Journal article Open Access

Evidences of CTLA-4 and PD-1 Blocking Agents-Induced Cardiotoxicity in Cellular and Preclinical Models

Vincenzo Quagliariello; Margherita Passariello; Domenica Rea; Antonio Barbieri; Martina Iovine; Annamaria Bonelli; Antonietta Caronna; Gerardo Botti; Claudia De Lorenzo; Nicola Maurea


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    "description": "<p>Several strategies based on immune checkpoint inhibitors (ICIs) have been developed for cancer therapy, opening to advantages in cancer outcomes. However, several ICI-induced side effects have emerged in these patients, especially a rare but clinically significant cardiotoxicity with high rate of mortality. We studied the cytotoxic and pro-inflammatory properties of Ipilimumab and Nivolumab, the underlying pathways and cytokine storm involved. Methods: Co-cultures of human cardiomyocytes and lymphocytes were exposed to Ipilimumab or Nivolumab; cell viability and expression of leukotrienes, NLRP3, MyD88, and p65/NF-kB were performed. C57 mice were treated with Ipilimumab (15 mg/kg); analysis of fractional shortening, ejection fraction, radial and longitudinal strain were made before and after treatments through 2D-echocardiography. Expression of NLRP3, MyD88, p65/NF-kB, and 12 cytokines were analyzed in murine myocardium. Results: Nivolumab and Ipilimumab exert effective anticancer, but also significant cardiotoxic effects in co-cultures of lymphocytes and tumor or cardiac cells. Both ICIs increased NLRP3, MyD88, and p65/NF-kB expression compared to untreated cells, however, the most pro-inflammatory and cardiotoxic effects were seen after exposure to Ipilimumab. Mice treated with Ipilimumab showed a significant decrease in fractional shortening and radial strain with respect to untreated mice, coupled with a significant increase in myocardial expression of NLRP3, MyD88, and several interleukins. Conclusions: Nivolumab and Ipilimumab exert cytotoxic effects mediated by the NLRP3/IL-1&beta; and MyD88 pathways, leading to pro-inflammatory cytokine storm in heart tissue.</p>", 
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    "title": "Evidences of CTLA-4 and PD-1 Blocking Agents-Induced Cardiotoxicity in Cellular and Preclinical Models", 
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    "publication_date": "2020-10-19", 
    "creators": [
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        "affiliation": "Division of Cardiology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale", 
        "name": "Vincenzo Quagliariello"
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      {
        "affiliation": "CEINGE\u2014Biotecnologie Avanzate s.c.a.r.l.,", 
        "name": "Margherita Passariello"
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      {
        "affiliation": "Animal Facility, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale", 
        "name": "Domenica Rea"
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      {
        "affiliation": "Animal Facility, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale", 
        "name": "Antonio Barbieri"
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      {
        "affiliation": "Division of Cardiology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale", 
        "name": "Martina Iovine"
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        "affiliation": "Division of Cardiology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale", 
        "name": "Annamaria Bonelli"
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      {
        "affiliation": "Division of Cardiology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale", 
        "name": "Antonietta Caronna"
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      {
        "affiliation": "Scientific Direction, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale", 
        "name": "Gerardo Botti"
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      {
        "affiliation": "Department of Molecular Medicine and Medical Biotechnology, University of Naples \"Federico II\"", 
        "name": "Claudia De Lorenzo"
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      {
        "affiliation": "Division of Cardiology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale", 
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