Tumor necrosis factor alpha blockade prevents immune checkpoint inhibitor therapy-related cardiotoxicity
Authors: Michel L , Hendgen-Cotta U.B , Mincu R.I , Helfrich I , Korste S , Mrotzek S.M , Schadendorf D , Rassaf T , Totzeck M 
Published: November 2020

Abstract

Background
Increasing use of immune checkpoint inhibitor (ICI) therapy has recently been associated with latent left ventricular dysfunction as a common cardiotoxic side effect during early therapy. Considering the potential impact on morbidity and mortality, strategies to prevent ICI-related cardiotoxicity are urgently needed, but established immunosuppressive measures prevent the anti-tumor effect of the ICI therapy, thereby limiting its applicability to severe, life-threatening cases. Recently, tumor necrosis factor alpha (TNFα) blockade was shown to prevent ICI-related gut toxicity while preserving, or even enhancing, anti-tumor efficacy.

Purpose
This study aims to investigate a cardioprotective effect of TNFα blockade during anti programmed death 1 (PD1) ICI therapy in a preclinical model as a basis for a potential new, preventive therapeutic approach for ICI-related cardiotoxicity.

Methods
A melanoma mouse model was established as the basis to study PD1 blocking therapy and protective measures in a preclinical setting. Mice were subcutaneously transplanted with a syngeneic melanoma cell line and treated with anti-PD1 antibodies for 15 days. Response to therapy was monitored by assessment of tumor size. Cardiotoxicity was confirmed by mouse echocardiography. Mice were then simultaneously treated with anti-PD1 antibodies and TNFα-blocking antibodies. A cardioprotective effect was evaluated by echocardiography and flow cytometry was used to characterize myocardial immune cells.

Results
Mice receiving anti-PD1 showed smaller tumor sizes with increased immune cell infiltration compared to control littermates as a sign for a profound response to therapy. Cardiotoxicity was confirmed as demonstrated by reduced left ventricular ejection fraction and reduced global radial strain in anti-PD1-treated mice. Mice receiving anti-PD1 ICI therapy showed 2-fold elevated concentrations of CD4+ and CD8+ T-lymphocytes in the murine heart as determined by flow cytometry. CD44 expression was upregulated in cytotoxic T-cells as a marker of enhanced T-cell activity in anti-PD1 treated mice. Administration of TNFα-blocking antibodies did not alter tumor sizes during anti-PD1 treatment as a sign for a sustained response to therapy. Remarkably, mice receiving TNFα-blocking antibodies together with anti-PD1 ICI therapy showed increased left ventricular function compared to mice receiving anti-PD1 monotherapy. Flow cytometry revealed increased expression of T cell exhaustion markers in mice receiving TNFα blockade as a potential underlying mechanism.

Conclusions
ICI therapy targeting PD1 induces latent cardiotoxicity with left ventricular dysfunction. TNFα blockade may serve as a novel cardioprotective treatment without compromising the anti-tumor efficacy of ICI therapy. Prospective studies are needed to further characterize ICI-related cardiotoxicity in patients and to evaluate the cardioprotective effect of TNFα blockade.

Funding Acknowledgement
Type of funding source: Public hospital(s). Main funding source(s): IFORES research grant, Medical Faculty, University Duisburg-Essen, Essen, Germany