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
2421 - Lenvatinib plus PD-1 blockade in advanced bile tract carcinoma.
Presenter: Jianzhen Lin
Session: Poster Display session 3
Resources:
Abstract
5368 - Durvalumab and Paclitaxel Combination for treatment of metastatic triple negative breast cancer is safe with very promising efficacy
Presenter: Hazem Ghebeh
Session: Poster Display session 3
Resources:
Abstract
1520 - A prospective cohort study on the pharmacokinetics of nivolumab in metastatic non-small cell lung cancer, melanoma, and renal cell cancer patients
Presenter: Daan Hurkmans
Session: Poster Display session 3
Resources:
Abstract
1603 - Safety and clinical activity of subcutaneously (SC) administered anti-PD-1 antibody PF-06801591 in phase I dose-expansion cohorts of locally advanced or metastatic non-small-cell lung cancer (NSCLC) and urothelial carcinoma (UC)
Presenter: Byoung Cho
Session: Poster Display session 3
Resources:
Abstract
3922 - Development of the Functional Assessment of Cancer Therapy-Immune Checkpoint Modulator (FACT-ICM): A scale to measure quality of life in cancer patients treated with ICMs
Presenter: Aaron Hansen
Session: Poster Display session 3
Resources:
Abstract
2408 - Immune checkpoint inhibitors (ICIs) as “chemotherapy (Ctx) sensitization” strategy in advanced solid tumors
Presenter: Francisco Javier Ros Montana
Session: Poster Display session 3
Resources:
Abstract
3612 - Validation of progression-free survival (PFS) as surrogate endpoint in randomised trials of immune checkpoint inhibitors in advanced solid cancers
Presenter: Peey Sei Kok
Session: Poster Display session 3
Resources:
Abstract
3827 - Pharmacokinetic (PK) analysis of weight-based and fixed dose cemiplimab in patients (pts) with advanced malignancies
Presenter: Michael Migden
Session: Poster Display session 3
Resources:
Abstract
2120 - A burst of highly differentiated CD4 TL identifies a subset of fast progressors, and correlates with hyperprogressive disease in NSCLC patients treated with ICI
Presenter: Hugo Arasanz
Session: Poster Display session 3
Resources:
Abstract
4254 - Nivolumab treatment in advanced non-small cell lung cancer (aNSCLC): a French nationwide retrospective cohort (UNIVOC Study)
Presenter: Christos Chouaid
Session: Poster Display session 3
Resources:
Abstract