Department of Autoimmune Diseases, ICMiD, Barcelona, Spain; Department of Medicine, University of Barcelona, Hospital Clínic, Barcelona, Spain.
Department of Autoimmune Diseases, ICMiD, Barcelona, Spain; Consejo Nacional de Ciencia y Tecnología (CONACYT), México DF, Mexico.
Pharmacol Ther. 2022 Sep;237:108250. doi: 10.1016/j.pharmthera.2022.108250. Epub 2022 Jul 14.
Immunotherapies are designed to target a specific molecule of the immune system and emerged at the end of the last century as effective therapies the treatment of a widening spectrum of inflammatory diseases. Paradoxically, their use was quickly linked to the development of autoimmune disorders, whose treatment indications often include the very biological agent producing the adverse event. The scenario has changed dramatically in recent years due to the increasing use of immunotherapies in patients with solid cancers (mainly checkpoint inhibitors, but also tyrosine-kinase inhibitors and others). Cancer immunotherapies are broadly defined as therapies directly or indirectly targeting any component of the immune system involved in the immune response against cancer. These therapies include different molecules (monoclonal antibodies, small proteins, fusion proteins) that target specific proteins of cancer or immune cells. A key challenge that has emerged with the progressive broad implementation of these treatments in daily practice has been the collateral side effects on the immune system of treatment, which may lead to immune-related adverse events (irAEs). The cumulated number of cases of irAEs related to cancer immunotherapies has increased exponentially during this century. As the objective of cancer immunotherapy is to stimulate the immune system, these autoimmune and inflammatory irAEs were expected. The pharmacological targeting of kinases has led to a significant change in the therapeutic management of cancer. About one-third of all protein targets under research in the pharmaceutical industry are kinase inhibitors, overwhelmingly used in the treatment of malignancies. Very few studies have reviewed the broad scenario of irAEs related to kinase inhibitors, in contrast with the large number of studies published on irAEs caused by checkpoint inhibitors, with an often-fragmented view according to the specialty. The purpose of this review is to update current knowledge on the wide pharmacological and phenotypic scenario of irAEs associated with kinase inhibitors from a multidisciplinary perspective.
免疫疗法旨在针对免疫系统的特定分子，是上世纪末出现的有效疗法，可治疗不断扩大的炎症性疾病谱。具有讽刺意味的是，它们的使用很快与自身免疫性疾病的发展联系在一起，而这些疾病的治疗适应症通常包括产生不良事件的生物制剂。近年来，由于免疫疗法在实体瘤患者中的广泛应用（主要是检查点抑制剂，但也有酪氨酸激酶抑制剂等），这种情况发生了巨大变化。癌症免疫疗法被广泛定义为直接或间接靶向参与针对癌症免疫反应的免疫系统任何成分的疗法。这些疗法包括针对癌症或免疫细胞特定蛋白的不同分子（单克隆抗体、小分子、融合蛋白）。随着这些治疗方法在日常实践中的广泛应用，一个关键挑战是治疗对免疫系统的潜在副作用，这可能导致免疫相关不良事件（irAEs）。本世纪以来，与癌症免疫疗法相关的 irAEs 病例数量呈指数级增长。由于癌症免疫疗法的目的是刺激免疫系统，因此预计会出现这些自身免疫和炎症性 irAEs。激酶的药理学靶向已导致癌症治疗管理的重大变化。制药行业研究的所有蛋白质靶点中，约有三分之一是激酶抑制剂，它们在恶性肿瘤的治疗中被广泛使用。很少有研究综述与激酶抑制剂相关的 irAEs 的广泛情况，相比之下，发表的关于检查点抑制剂引起的 irAEs 的研究数量很多，而且往往根据专业领域进行碎片化观察。本综述的目的是从多学科角度更新与激酶抑制剂相关的 irAEs 的广泛药理学和表型情况的最新知识。
