br Immune checkpoint inhibitors ICI br
3.4. Immune checkpoint inhibitors (ICI)
In addition to cytotoxic chemotherapy and small molecule inhibitors a new class of agents, ICI, has recently emerged as another pillar of sys-temic cancer therapy. Approved drugs include Calpain Inhibitor I directed against programmed cell death receptor 1 (PD-1), programmed-cell death ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) .
T-cells interact with target tissues through multiple receptor–ligand interactions. PD-1 on T-cells and its ligand PD-L1 on cancer cells as well as microenvironmental cells are prototypic regulators of immune acti-vation. PD-1-related signaling promotes self-tolerance and prevents au-toimmunity by locally suppressing the immune system through anergization and apoptosis of antigen-specific T cells and diminished apoptosis of regulatory T cells . Tumor cells may express PD-L1, and the interaction with PD-1 on T-cells results in immune evasion. [76,77] Clinically, ICI therapy can induce a fulminant lymphocytic myo-carditis with high mortality. An autoimmune reaction against myocar-dial antigens is the assumed underlying pathomechanism in these patients.
Based on early signals of clinical activity, which triggered pivotal tri-als, ICI were first approved in cutaneous malignant melanoma, a disease, which is practically insensitive to cytotoxic agents. Today ICI are stan-dard of care in the management of metastatic melanoma and have also moved into adjuvant therapy for high-risk populations. Due to their unique mode of action, ICI are potentially applicable in numerous cancer entities, and thus have been studied in multiple clinical trials. Currently, ICI are approved standard of care in patients with metastatic non-small cell lung cancer, bladder cancer, renal cell cancer, head and neck cancers, Hodgkin's disease, and Merkel cell cancer. More entities are continuously added to this list. Interestingly, FDA has also granted entity-independent approval for PD-1 antibodies in patients with microsatellite-instable cancers. The power of ICI is their potential to
induce long-term remissions and disease-control in patients with met-astatic cancers who previously had very limited life expectancy. Unfor-tunately only an imprecisely defined subgroup of cancer patients derives this benefit so far. However, considerable numbers of patients already enjoy long-term survival in cancers that are frequently associ-ated with significant cardiovascular comorbidities (e.g. lung cancer, bladder cancer). These patients may experience not only early but also late toxicities from these new therapeutic immune interventions. Adverse events associated with ICI range from arrhythmias to myocar-ditis (Supplementary Table 1) [5,6,74,77–79]. Although infrequent, cardiotoxicity may be life threatening. The molecular basis of these adverse events remains incompletely understood, but immune mecha-nisms are clearly expected. The development of auto-reactive antibod-ies against cardiomyocytes (e.g., contractile elements) has been suggested but not confirmed in human biopsies [78,80].
4. Diagnosis of cardiotoxicity
Currently the main strategy in cardio-oncology is early detection and treatment of cardiovascular disease . Risk factors predispose to cardiotoxicity and/or result from cancer therapy. The detection of sub-clinical structural heart disease is more challenging. There are currently no data and no general recommendations for the use of biomarkers in cardio-oncology patients, but troponin and brain natriuretic peptide (BNP) levels are routinely measured in cardio-oncology centers. In tumor patients receiving chemotherapy, troponin elevation has been used to reflect the susceptibility to cardiomyopathy-inducing drugs, particularly anthracycline therapies [16,82,83]. Indeed, the combined use of troponin measurement and echocardiography has been superior in the diagnosis of cardiotoxicity over echocardiography alone . Fu-ture trials must assess the value of troponin in larger cancer cohorts for the exact definition of biomarker distribution and cut-off levels. Cur-rently, troponin should be assessed in patients before and during anthracycline therapy, during checkpoint inhibitor medication, and whenever ischemic heart disease is suspected.
Echocardiography, particularly 2D assessment of left ventricular ejection fraction, remains the standard method for the evaluation of car-diac function, but 3D, when available, is more precise . Cardiotoxicity is defined as a decrease in 3D ejection fraction by 10% to a level below 50% . Speckle tracking global longitudinal strain (GLS) imaging has comparably high specificity and sensitivity, low intra- and inter-observer variability, and provides comparable results to magnetic reso-nance imaging (MRI) . In patients undergoing bone marrow trans-plantation for either non-Hodgkin's lymphoma or leukemia, early GLS changes predict changes in ejection fraction after 1 year . Compara-ble results were obtained in breast cancer patients under combined treatment with anthracycline and trastuzumab . MRI remains the gold standard for the quantification of cardiac dimensions and ventric-ular function, but is often only used as a secondary option – mainly in patients with poor echocardiography windows or inconclusive results.