scholarly journals 88 Differential cardiotoxicity of immune checkpoint inhibitors involves damps fibronectin-EDA, calgranulin, galectine-3, and associated nlrp3 inflammasome-interleukins pathway in preclinical models

2021 ◽  
Vol 23 (Supplement_G) ◽  
Author(s):  
Vincenzo Quagliariello ◽  
Annabella Di Mauro ◽  
Giosuè Scognamiglio ◽  
Ciro Cipullo ◽  
Margherita Passariello ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Vascular Inflammation ◽  
High Rate ◽  
Preclinical Models ◽  
Cardiac Tissues ◽  
2D Echocardiography ◽  
Before And After

Abstract Aims Several strategies based on immune checkpoint inhibitors (ICIs) have been developed or are under investigation for cancer therapy, opening to advantages in cancer outcomes. However, several ICIs-induced side effects emerged in these patients, especially a rare but clinically significant cardiotoxicity with high rate of mortality. We analysed the differential vasculo and cardiotoxicity of Pembrolizumab, Nivolumab and Ipilimumab in preclinical models highlighting on the molecular pathways involved. Methods C57 female mice were treated with Ipilimumab, Pembrolizumab or Nivolumab (15 mg/kg) through intraperitoneal injection for 10 days. Before and after treatments, analysis of fractional shortening, ejection fraction, radial and longitudinal strain was performed through 2D-echocardiography (Vevo 2100, Visual Sonics Fujfilm). Fibrosis, necrosis, hypertrophy and vascular/myocardial NF-kB expression were analysed through Immunohistochemistry (IHC). DAMPs, NLRP3, MyD88, p65/NF-kB and 12 cytokines have been analysed in murine myocardium and in cardiomyocytes co-incubated with hPBMC. Results In preclinical models, treatment with Nivolumab leads to increased vascular and myocardial NF-kB expression without affecting fibrosis unlike Ipilimumab which also increases cardiac collagen production. Pembrolizumab increased myocardial hypertrophy and fibrosis in cardiac tissues with a strong vascular NF-kB expression. All tested ICIs increased DAMPs, NLRP3 inflammasome-IL1β-IL18 axis and only Pembrolizumab increased significantly the MyD88 expression vs. untreated mice. Conclusions In preclinical models, Pembrolizumab exerts the most relevant cardiotoxicity compared to Nivolumab and Ipilimumab, increasing immune infiltration in the myocardium and vascular inflammation. All tested ICIs increased DAMPs, NLRP3/IL-1β and MyD88 expression, leading to pro-inflammatory cytokine storm in heart tissues.

scholarly journals Increased frequency of anti-Ma2 encephalitis associated with immune checkpoint inhibitors

2019 ◽  
Vol 6 (6) ◽  
pp. e604 ◽  
Author(s):  
Alberto Vogrig ◽  
Marine Fouret ◽  
Bastien Joubert ◽  
Géraldine Picard ◽  
Véronique Rogemond ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Clinical Presentation ◽  
Limbic Encephalitis ◽  
Checkpoint Inhibitors ◽  
Antibody Detection ◽  
Paraneoplastic Neurologic Syndrome ◽  
Clinical Difference ◽  
Clinical Syndromes ◽  
Before And After

ObjectiveTo report the induction of anti–Ma2 antibody–associated paraneoplastic neurologic syndrome (Ma2-PNS) in 6 patients after treatment with immune checkpoint inhibitors (ICIs). We also analyzed (1) patient clinical features compared with a cohort of 44 patients who developed Ma2-PNS without receiving ICI treatment and (2) the frequency of neuronal antibody detection before and after ICI implementation.MethodsRetrospective nationwide study of all patients with Ma2-PNS developed during ICI treatment between 2017 and 2018.ResultsOur series of patients included 5 men and 1 woman (median age, 63 years). The patients were receiving nivolumab (n = 3), pembrolizumab (n = 2), or a combination of nivolumab and ipilimumab (n = 1) for treatment of neoplasms that included lung (n = 4) and kidney (n = 1) cancers and pleural mesothelioma (n = 1). Clinical syndromes comprised a combination of limbic encephalitis and diencephalitis (n = 3), isolated limbic encephalitis (n = 2), and a syndrome characterized by ophthalmoplegia and head drop (n = 1). No significant clinical difference was observed between our 6 patients and the overall cohort of Ma2-PNS cases. Post-ICI Ma2-PNS accounted for 35% of the total 17 Ma2-PNS diagnosed in our center over the 2017–2018 biennium. Eight cases had been detected in the preceding biennium 2015–2016, corresponding to a 112% increase of Ma2-PNS frequency since the implementation of ICIs in France. Despite ICI withdrawal and immunotherapy, 4/6 patients died, and the remaining 2 showed a moderate to severe disability.ConclusionsWe show a clear association between ICI use and increased diagnosis of Ma2-PNS. Physicians need to be aware that ICIs can trigger Ma2-PNS because clinical presentation can be challenging.

Preclinical models of breast cancer: Two-way shuttles for immune checkpoint inhibitors from and to patient bedside

2019 ◽  
Vol 122 ◽  
pp. 22-41
Author(s):  
Amal Kamal Abdel-Aziz ◽  
Mona Kamal Saadeldin ◽  
Paolo D'Amico ◽  
Stefania Orecchioni ◽  
Francesco Bertolini ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Preclinical Models

Changes in skeletal muscle mass during PD-1 and PD-L1 checkpoint inhibitor therapy in advanced-stage non-small cell lung cancer patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14061-e14061
Author(s):  
Maneet Multani ◽  
Imad Tarhoni ◽  
Ibdihaj Fughhi ◽  
Sanjib Basu ◽  
Marta Batus ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Skeletal Muscle ◽  
Overall Survival ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Cancer Cachexia ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
Before And After

e14061 Background: Severe skeletal muscle loss (sarcopenia) is a principle property of cancer cachexia and is found to be a hallmark of poor prognosis in patients with advanced non-small cell lung cancer (NSCLC). With the latest advancements of PD-1 and PD-L1 checkpoint immunotherapy, we aim to examine changes in sarcopenia before and after treatment with these agents. Methods: : In this study, patients with stage IIIB/IV NSCLC receiving PD-1 and PD-L1 immune checkpoint inhibitors were evaluated. CT images obtained before and after treatment were used for skeletal muscle analyses with the SliceOmatic software (Tomovision) at the level of the first lumbar vertebra. Skeletal muscle index (SMI) was assessed by measuring the cross-sectional muscle area, normalized to patient height. Height, weight, disease progression status, and overall survival (OS) was extracted from EPIC under an IRB-approved protocol. Data was then compared with baseline and clinical outcome was used for survival analysis. Results: In 100 pre-treatment subjects (48% women, mean age of 68), patients with < 32 cm2/m2 SMI had a significantly lower OS (median OS = 1.41 mo, n = 16) compared to those with SMI > 32 cm2/m2 (median OS = 9.44 mo, n = 84, p = 0.024). In 74 patients with pre- and post-treatment data, (avg 2.66 mo interval) an increase of > 5% SMI from baseline occurred in 17 (23%) patients, while a decrease of > 5% SMI from baseline occurred in 26 (35%) patients. Mean reduction in SMI from pre- to post-immunotherapy was 0.921 cm2/m2 while median reduction in SMI was 1.087 cm2/m2. Conclusions: Patients with high pretreatment SMI had a significantly greater overall survival when compared to those with low pretreatment SMI. Two-thirds of patients experienced stability or increase in SMI during immunotherapy. These results suggest that immune checkpoint inhibitors may dampen mechanisms of cancer cachexia in some patients.

scholarly journals PATH-17. HYPERPROGRESSIVE DISEASE IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMAS TREATED WITH IMMUNE CHECKPOINT INHIBITORS OR CYTOTOXIC THERAPIES

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi146-vi146
Author(s):  
Laura Donovan ◽  
Samuel Gedailovich ◽  
Adela Joanta-Gomez ◽  
Andrew Lassman ◽  
Fabio Iwamoto
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Fold Increase ◽  
Tumor Growth Rate ◽  
Control Group ◽  
High Grade ◽  
Before And After ◽  
High Grade Gliomas ◽  
Hyperprogressive Disease

Abstract BACKGROUND Hyperprogressive disease (HPD), defined as a ≥ 2-fold increase in tumor growth rate (TGR) compared to baseline following initiation of immune checkpoint inhibitors (ICI), has been described in solid tumors but is not well explored high grade gliomas (HGG). We investigated the rate of HPD in HGG patients receiving ICIs for first or second recurrence compared to those treated with non-immunotherapy agents. METHODS Patients with HGG receiving ICIs for 1st or 2nd recurrence compared to a controls receiving other therapies at first progression. Prior or concurrent bevacizumab or anti-VEGFR were exclusionary due to pseudoresponse and decreased enhancement with these drugs. HPD was calculated by comparing TGR immediately before and after treatment. RESULTS 49 patients met inclusion criteria (27 ICI, 25 control). 25/27 patients receiving ICIs and 20/22 patients in the control group were evaluable in the analysis. The ICI group included 60% men (15/25) and 80% (20/25) had a diagnosis of primary GBM. 68% were treated at first progression (17/25). Controls were 80% male (16/20) and all had a diagnosis of primary GBM. 28% (7/25) of patients met criteria for HPD in the ICI group compared to 4/20 controls (20%). Median OS in patients with primary GBM was 26mo in the ICI group vs. 15.9mo in controls. Median survival past progression in patients with primary GBM receiving ICI for 1st recurrence (13/25) was 12mo vs. 10.6mo in controls. 40% of patients in both groups had next generation sequencing (5/7 with HPD in ICI and 2/4 in control). EGFR alterations and MDM2/4 amplifications were not associated with HPD whereas PTEN mutations were more common in HPD (71% vs. 33.3%). CONCLUSION HPD is observed in patients with HGG treated with ICI at comparable rates to those with other cancers, but was also observed in 20% of patients receiving other therapies.

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