Abstract 3267
Background
Recently, the world of oncology has been revolutionized by immunotherapy which has shown 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 cardiactoxicity has not been properly studied.
Methods
In human fetal cardiomyocytes exposed to Trastuzumab and Pembrolizumab alone or in combination, we studied: the cell viability (through MTS assay), the quantification of intracellular calcium, Interleukin 1β, 6 and 8; the expression of NF-kB and Leukotrienes. Preclinical studies were also performed in C57BL6 mice dividing them in 4 groups (6/group: untreated mice (control) ; mice treated with Pembrolizumab at 10 mg/Kg for the first dose, followed by 5 mg/Kg dose every 5 days until the study end point, according to literature; mice treated with Trastuzumab at 10 mg/kg/day; mice treated with both drugs in combination. After the administration period, we analyzed the fibrosis and inflammation in heart tissues.
Results
The combination of Pembrolizumab and Trastuzumab increases the intracellular calcium overload (of 3 times compared to untreated cells) and reduces the cardiomyocytes viability (of 65 and 20-25%, compared to untreated and Pembrolizumab or Trastuzumab treated cells, respectively; p < 0.01 for both). 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 cardiac fibrosis and Interleukins expression of 40-50 % compared to the single treatments; the expression of NF-kB and Leukotriene B4 were also significantly increased, compared to the single treatments.
Conclusions
The association of Pembrolizumab and Trastuzumab exerts pro-inflammatory and pro fibrotic effects in the heart; these effects are mainly mediated by overexpression of NF-kB and Leukotriene B4 related pathways and pro-inflamamtory cytokines.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
This work was funded by the “Ricerca Corrente” grant from the Italian Ministry of Health.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
5655 - Bioactivation of napabucasin triggers reactive oxygen species–mediated cancer cell death
Presenter: Fieke Froeling
Session: Poster Display session 3
Resources:
Abstract
4097 - Targeting NRG1-fusions in multiple tumour types: Afatinib as a novel potential treatment option
Presenter: Stephen V Liu
Session: Poster Display session 3
Resources:
Abstract
1129 - Aspirin and Ticagrelor for the prevention of tumour cell induced platelet aggregation
Presenter: Meera Chauhan
Session: Poster Display session 3
Resources:
Abstract
4514 - Pharmacokinetic/ pharmacodynamic (PK/PD) exposure-response characterization of GSK3359609 (GSK609) from INDUCE-1, a phase I open-label study
Presenter: Michele Maio
Session: Poster Display session 3
Resources:
Abstract
5169 - In vitro functional interrogation of viable Circulating Tumor Associated Cells (C-TACs) for evaluating Platin resistance.
Presenter: Stefan Schuster
Session: Poster Display session 3
Resources:
Abstract
5827 - Targeting ARG2 as a novel therapeutic approach for cancer
Presenter: Marcin Grzybowski
Session: Poster Display session 3
Resources:
Abstract
3129 - MPS1 and PLK1 as new therapy targets in TP53 mutated solid tumors
Presenter: Balazs Gyorffy
Session: Poster Display session 3
Resources:
Abstract
2129 - The Tumor Static Exposure (TSE) concept & utility: application to combination treatment of radiation and radiosensitizing agent in tumor xenograft experiments
Presenter: Samer El Bawab
Session: Poster Display session 3
Resources:
Abstract
1814 - General Methodology to Optimize Tumor Treating Fields Delivery Utilizing Numerical Simulations
Presenter: Noa Urman
Session: Poster Display session 3
Resources:
Abstract
3010 - The Australian Exceptional Responders Program: a National collaboration
Presenter: Megan Barnet
Session: Poster Display session 3
Resources:
Abstract