Title : Immune checkpoint inhibitors (ICIs) and immune-related adverse drug reactions: Focus on their neurotoxicity
Harnessing the power of the immune system to target cancer has been the aim of scientific research for over centuries. The irruption of immune checkpoint inhibitors (ICI) in 2011 has changed the therapeutic landscape of several tumors and, consequently, the prognosis of cancer patients. To survive, cancer cells must develop mechanisms to evade the immune response and the key role in the regulation of the immune response is given by the activation of T cells, in which stimulatory and inhibitory immune checkpoints are involved. Immune checkpoint inhibitors (ICI) are humanized monoclonal antibodies which block the interaction between the checkpoint receptors of inhibitory type (CTLA-4, PD-1, PDL-1) expressed on T cells and their ligands on antigen-presenting cells or tumor cells. Therefore, a cytotoxic T cell response can emerge and provide powerful antitumoral activity. To date, seven ICIs are available in the Europe, divided into three different groups, based on their target: anti-CTLA-4 (Ipilimumab), anti-PD-1 (Nivolumab, Pembrolizumab, and Cemiplimab) and anti-PDL-1 (Atezolimumab, Durvalumab and Avelumab). Due to ICIs mechanism of action is not tissue antigen-specific and not limited to the tumor microenvironment, the use of these drugs can produce a broad spectrum of toxicities, known as immune-related adverse events (irAEs). As reported in the literature, dermatologic, gastrointestinal and endocrine toxicities have been commonly described and they can occur in up to 65% of ICI-exposed patients, in addition to more severe toxicities affecting cardiac, pulmonary and neurological functions. Neurological immune-related adverse events (NirAEs) are rare, and affecting both the peripheral and central nervous systems, often requiring treatment discontinuation and sometimes with a significant deterioration of patients’ quality of life. Evidence on neurological complications by ICIs is limited, most of which are brief safety reports from clinical trials or individual case reports, besides to few epidemiological data from meta-analysis of clinical trials and pharmacovigilance databases. Currently, the pathogenesis of these neurological complications is not completely understood, and this neurotoxicity remains one of the most ambiguous of all irAEs associated with ICI. As a result, the optimal management of NirAEs has not yet been established, even if several Scientific Societies have provided expert consensus-based recommendations regarding the treatment of neurotoxicity based upon its severity. In conclusion, IrAEs presents a great challenge in modern oncology and innovation in the research of irAEs due to immunotherapy in the future probably could define sophisticated biomarkers to identify patients who are not only responsive to such therapies but also at higher risk of developing toxicity. These advances will support optimal care for all patients receiving ICIs.