Pfizer Inc., 1 Burtt Rd, Andover, MA, 01810, USA.
Precision for Medicine, 2686 Middlefield Road, Redwood City, CA, 94063, USA.
BioDrugs. 2019 Jun;33(3):275-284. doi: 10.1007/s40259-019-00354-5.
Chimeric antigen receptor (CAR) T-cell immunotherapy has gained significant attention in the past decade due to its considerable potential in the treatment of various types of malignancies, particularly hematological. While success has been achieved in a number of studies, and two CAR-T-cell products were recently approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) (YESCARTA, KYMRIAH), this treatment modality continues to present challenges for clinical development. One major potential side effect is the ability of CAR-T products to induce host immune responses. Immunogenicity induction risk factors have been shown to be associated with the presence of non-human or partially human sequences in the CAR construct, suicide domain, or other components of the CAR-T, and also with the presence of residual viral proteins or other non-human origin proteins utilized as part of the gene editing step of CAR-T production. Both humoral (antibody-based) and cellular-type responses have been described, leading to various degrees of impact on CAR-T expansion and persistence, and therefore the overall safety and clinically meaningful response of the treatment. In this article we discuss various types of immune responses specific to CAR-T therapy, their impact on treatment outcome, and methodologies used to detect them.
嵌合抗原受体 (CAR) T 细胞免疫疗法在过去十年中受到了极大关注，因为它在治疗各种类型的恶性肿瘤方面具有相当大的潜力，尤其是血液系统恶性肿瘤。虽然在许多研究中已经取得了成功，并且两种 CAR-T 细胞产品最近已被美国食品和药物管理局 (FDA) 和欧洲药品管理局 (EMA) 批准(YESCARTA、KYMRIAH)，但这种治疗方法在临床开发方面仍然存在挑战。一个主要的潜在副作用是 CAR-T 产品诱导宿主免疫反应的能力。已经表明，免疫原性诱导的风险因素与 CAR 构建体、自杀结构域或 CAR-T 的其他成分中的非人类或部分人类序列以及作为 CAR-T 生产的基因编辑步骤的一部分使用的残留病毒蛋白或其他非人类来源的蛋白的存在有关。已经描述了体液（基于抗体）和细胞类型的反应，导致对 CAR-T 扩增和持久性产生不同程度的影响，因此对治疗的整体安全性和临床有意义的反应产生影响。在本文中，我们讨论了特定于 CAR-T 治疗的各种类型的免疫反应、它们对治疗结果的影响以及用于检测它们的方法。
