文章：

工程T细胞：癌症免疫治疗的希望与挑战

Engineered T cells: the promise and challenges of cancer immunotherapy

原文发布日期：2016-08-23

DOI: 10.1038/nrc.2016.97

类型: Review Article

开放获取: 否

要点：

1. Adoptive immunotherapy has rapidly evolved to harness modern genetic techniques to create T cells with enhanced specificity, efficacy and safety. Artificial expression of chimeric antigen receptors (CARs) or engineered T cell receptors (TCRs) in autologous T cells has enabled a new generation of targeted cellular therapeutics.
2. Early clinical trials targeting B cell malignancies have shown great promise, generating unprecedented response rates to treatment of patients with relapsed and refractory B cell acute lymphoblastic leukaemia (B-ALL). As more patients with different B cell malignancies are treated, areas for further optimization are brought to light.
3. Engineered T cell therapy has been adapted to treat non-B cell malignancies, including multiple myeloma and myeloid malignancies as well as solid tumours. To date, target selection has proved challenging as many tumour-conserved markers are also expressed on benign tissues (for example, mesothelin) and other tumour-specific markers are less uniformly expressed (for example, epidermal growth factor receptor variant III (EGFRvIII)).
4. More precise targeting of tumour cell subsets, such as cancer stem cells, or targeting of portions of intracellular tumour markers in the context of the major histocompatibility complex (MHC), may enhance specificity and limit off-tumour effects. Combining non-specific and specific immune responses (for example, T cells redirected for universal cytokine killing (TRUCKs), fluorescein isothiocyanate (FITC)–folate plus FITC-CAR T cell) could further enhance antitumour immune response, while minimizing off-tumour effects.
5. Although lentiviral and retroviral transduction are still the most common approaches to ex vivo T cell gene modification, DNA and RNA transfection have some advantages. In particular, RNA transfection of short guide RNAs enables CRISPR–Cas9 modification of T cells. This targeted gene disruption approach could help to create engineered T cells with supraphysiological antitumour capabilities.
6. In addition to specificity-enhancing artificial receptor expression, the next generation of engineered T cells may include modifications to overcome tumour-mediated immune suppression, additional receptors to enable Boolean gating of signal transduction or safety switches to enhance precision control of in vivo engineered T cell activity.

要点翻译：

1. 过继性免疫疗法迅速发展，利用现代基因技术创造出具有更高特异性、疗效和安全性的T细胞。通过自体T细胞中嵌合抗原受体（CAR）或工程化T细胞受体（TCR）的人工表达，新一代靶向细胞疗法得以实现。
2. 针对B细胞恶性肿瘤的早期临床试验显示出巨大潜力，在复发难治性B细胞急性淋巴细胞白血病（B-ALL）患者的治疗中产生了前所未有的缓解率。随着更多不同B细胞恶性肿瘤患者接受治疗，需要进一步优化的领域也逐渐显现。
3. 工程化T细胞疗法已应用于非B细胞恶性肿瘤的治疗，包括多发性骨髓瘤、髓系恶性肿瘤以及实体瘤。迄今为止，靶点选择仍具挑战性，因为许多肿瘤保守标志物在正常组织中也有表达（如间皮素），而其他肿瘤特异性标志物的表达则较不均衡（如表皮生长因子受体变体III）。
4. 更精确地靶向肿瘤细胞亚群（如癌症干细胞），或在主要组织相容性复合体（MHC）背景下靶向细胞内肿瘤标志物片段，可增强特异性并限制脱瘤效应。将非特异性与特异性免疫应答相结合（例如通用细胞因子杀伤重定向T细胞、异硫氰酸荧光素-叶酸联合FITC-CAR T细胞），可进一步增强抗肿瘤免疫应答，同时最大程度减少脱瘤效应。
5. 虽然慢病毒和逆转录病毒转导仍是体外T细胞基因修饰最常用的方法，但DNA和RNA转染具有特定优势。特别是短向导RNA的RNA转染可实现T细胞的CRISPR-Cas9基因编辑。这种靶向基因破坏技术有助于创建具有超生理抗肿瘤能力的工程化T细胞。
6. 除增强特异性的人工受体表达外，下一代工程化T细胞可能包含以下修饰：克服肿瘤介导的免疫抑制、增加实现信号转导布尔门控的受体、或配置安全开关以增强体内工程化T细胞活性的精准控制。

英文摘要：

The immune system evolved to distinguish non-self from self to protect the organism. As cancer is derived from our own cells, immune responses to dysregulated cell growth present a unique challenge. This is compounded by mechanisms of immune evasion and immunosuppression that develop in the tumour microenvironment. The modern genetic toolbox enables the adoptive transfer of engineered T cells to create enhanced anticancer immune functions where natural cancer-specific immune responses have failed. Genetically engineered T cells, so-called 'living drugs', represent a new paradigm in anticancer therapy. Recent clinical trials using T cells engineered to express chimeric antigen receptors (CARs) or engineered T cell receptors (TCRs) have produced stunning results in patients with relapsed or refractory haematological malignancies. In this Review we describe some of the most recent and promising advances in engineered T cell therapy with a particular emphasis on what the next generation of T cell therapy is likely to entail.

摘要翻译： 

免疫系统进化出区分“非己”与“己”的能力以保护机体。由于癌症源于自身细胞，对失控生长的细胞产生免疫反应面临独特挑战；加之肿瘤微环境中形成的免疫逃逸与免疫抑制机制，问题更为复杂。现代基因工具箱使得我们可以过继转移经工程化改造的T细胞，在自然抗癌免疫应答失败的情况下创造出增强的抗癌免疫功能。基因工程T细胞，即所谓“活药物”，代表了抗癌治疗的新范式。近期临床试验中，表达嵌合抗原受体（CAR）或工程化T细胞受体（TCR）的T细胞在治疗复发/难治性血液恶性肿瘤患者中取得了惊人疗效。本文综述了工程化T细胞治疗领域最新且最具前景的进展，并重点展望下一代T细胞治疗可能涵盖的方向。

原文链接：

Engineered T cells: the promise and challenges of cancer immunotherapy