Page Audrey, Fusil Floriane, Cosset François-Loïc
CIRICentre International de Recherche en Infectiologie, Univ Lyon, Université Claude Bernard Lyon 1, Inserm, U1111, CNRS, UMR5308, ENS Lyon, 46 allée d'Italie, F-69007 Lyon, France.
Cancers (Basel). 2020 Apr 13;12(4):962. doi: 10.3390/cancers12040962.
Cancers represent highly significant health issues and the options for their treatment are often not efficient to cure the disease. Immunotherapy strategies have been developed to modulate the patient's immune system in order to eradicate cancerous cells. For instance, passive immunization consists in the administration at high doses of exogenously produced monoclonal antibodies directed either against tumor antigen or against immune checkpoint inhibitors. Its main advantage is that it provides immediate immunity, though during a relatively short period, which consequently requires frequent injections. To circumvent this limitation, several approaches, reviewed here, have emerged to induce in vivo antibody secretion at physiological doses. Gene delivery vectors, such as adenoviral vectors or adeno-associated vectors, have been designed to induce antibody secretion in vivo after in situ cell modification, and have driven significant improvements in several cancer models. However, anti-idiotypic antibodies and escape mutants have been detected, probably because of both the continuous expression of antibodies and their expression by unspecialized cell types. To overcome these hurdles, adoptive transfer of genetically modified B cells that secrete antibodies either constitutively or in a regulated manner have been developed by ex vivo transgene insertion with viral vectors. Recently, with the emergence of gene editing technologies, the endogenous B cell receptor loci of B cells have been modified with the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated endonuclease (Cas-9) system to change their specificity in order to target a given antigen. The expression of the modified BCR gene hence follows the endogenous regulation mechanisms, which may prevent or at least reduce side effects. Although these approaches seem promising for cancer treatments, major questions, such as the persistence and the re-activation potential of these engineered cells, remain to be addressed in clinically relevant animal models before translation to humans.
癌症是极为严重的健康问题，其治疗方案往往难以有效治愈疾病。人们已开发出免疫疗法策略来调节患者的免疫系统，以根除癌细胞。例如，被动免疫是指高剂量注射外源性产生的单克隆抗体，这些抗体要么针对肿瘤抗原，要么针对免疫检查点抑制剂。其主要优点是能立即提供免疫力，尽管持续时间相对较短，因此需要频繁注射。为克服这一局限性，本文综述了几种在生理剂量下诱导体内抗体分泌的方法。基因递送载体，如腺病毒载体或腺相关载体，已被设计用于在原位细胞修饰后诱导体内抗体分泌，并在多种癌症模型中取得了显著进展。然而，已检测到抗独特型抗体和逃逸突变体，这可能是由于抗体的持续表达及其在非特异性细胞类型中的表达所致。为克服这些障碍，通过用病毒载体进行体外转基因插入，已开发出组成性或受调控分泌抗体的基因修饰B细胞的过继转移。最近，随着基因编辑技术的出现，已利用成簇规律间隔短回文重复序列（CRISPR）/CRISPR相关内切酶（Cas-9）系统对B细胞的内源性B细胞受体基因座进行修饰，以改变其特异性，从而靶向特定抗原。修饰后的BCR基因的表达遵循内源性调控机制，这可能预防或至少减少副作用。尽管这些方法在癌症治疗方面似乎很有前景，但在转化应用于人类之前，一些重大问题，如这些工程细胞的持久性和重新激活潜力，仍有待在临床相关动物模型中加以解决。
