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Cardiotoxicity and pro-inflammatory effects of the immune checkpoint inhibitor Pembrolizumab associated to Trastuzumab
- Publication Year :
- 2019
-
Abstract
- Background The immunotherapy has revolutionized the world of oncology in the last decades with considerable advantages in terms of overall survival in cancer patients. The association of Pembrolizumab and Trastuzumab was recently proposed in clinical trials for the treatment of Trastuzumab-resistant advanced HER2-positive breast cancer. Although immunotherapies are frequently associated with a wide spectrum of immune-related adverse events, the cardiac toxicity has not been properly studied. Purpose We studied, for the first time, the putative cardiotoxic and pro-inflammatory effects of Pembrolizumab associated to Trastuzumab. Methods Cell viability, intracellular calcium quantification and pro-inflammatory studies (analyses of the production of Interleukin 1β, 6 and 8, the expression of NF-kB and Leukotriene B4) were performed in human fetal cardiomyocytes. Preclinical studies were also performed in C57BL6 mice by analyzing fibrosis and inflammation in heart tissues. Results The combination of Pembrolizumab and Trastuzumab leads to an increase of the intracellular calcium overload (of 3 times compared to untreated cells) and to a reduction of the cardiomyocytes viability (of 65 and 20–25%, compared to untreated and Pembrolizumab or Trastuzumab treated cells, respectively) indicating cardiotoxic effects. Notably, combination therapy increases the inflammation of cardiomyocytes by enhancing the expression of NF-kB and Interleukins. Moreover, in preclinical models, the association of Pembrolizumab and Trastuzumab increases the Interleukins expression of 40–50% compared to the single treatments; the expression of NF-kB and Leukotriene B4 was also increased. Conclusion Pembrolizumab associated to Trastuzumab leads to strong cardiac pro-inflammatory effects mediated by overexpression of NF-kB and Leukotriene B4 related pathways.
- Subjects :
- Combination therapy
Cell Survival
Leukotriene B4
medicine.medical_treatment
Inflammation
Pembrolizumab
030204 cardiovascular system & hematology
Antibodies, Monoclonal, Humanized
Cardiotoxins
Mice
03 medical and health sciences
chemistry.chemical_compound
Antineoplastic Agents, Immunological
0302 clinical medicine
Trastuzumab
Animals
Humans
Medicine
Myocytes, Cardiac
030212 general & internal medicine
skin and connective tissue diseases
Cardiotoxicity
business.industry
Cancer
Immunotherapy
Interleukin
medicine.disease
Coculture Techniques
Mice, Inbred C57BL
Drug Combinations
Cardio-oncology
chemistry
Cancer research
Female
Inflammation Mediators
medicine.symptom
Cardiology and Cardiovascular Medicine
business
medicine.drug
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....93cf0325727fcc210c44ac62a6d93928