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
3524 - Cabazitaxel For Octogenarian Patients With Metastatic Castration-Resistant Prostate Cancer (MCRPC).
Presenter: Paolo Tralongo
Session: Poster Display session 3
Resources:
Abstract
5637 - External Validation of a Prognostic Score in First-Line Metastastic Castration-Resistant Prostate Cancer (mCRPC)
Presenter: David Lorente
Session: Poster Display session 3
Resources:
Abstract
3228 - Treatment outcomes of 3rd treatment in a real-world metastatic castration resistant prostate cancer (mCRPC) population: results from the Dutch CAPRI-registry
Presenter: Jessica Notohardjo
Session: Poster Display session 3
Resources:
Abstract
4695 - Pelvic lymph node dissection and its extent on survival benefit in prostate cancer patients with a risk of lymph node invasion>5%: a propensity score matching analysis from SEER database
Presenter: Junru Chen
Session: Poster Display session 3
Resources:
Abstract
4438 - Multi-institutional evaluation of therapeutic management for oligometastatic cancer prostate recurrence with choline-PET/CT
Presenter: Morgane Guibert-broudic
Session: Poster Display session 3
Resources:
Abstract
4574 - Safety of new androgen receptor inhibitors (ARi) in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC): a network meta-analysis of randomized controlled trials (RCT)
Presenter: Amelia Altavilla
Session: Poster Display session 3
Resources:
Abstract
3816 - Real-world use of radium-223 for treatment of metastatic castration resistant-prostate cancer (mCRPC): results from the Dutch CAPRI registry
Presenter: Malou Kuppen
Session: Poster Display session 3
Resources:
Abstract
5180 - A phase 2a study of radium-223 dichloride (Ra-223) alone or in combination with abiraterone acetate or enzalutamide in metastatic castration-resistant prostate cancer (mCRPC)
Presenter: Daniel Petrylak
Session: Poster Display session 3
Resources:
Abstract
1067 - Adding ADT to PSMA-PET/CT-guided SBRT for oligometastatic prostate cancer improves distant progression-free survival
Presenter: Carole Mercier
Session: Poster Display session 3
Resources:
Abstract
5529 - Safety and efficacy of Ac-225-PSMA-617 in metastatic castration resistant prostate cancer (mCRPC) after failure of Lu-177-PSMA
Presenter: Robert Tauber
Session: Poster Display session 3
Resources:
Abstract