The Central Role of Inflammation Associated with Checkpoint Inhibitor Treatments

Vâjâitu, Cristina; Drăghici, Carmen; Solomon, Iulia; Lisievici, Cristina; Popa, Adina; Lupu, Mihai; Căruntu, Constantin; Constantin, Maria Magdalena; Voiculescu, Vlad Mihai

doi:10.1155/2018/4625472

Cited by 28 publications

(23 citation statements)

References 59 publications

(56 reference statements)

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“…A decrease in k 3 was also observed after therapy with a dual TORC1/2 inhibitor, TAK-228, because the inhibition of mTORC1 activity suppresses the conversion of glutamine to a-ketoglutarate (28). On the other hand, treatment with nivolumab and pembrolizumab, human IgG4 anti-PD-1 monoclonal antibodies that work as checkpoint inhibitors and are believed to often provoke tumor inflammation when effective (29), led to an elevated glutaminolysis rate as reflected in higher k 3 . Albina et al reported that the intracellular free glutamine concentration is decreased in inflammation and that the cellular FIGURE 5.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Assessment of ¹⁸F-(2S,4R)-4-Fluoroglutamine in Patients with Cancer

et al. 2019

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18 F-(2S,4R)-4-fluoroglutamine (18 F-FGln) is an investigational PET radiotracer for imaging tumor glutamine flux and metabolism. The aim of this study was to investigate its pharmacokinetic properties in patients with cancer. Methods: Fifty lesions from 41 patients (21 men and 20 women, aged 54 ± 14 y) were analyzed. Thirty-minute dynamic PET scans were performed concurrently with a rapid intravenous bolus injection of 232 ± 82 MBq of 18 F-FGln, followed by 2 static PET scans at 97 ± 14 and 190 ± 12 min after injection. Five patients also underwent a second 18 F-FGln study 4-13 wk after initiation of therapy with glutaminase, dual TORC1/2, or programmed death-1 inhibitors. Blood samples were collected to determine plasma and metabolite fractions and to scale the image-derived input function. Regions of interest were manually drawn to calculate SUVs. Pharmacokinetic modeling with both reversible and irreversible 1-and 2-tissue-compartment models was performed to calculate the kinetic rate constants K 1 , k 2 , k 3 , and k 4. The analysis was repeated with truncated 30-min dynamic datasets. Results: Intratumor 18 F-FGln uptake patterns demonstrated substantial heterogeneity in different lesion types. In most lesions, the reversible 2-tissue-compartment model was chosen as the most appropriate according to the Akaike information criterion. K 1 , a surrogate biomarker for 18 F-FGln intracellular transport, was the kinetic rate constant that was most correlated both with SUV at 30 min (Spearman ρ 5 0.71) and with SUV at 190 min (ρ 5 0.51). Only K 1 was reproducible from truncated 30-min datasets (intraclass correlation coefficient, 0.96). k 3 , a surrogate biomarker for glutaminolysis rate, was relatively low in about 50% of lesions. Treatment with glutaminase inhibitor CB-839 substantially reduced the glutaminolysis rates as measured by k 3. Conclusion: 18 F-FGln dynamic PET is a sensitive tool for studying glutamine transport and metabolism in human malignancies. Analysis of dynamic data facilitates better understanding of 18 F-FGln pharmacokinetics and may be necessary for response assessment to targeted therapies that impact intracellular glutamine pool size and tumor glutaminolysis rates.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Assessment of ¹⁸F-(2S,4R)-4-Fluoroglutamine in Patients with Cancer

et al. 2019

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“…ipilimumab) in MM. We selected markers on the basis that they reflected activation of pathways that are relevant for melanoma progression as well as the effects of ipilimumab . Against this background we examined general downstream markers of inflammation [i.e.…”

Section: Introductionmentioning

confidence: 99%

Prognostic biomarkers for immunotherapy with ipilimumab in metastatic melanoma

Nyakas

Aamdal

Jacobsen

et al. 2019

Clinical and Experimental Immunology

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Summary New therapies, including the anti‐cytotoxic T lymphocyte antigen (CTLA)‐4 antibody, ipilimumab, is approved for metastatic melanoma. Prognostic biomarkers need to be identified, because the treatment has serious side effects. Serum samples were obtained before and during treatment from 56 patients with metastatic or unresectable malignant melanoma, receiving treatment with ipilimumab in a national Phase IV study (NCT0268196). Expression of a panel of 17 inflammatory‐related markers reflecting different pathways including extracellular matrix remodeling and fibrosis, vascular inflammation and monocyte/macrophage activation were measured at baseline and the second and/or third course of treatment with ipilimumab. Six candidate proteins [endostatin, osteoprotegerin (OPG), C‐reactive protein (CRP), pulmonary and activation‐regulated chemokine (PARC), growth differentiation factor 15 (GDF15) and galectin‐3 binding‐protein (Gal3BP)] were persistently higher in non‐survivors. In particular, high Gal3BP and endostatin levels were also independently associated with poor 2‐year survival after adjusting for lactate dehydrogenase, M‐stage and number of organs affected. A 1 standard deviation increase in endostatin gave 1·74 times [95% confidence interval (CI) = 1·10–2·78, P = 0·019] and for Gal3BP 1·52 times (95% CI = 1·01–2·29, P = 0·047) higher risk of death in the adjusted model. Endostatin and Gal3BP may represent prognostic biomarkers for patients on ipilimumab treatment in metastatic melanoma and should be further evaluated. Owing to the non‐placebo design, we could only relate our findings to prognosis during ipilimumab treatment.

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“…RCM, Cutometer could be a potential diagnostic tool for cutaneous inflammatory disorders (21). Furthermore, early assessment of inflammation caused by checkpoint inhibitor therapy can predict the type of response to immunotherapy (22).…”

Section: Discussionmentioning

confidence: 99%

Measurement of skin viscoelasticity: A non‑invasive approach in allergic contact dermatitis

et al. 2020

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Non-invasive bioengineering technologies are constantly being developed, as they can provide useful insights and contribute to the improvement of medical care and scientific education. The purpose of this study was to assess skin viscoelasticity using the suction chamber method in patients with allergic contact dermatitis vs. healthy subjects, before and after applying a moisturizer safety testing cream. This was a prospective controlled study over a 3-year period (March 2016-March 2019), with 81 subjects being divided in two balanced groups: Patients with allergic contact dermatitis and healthy subjects, respectively. The skin viscoelasticity was determined for all subjects with Cutometer ® , using the suction method, by performing a dynamic assessment of parameters before and after applying a moisturizing cream. The results indicate a decrease in the elasticity parameters in both groups, indicating an improvement of the elastic properties under the treatment. Skin capacity to return to its previous form after the deformation, i.e., pure elasticity and biological elasticity, showed overall elevated values in the group with contact dermatitis, demonstrating the efficacy of the emollient cream after applying it for 28 days (increase by 11.7 and 4.9% respectively, compared with baseline, when patients had dry, untreated skin). However, in healthy subjects, these parameters do not achieve important values, but they remain rather stable over time with a very slight improvement (6.6% after 28 days). The Cutometer is an easy to use, efficient and widely used instrument for measurements in studies that perform a quantitative assessment of the effectiveness of different formulations intended for application on the skin.

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The Central Role of Inflammation Associated with Checkpoint Inhibitor Treatments

Cited by 28 publications

References 59 publications

Pharmacokinetic Assessment of ¹⁸F-(2S,4R)-4-Fluoroglutamine in Patients with Cancer

Pharmacokinetic Assessment of ¹⁸F-(2S,4R)-4-Fluoroglutamine in Patients with Cancer

Prognostic biomarkers for immunotherapy with ipilimumab in metastatic melanoma

Measurement of skin viscoelasticity: A non‑invasive approach in allergic contact dermatitis

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The Central Role of Inflammation Associated with Checkpoint Inhibitor Treatments

Cited by 28 publications

References 59 publications

Pharmacokinetic Assessment of 18F-(2S,4R)-4-Fluoroglutamine in Patients with Cancer

Pharmacokinetic Assessment of 18F-(2S,4R)-4-Fluoroglutamine in Patients with Cancer

Prognostic biomarkers for immunotherapy with ipilimumab in metastatic melanoma

Measurement of skin viscoelasticity: A non‑invasive approach in allergic contact dermatitis

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Product

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Pharmacokinetic Assessment of ¹⁸F-(2S,4R)-4-Fluoroglutamine in Patients with Cancer

Pharmacokinetic Assessment of ¹⁸F-(2S,4R)-4-Fluoroglutamine in Patients with Cancer