Cardiotoxicity and pro-inflammatory effects of the immune checkpoint inhibitor Pembrolizumab associated to Trastuzumab

V Quagliariello, M Passariello, C Coppola, D Rea, A Barbieri, M Scherillo, M G Monti, R V Iaffaioli, M De Laurentiis, P A Ascierto, G Botti, C De Lorenzo, N Maurea

Research output: Contribution to journalArticle

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 (analyzing 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 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.

Original languageEnglish
JournalInternational Journal of Cardiology
DOIs
Publication statusPublished - 2019

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NF-kappa B
Leukotriene B4
Cardiac Myocytes
Interleukins
Immunotherapy
Inflammation
Calcium
pembrolizumab
Cardiotoxicity
Trastuzumab
Interleukin-8
Interleukin-1
Interleukin-6
Cell Survival
Fibrosis
Therapeutics
Clinical Trials
Breast Neoplasms
Survival
Neoplasms

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Cardiotoxicity and pro-inflammatory effects of the immune checkpoint inhibitor Pembrolizumab associated to Trastuzumab. / Quagliariello, V; Passariello, M; Coppola, C; Rea, D; Barbieri, A; Scherillo, M; Monti, M G; Iaffaioli, R V; De Laurentiis, M; Ascierto, P A; Botti, G; De Lorenzo, C; Maurea, N.

In: International Journal of Cardiology, 2019.

Research output: Contribution to journalArticle

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title = "Cardiotoxicity and pro-inflammatory effects of the immune checkpoint inhibitor Pembrolizumab associated to Trastuzumab",
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 (analyzing 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 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.",
author = "V Quagliariello and M Passariello and C Coppola and D Rea and A Barbieri and M Scherillo and Monti, {M G} and Iaffaioli, {R V} and {De Laurentiis}, M and Ascierto, {P A} and G Botti and {De Lorenzo}, C and N Maurea",
note = "Copyright {\circledC} 2019 Elsevier B.V. All rights reserved.",
year = "2019",
doi = "10.1016/j.ijcard.2019.05.028",
language = "English",
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TY - JOUR

T1 - Cardiotoxicity and pro-inflammatory effects of the immune checkpoint inhibitor Pembrolizumab associated to Trastuzumab

AU - Quagliariello, V

AU - Passariello, M

AU - Coppola, C

AU - Rea, D

AU - Barbieri, A

AU - Scherillo, M

AU - Monti, M G

AU - Iaffaioli, R V

AU - De Laurentiis, M

AU - Ascierto, P A

AU - Botti, G

AU - De Lorenzo, C

AU - Maurea, N

N1 - Copyright © 2019 Elsevier B.V. All rights reserved.

PY - 2019

Y1 - 2019

N2 - 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 (analyzing 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 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.

AB - 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 (analyzing 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 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.

U2 - 10.1016/j.ijcard.2019.05.028

DO - 10.1016/j.ijcard.2019.05.028

M3 - Article

C2 - 31160077

JO - International Journal of Cardiology

JF - International Journal of Cardiology

SN - 0167-5273

ER -