and malignant tissues. The higher lipophilicity of brominated misonidazole increased its concentration in the hypoxic portion of tumors at 2 hr, but high blood levels contributed to excessive background, incompatible with imaging. Hydrogen-3-fluoromisonidazole diffused into tumors at a slower rate than misonidazole but it also cleared from normal tissues so that after 2 hr tumor-to-blood ratios favorable for imaging were achieved. In the compounds that were studied, fluorine at the end of the alkyl chain is more stable in vivo than bromine on the imidazole ring. Our results indicate that [18F] fluoromisonidazole may be a useful tracer for imaging hypoxia at approximately 4 hr after injection.
Topics: Animals; Bromine; Chromatography, Gel; Chromatography, High Pressure Liquid; Drug Evaluation, Preclinical; Fluorine; Hypoxia; Isotope Labeling; Mice; Misonidazole; Neoplasms, Experimental; Radioisotopes; Radionuclide Imaging; Tissue Distribution; Tritium
PubMed: 3794812
DOI: No ID Found -
Journal of Nuclear Medicine : Official... Feb 2011A wide variety of imaging approaches have been developed in the past few decades for monitoring tumor oxygenation and hypoxia in vivo. In particular, nuclear medicine... (Review)
Review
A wide variety of imaging approaches have been developed in the past few decades for monitoring tumor oxygenation and hypoxia in vivo. In particular, nuclear medicine has seen the development of several radiolabeled hypoxia markers and is the preferred method for imaging of tumor hypoxia. Hypoxia imaging is increasingly being used in the clinical setting and is progressing from a mere detection method to application in individualization of chemoradiotherapy.
Topics: Humans; Hypoxia; Misonidazole; Neoplasms; Neovascularization, Pathologic; Nitroimidazoles; Positron-Emission Tomography; Radiography; Radiopharmaceuticals
PubMed: 21233176
DOI: 10.2967/jnumed.110.075663 -
British Journal of Cancer Sep 1984Benznidazole is a lipophilic analogue of misonidazole (MISO) which shows promise as a chemosensitizer for clinical use, particularly in combination with CCNU. We have...
Benznidazole is a lipophilic analogue of misonidazole (MISO) which shows promise as a chemosensitizer for clinical use, particularly in combination with CCNU. We have investigated the detailed pharmacokinetics of benznidazole in mice, dogs and sheep to provide a data base for the estimation of doses required for chemosensitization in man. Pharmacokinetic behaviour was linear except at high doses in mice. Absorption was fairly rapid and bioavailability was complete following both i.p. administration in mice and oral administration in dogs. Elimination t1/2 values were longer than for MISO, being 90 min in mice, 4-5 h in sheep and 9-11 h in dogs. At doses giving linear kinetics, peak whole plasma concentrations per administered mg kg-1 were 0.75 micrograms ml-1 for the i.p. route in mice and 1.8 micrograms ml-1 for the oral route in dogs. Though between 39 and 59% of plasma benznidazole was bound to protein, tissue penetration was generally good. Tissue/whole plasma ratios ranged from 59-99% for transplantable mouse tumours and from 14-70% for spontaneous dog neoplasms. Nervous tissue penetration was similar to that in tumours: brain/whole plasma ratios averaged between 61 and 76% in mice and 42% in dogs, while peripheral nerve/whole plasma ratios in dogs averaged 74%. Mean liver/whole plasma ratios were 42% and 71% in BALB/c and C3H/He mouse strains respectively. Only approximately 5% of the administered dose was excreted unchanged in the urine, indicating the likelihood of extensive metabolism. These data show that benznidazole should have suitable pharmacokinetic properties for clinical use as a chemosensitizer. Enhancement of CCNU response is likely to require circulating benznidazole concentrations of 10-30 micrograms ml-1 and we predict that these will be obtained with oral doses of 6-20 mg kg-1 in man.
Topics: Animals; Antineoplastic Agents; Brain; Chromatography, High Pressure Liquid; Dogs; Drug Evaluation, Preclinical; Female; Kinetics; Liver; Male; Mice; Mice, Inbred Strains; Neoplasms, Experimental; Nitroimidazoles; Pharmaceutical Vehicles; Sheep
PubMed: 6466543
DOI: 10.1038/bjc.1984.176 -
World Journal of Nuclear Medicine 2021The aim of this study was to correlate endogenous tissue biomarkers of hypoxia with quantitative imaging parameters derived from F-fluoro-misonidazole (F-MISO) and...
The aim of this study was to correlate endogenous tissue biomarkers of hypoxia with quantitative imaging parameters derived from F-fluoro-misonidazole (F-MISO) and F-fluoro-deoxy-glucose (FDG) positron emission tomography/computed tomography (PET/CT) and clinical outcomes in locoregionally advanced head and neck squamous cell carcinoma (HNSCC). Tumor-tissue blocks of HNSCC patients with pretreatment F-MISO-PET/CT and FDG-PET/CT were de-archived for expression of hypoxia-inducible factor-1 alpha (HIF-1α) subunit, carbonic anhydrase-IX (CA-IX), and glucose transporter subunit-1 (GLUT-1) using immunohistochemistry (IHC). The intensity of staining was graded and correlated with quantitative imaging parameters and with disease-related outcomes. Tissue blocks were analyzed for 14 of 20 patients. On IHC, median H-scores for HIF-1α, CA-IX, and GLUT-1 were 130, 0, and 95, respectively. No significant correlation of tissue biomarkers of hypoxia with quantitative imaging parameters was found. However, borderline significant correlation was seen for H-scores of CA-IX with hypoxic tumor volume (HTV) ( = 0.873, = 0.054) and fractional hypoxic volume ( = 0.824, = 0.086) derived from F-MISO-PET/CT. At a median follow-up of 43 months, 5-year Kaplan-Meier estimates of locoregional control, disease-free survival, and overall survival were 53%, 43%, and 40%, respectively. Increased expression of HIF-1α or GLUT-1 (dichotomized by median H-scores) was not individually associated with disease-related outcomes. However, a combination of high HTV (>4.89cc) with above median H-scores of either HIF-1α (>130) and/or GLUT-1 (>95) was associated with worse clinical outcomes. None of the three patients with such "adverse hypoxic profile" were long-term survivors. There is no significant correlation of endogenous tissue biomarkers of hypoxia (HIF-1α, CA-IX, and GLUT-1) with quantitative imaging parameters (on F-MISO-PET/CT and FDG-PET/CT) or long-term outcomes in HNSCC. However, a combination of both can identify a subgroup of patients with adverse outcomes.
PubMed: 34703390
DOI: 10.4103/wjnm.WJNM_91_20