PhD Scientific Days 2023

Translational Medicine II.

Cardiotoxicity of anti-PD-1 immune checkpoint inhibitor in mice with prior cardiac ischemic injury

Előadó neve

Dr. Gergely, Tamás

Neptun code

CQN2WF

Előadó munkahelye

Semmelweis University, Department of Pharmacology and Pharmacotherapy

Előadó telefonszáma

06209504707

Előadó e-mail címe

gergely.tamas@med.semmelweis-univ.hu

Az előadás címe

Cardiotoxicity of anti-PD-1 immune checkpoint inhibitor in mice with prior cardiac ischemic injury

Szerző(k) neve és munkahelye

Tamás G. Gergely1,2,3, Tamás Kovács1,2,3, Nabil V. Sayour1,2,3, Viktória E. Tóth1,2,3, Dániel Kucsera1,2,3, Zsófia Onódi1,2,3, Imre Vörös1,2,3, Márton Kocsis1,2,3, Gábor M. Mórotz1,2,3, Péter Ferdinandy1,4, Zoltán V. Varga1,2,3

1Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest 2HCEMM-SU Cardiometabolic Immunology Research Group, Budapest
3MTA-SE Momentum Cardio-oncology and Cardioimmunology Research Group, Budapest
4Pharmahungary Group, Szeged

Bemutatás módja

Szóbeli

Szekció

Translational Medicine II.

Language of the presentation

Hungarian

Preferred session

Theoretical and Translational Medicine

Összefoglaló szövege

Introduction: Immune checkpoint inhibitors (ICI), such as monoclonal antibodies targeting programmed death ligand-1 (PD-1), revolutionized cancer treatment. However, they can lead to several cardiovascular adverse effects, ranging from mild cardiac dysfunction to fulminant, lethal myocarditis. Nevertheless, the mechanisms and risk factors behind the diverse forms of ICI-induced cardiotoxicity are not understood currently.
Hypothesis: In this study, we hypothesized that a prior cardiac ischemic injury, leading to acute immune cell infiltration and activation, but without subsequent heart failure, can exacerbate the cardiotoxicity and cardiac inflammation caused by anti-PD-1 monoclonal antibodies. Furthermore, we aimed to investigate in our mouse model whether abatacept, an inhibitor of T-cell co-stimulation, can ameliorate the ICI-induced cardiac effects.
Methods: First, we treated 8 weeks-old C57BL/6J mice with isoprenaline (ISOP group, 160 mg/kg, n = 43) or with its solvent (CON group, n = 38), to induce reversible cardiac ischemia. Validation of the ischemic injury was performed in 6 randomly selected animals from each group two days after the treatment with histology and echocardiography. After this, the animals underwent 16 weeks of recovery period, followed by echocardiography to confirm cardiac functional recovery. Here, mice from both groups were randomized to three further treatment groups: isotype control, anti-PD-1 alone, or anti-PD-1 combined with abatacept, and were treated for two weeks, with three weekly intraperitoneal injections (immune checkpoint inhibition phase). Echocardiography, qRT-PCR, and histology were performed to evaluate cardiac function and inflammation.
Results: Two days after the initial ISOP treatment, mice displayed a significant reduction in ejection fraction, and infiltration of inflammatory cells was seen on histology. During the recovery period, 8 mice from the ISOP group and one mouse from the CON died. After the immune checkpoint inhibition phase, mice with prior ischemic injury and anti-PD-1 treatment (ISOP + anti-PD-1 alone) showed significant cardiac dysfunction on echocardiography, while animals with abatacept treatment (ISOP+anti-PD-1+abatacept) showed normal cardiac function. With qRT-PCR and histology, increased infiltration of T-cells and macrophages was seen in the myocardium of the ISOP+anti-PD-1 treated group compared to CON animals, with increased expression of pro-inflammatory cytokines, including Il17a, Il23, and Ifng. However, no cardiac infiltration was seen in mice without prior ischemic injury and the pro-inflammatory cytokine response was less pronounced as well.
Conclusion: Prior cardiac ischemic injury without overt cardiac dysfunction exacerbates cardiac inflammation and cardiotoxicity induced by anti-PD-1 immune checkpoint inhibition therapy. Patients with pre-existing ischemic heart disease may be at greater risk for developing ICI-induced severe cardiac adverse events.
Funding: The work was supported by the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement no. 739593 and by a Momentum Research Grant from the Hungarian Academy of Sciences (LP-2021-14). TGG was supported by “Semmelweis 250+ Kiválósági PhD Ösztöndíj” (EFOP-3.6.3-VEKOP-16-2017-00009) and by Gedeon Richter Talentum Foundation’s scholarship.

University and Doctoral School

Semmelweis University, Doctoral School of Pharmaceutical Sciences

Supervisor

Dr. Zoltán Varga

Publication of my abstract

I do not give consent to the publication of my abstract on the website of the congress.

Kind

Szabad

Status

elfogadva

Accepted presentation method

szóbeli

Előadás fájl jóváhagyás

nem rendelkezett róla

Előadó

6119

Start

12:30

End

12:45

Authors (legacy)

Tamás G. Gergely1,2,3, Tamás Kovács1,2,3, Nabil V. Sayour1,2,3, Viktória E. Tóth1,2,3, Dániel Kucsera1,2,3, Zsófia Onódi1,2,3, Imre Vörös1,2,3, Márton Kocsis1,2,3, Gábor M. Mórotz1,2,3, Péter Ferdinandy1,4, Zoltán V. Varga1,2,3

1Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest 2HCEMM-SU Cardiometabolic Immunology Research Group, Budapest
3MTA-SE Momentum Cardio-oncology and Cardioimmunology Research Group, Budapest
4Pharmahungary Group, Szeged