Pharmaceutical Sciences - Posters E
Tamás Kovács1,2,3, Tamás G Gergely1,2,3, Nabil V Sayour1,2,3, Dániel Kucsera1,2,3, Viktória E Tóth1,2,3, Varga V Zoltán1,2,3
1Deparment of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, 2HCEMM-SU Cardiometabolic Immunology Research Group, Budapest,
3HAS-SU Momentum Cardiooncology and Cardioimmunology Research Group, Budapest
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of many types of cancer. However, the use of ICIs can result in immune-related adverse events including cardiotoxicity. To treat life-threatening ICI-induced side effects, current therapeutic options are limited, often resulting in discontinuation of ICI therapy. The combination of ICIs with another class of anticancer drug that increases treatment efficacy and at the same time mitigating side effects would be extremely valuable in the clinical practice.
PARP inhibitors are indicated in primary peritoneal, fallopian tube and pancreatic cancers, as well as in advanced ovarian carcinomas, where use of ICI is limited. Several clinical trials are currently underway to investigate the use of PARP inhibitors in combination with ICIs in different cancer types, including metastatic melanoma.
PARP inhibitors have been shown to have beneficial effects in heart failure in preclinical models, in addition to their anti-cancer activity. However, the combined effect of PARP and immune checkpoint inhibition on the heart has not been previously investigated.
We aimed to test our hypothesis in a preclinical mouse model, to see if combination of a clinically used PARP inhibitor (Olaparib, OLA) and an ICI (anti-PD1) would reduce ICI-induced cardiotoxicity. We randomized 8 weeks old C57Bl/6J mice based on their baseline (BL) echocardiography and weight to the following groups: Control (CON), ICI-treated, OLA-treated with corresponding vehicle controls, and ICI+OLA combination treatment. The mice were injected intraperitoneally with 10 mg/kg Olaparib every day and with 200 µg anti-PD1 monoclonal antibody 6 times during the two weeks of the study. Before termination (TRM) we measured the echocardiographic parameters of the animals.
The results show that the anti-PD1 treatment led to reduced cardiac function. We compared treatment groups and time points with repeated measures two-way ANOVA, post-hoc Sidak’s test. Ejection fraction (EF) significantly decreased in ICI group (45,74±1,78%) compared to CON (54,75±1,15%) and compared to ICI-BL (54,63±1,37%). No significant unfavourable change in echo parameters was observed with OLA treatment, in fact the combination therapy (ICI+OLA) resulted in significantly (padj=0,0029) better EF than ICI suggesting the cardioprotective effect of OLA.
Following the successful confirmation of the cardioprotective effect of Olaparib, we aim to further investigate the mechanisms by which the PARP inhibitor mitigates and protects against ICI cardiotoxicity.