T-cell Immunotherapy and Cardiovascular Disease: Chimeric Antigen Receptor T-cell and Bispecific T-cell Engager Therapies.

Chimeric antigen receptor (CAR) T-cell and bispecific T-cell engager (BiTE) therapies have revolutionized the treatment of refractory or relapsed leukemia and lymphoma. Increased use of these therapies has revealed signals of significant cardiotoxicity, including cardiomyopathy/heart failure, arrhythmia, myocardial injury, hemodynamic instability, and cardiovascular death mainly in the context of a profound inflammatory response to CAR T-cell antitumor effects known as cytokine release syndrome (CRS). Preexisting cardiovascular risk factors and disease may increase the risk of such cardiotoxicity. High index of suspicion and close monitoring is required for prompt recognition. Supportive hemodynamic care and targeted anti-IL-6 therapy, as well as possibly broader immunosuppression with corticosteroids, are the cornerstones of the management.

Novel Therapeutics for Anthracycline Induced Cardiotoxicity.

Anthracyclines remain an essential component of the treatment of many hematologic and solid organ malignancies, but has important implications on cardiovascular disease. Anthracycline induced cardiotoxicity (AIC) ranges from asymptomatic LV dysfunction to highly morbid end- stage heart failure. As cancer survivorship improves, the detection and treatment of AIC becomes more crucial to improve patient outcomes. Current treatment modalities for AIC have been largely extrapolated from treatment of conventional heart failure, but developing effective therapies specific to AIC is an area of growing research interest. This review summarizes the current evidence behind the use of neurohormonal agents, dexrazoxane, and resynchronization therapy in AIC, evaluates the clinical outcomes of advanced therapy and heart transplantation in AIC, and explores future horizons for treatment utilizing gene therapy, stem cell therapy, and mechanism-specific targets.

Immune Checkpoint Therapies and Atherosclerosis: Mechanisms and Clinical Implications: JACC State-of-the-Art Review.

Immune checkpoint inhibitor therapy has revolutionized the treatment of advanced malignancies in recent years. Numerous reports have detailed the myriad of possible adverse inflammatory effects of immune checkpoint therapies, including within the cardiovascular system. However, these reports have been largely limited to myocarditis. The critical role of inflammation and adaptive immunity in atherosclerosis has been well characterized in preclinical studies, and several emerging clinical studies indicate a potential role of immune checkpoint targeting therapies in the development and exacerbation of atherosclerosis. In this review, we provide an overview of the role of T-cell immunity in atherogenesis and describe the molecular effects and clinical associations of both approved and investigational immune checkpoint therapy on atherosclerosis. We also highlight the role of cholesterol metabolism in oncogenesis and discuss the implications of these associations on future treatment and monitoring of atherosclerotic cardiovascular disease in the oncologic population receiving immune checkpoint therapy.

Keeping immune checkpoint inhibitor myocarditis in check: advanced circulatory mechanical support as a bridge to recovery.

Immune checkpoint inhibitor (ICI)-associated myocarditis is a rare, potentially life-threatening complication of immunotherapy. We report a case of a 60-year-old female with a history of colorectal cancer treated with nivolumab immunotherapy who presented with new cardiomyopathy complicated by cardiogenic shock and ventricular arrhythmias. Treatment of ICI-associated myocarditis requires aggressive immunosuppression and supportive therapy. In this case, the patient required advanced mechanical circulatory support as a bridge to recovery. This case highlights the complexity of diagnosis, haemodynamic management, and treatment of fulminant ICI myocarditis.

Cardiotoxicities of novel cancer immunotherapies.

Immunotherapy revolutionised oncology by harnessing the native immune system to effectively treat a wide variety of malignancies even at advanced stages. Off-target immune activation leads to immune-related adverse events affecting multiple organ systems, including the cardiovascular system. In this review, we discuss the current literature describing the epidemiology, mechanisms and proposed management of cardiotoxicities related to immune checkpoint inhibitors (ICIs), chimeric antigen receptor (CAR) T-cell therapies and bispecific T-cell engagers. ICIs are monoclonal antibody antagonists that block a co-inhibitory pathway used by tumour cells to evade a T cell-mediated immune response. ICI-associated cardiotoxicities include myocarditis, pericarditis, atherosclerosis, arrhythmias and vasculitis. ICI-associated myocarditis is the most recognised and potentially fatal cardiotoxicity with mortality approaching 50%. Recently, ICI-associated dysregulation of the atherosclerotic plaque immune response with prolonged use has been linked to early progression of atherosclerosis and myocardial infarction. Treatment strategies include immunosuppression with corticosteroids and supportive care. In CAR T-cell therapy, autologous T cells are genetically engineered to express receptors targeted to cancer cells. While stimulating an effective tumour response, they also elicit a profound immune reaction called cytokine release syndrome (CRS). High-grade CRS causes significant systemic abnormalities, including cardiovascular effects such as arrhythmias, haemodynamic compromise and cardiomyopathy. Treatment with interleukin-6 inhibitors and corticosteroids is associated with improved outcomes. The evidence shows that, although uncommon, immunotherapy-related cardiovascular toxicities confer significant risk of morbidity and mortality and benefit from rapid immunosuppressive treatment. As new immunotherapies are developed and adopted, it will be imperative to closely monitor for cardiotoxicity.

Immunotherapy-Associated Cardiotoxicity of Immune Checkpoint Inhibitors and Chimeric Antigen Receptor T Cell Therapy: Diagnostic and Management Challenges and Strategies.

PURPOSE OF REVIEW: Immunotherapies have demonstrated robust clinical efficacy in treating malignancies with increasing use and FDA approvals. We review the epidemiology, risk factors, diagnosis, and treatment of immunotherapy-associated cardiovascular toxicities. RECENT FINDINGS: Cardiotoxicity is reported in patients receiving immune checkpoint inhibitors (ICI) and chimeric antigen receptor (CAR) T cell therapies. The incidence of ICI-related cardiotoxicity is above 1% and includes myocarditis, pericardial disease, arrhythmia, acute coronary syndrome, and vasculitis. The incidence of CAR T cell-associated cardiotoxicities was shown to be as high as 26% and thought to be primarily mediated by cytokine release syndrome. The presentations of cardiotoxicities are variable but are associated with significant morbidity and mortality and benefit from prompt initiation of immunosuppressive therapy. There is increasing evidence for cardiotoxicities following cancer immunotherapy. Available evidence suggests that pretreatment evaluation, close monitoring, and early intervention may reduce cardiovascular morbidity and improve outcomes in the cancer immunotherapy population.

Atheroma Susceptible to Thrombosis Exhibit Impaired Endothelial Permeability In Vivo as Assessed by Nanoparticle-Based Fluorescence Molecular Imaging.

BACKGROUND: The role of local alterations in endothelial functional integrity in atherosclerosis remains incompletely understood. This study used nanoparticle-enhanced optical molecular imaging to probe in vivo mechanisms involving impaired endothelial barrier function in experimental atherothrombosis. METHODS AND RESULTS: Atherosclerosis was induced in rabbits (n=31) using aortic balloon injury and high-cholesterol diet. Rabbits received ultrasmall superparamagnetic iron oxide nanoparticles (CLIO) derivatized with a near-infrared fluorophore (CyAm7) 24 hours before near-infrared fluorescence imaging. Rabbits were then either euthanized (n=9) or underwent a pharmacological triggering protocol to induce thrombosis (n=22). CLIO-CyAm7 nanoparticles accumulated in areas of atheroma (P<0.05 versus reference areas). On near-infrared fluorescence microscopy, CLIO-CyAm7 primarily deposited in the superficial intima within plaque macrophages, endothelial cells, and smooth muscle cells. Nanoparticle-positive areas further exhibited impaired endothelial barrier function as illuminated by Evans blue leakage. Deeper nanoparticle deposition occurred in areas of plaque neovascularization. In rabbits subject to pharmacological triggering, plaques that thrombosed exhibited significantly higher CLIO-CyAm7 accumulation compared with nonthrombosed plaques (P<0.05). In thrombosed plaques, nanoparticles accumulated preferentially at the plaque-thrombus interface. Intravascular 2-dimensional near-infrared fluorescence imaging detected nanoparticles in human coronary artery-sized atheroma in vivo (P<0.05 versus reference segments). CONCLUSIONS: Plaques that exhibit impaired in vivo endothelial permeability in cell-rich areas are susceptible to subsequent thrombosis. Molecular imaging of nanoparticle deposition may help to identify biologically high-risk atheroma.

Blood Accessibility to Fibrin in Venous Thrombosis is Thrombus Age-Dependent and Predicts Fibrinolytic Efficacy: An In Vivo Fibrin Molecular Imaging Study.

Fibrinolytic therapy of venous thromboembolism (VTE) is increasingly utilized, yet limited knowledge is available regarding in vivo mechanisms that govern fibrinolytic efficacy. In particular, it is unknown how age-dependent thrombus organization limits direct blood contact with fibrin, the target of blood-based fibrinolytic agents. Utilizing high-resolution in vivo optical molecular imaging with FTP11, a near-infrared fluorescence (NIRF) fibrin-specific reporter, here we investigated the in vivo interrelationships of blood accessibility to fibrin, thrombus age, thrombus neoendothelialization, and fibrinolysis in murine venous thrombosis (VT). In both stasis VT and non-stasis VT, NIRF microscopy showed that FTP11 fibrin binding was thrombus age-dependent. FTP11 localized to the luminal surface of early-stage VT, but only minimally to subacute VT (p<0.001). Transmission electron microscopy of early stage VT revealed direct blood cell contact with luminal fibrin-rich surfaces. In contrast, subacute VT exhibited an encasing CD31+ neoendothelial layer that limited blood cell contact with thrombus fibrin in both VT models. Next we developed a theranostic strategy to predict fibrinolytic efficacy based on the in vivo fibrin accessibility to blood NIRF signal. Mice with variably aged VT underwent FTP11 injection and intravital microscopy (IVM), followed by tissue plasminogen activator infusion to induce VT fibrinolysis. Fibrin molecular IVM revealed that early stage VT, but not subacute VT, bound FTP11 (p<0.05), and experienced higher rates of fibrinolysis and total fibrinolysis (p<0.05 vs. subacute VT). Before fibrinolysis, the baseline FTP11 NIRF signal predicted the net fibrinolysis at 60 minutes (p<0.001). Taken together, these data provide novel insights into the temporal evolution of VT and its susceptibility to therapeutic fibrinolysis. Fibrin molecular imaging may provide a theranostic strategy to identify venous thrombi amenable to fibrinolytic therapies.