肿瘤过继性细胞免疫治疗中CAR-T及TCR-T疗法研究进展

近年来,新的生物技术不断被应用于临床,其中的肿瘤免疫治疗就是一种新型的抗肿瘤疗法。免疫治疗指在肿瘤微环境中,通过刺激免疫功能,增强抗肿瘤免疫,进而直接识别和杀伤肿瘤细胞。目前被应用于临床的肿瘤免疫治疗方法有免疫检查点治疗、细胞因子、肿瘤疫苗、过继性细胞免疫治疗（ACI）等。ACI是重要的肿瘤免疫治疗方法,由于ACI可以在不损害免疫系统及其功能的情况下杀死肿瘤细胞,而且能够避免肿瘤免疫逃逸,所以成为国内外研究的热点。经基因修饰改造T 淋巴细胞是ACI临床应用研究最深入的领域。经基因修饰改造的T淋巴细胞可分为嵌合抗原受体T细胞（CAR-T）及T细胞受体改造的T细胞（TCR-T）,该文就CAR-T及TCR-T疗法的研究进展进行综述。     

嵌合抗原受体T细胞免疫疗法在血液肿瘤治疗中的研究进展

近年来,经过基因工程改造的自体T淋巴细胞疗法在肿瘤治疗的临床试验中取得了令人瞩目的成果,其中嵌合抗原受体T细胞(CAR-T)免疫疗法已经在急性淋巴细胞白血病(ALL)中取得显著的疗效.嵌合抗原受体(CAR)是由抗原结合区与共刺激分子组成的融合分子.而CAR-T具有特异性结合肿瘤细胞的能力.与传统药物不同的是,CAR-T可以凭借免疫记忆效应在体内发挥长期的抗肿瘤作用.因此,CAR-T免疫疗法受到了越来越多的关注,已经成为治疗血液系统肿瘤,尤其是B淋巴细胞恶性肿瘤的极具前景治疗手段.笔者拟就CAR-T免疫疗法在血液系统肿瘤中的研究进展进行综述.     

嵌合抗原受体-T细胞免疫治疗在黑素瘤中的应用进展

嵌合抗原受体(chimeric antigen receptor,CAR)-T细胞疗法是一种过继性细胞免疫疗法,近年来在肿瘤免疫治疗中极具研究前景。目前,CAR-T细胞疗法已运用于血液系统恶性肿瘤(如急性B淋巴细胞白血病等)的研究和临床治疗中,并取得了不俗成果。但对于将CAR-T细胞运用于实体肿瘤的治疗仍存在相当多的困难。本文就CAR-T细胞疗法的原理、在黑素瘤治疗中的应用及面临的挑战、CAR-T细胞治疗的副作用和相应对策等方面进行综述。     

Strategies for enhancing adoptive T-cell immunotherapy against solid tumors using engineered cytokine signaling and other modalities

Introduction: Cancer therapy has been transformed by the demonstration that tumor-specific T-cells can eliminate tumor cells in a clinical setting with minimal long-term toxicity. However, significant success in the treatment of leukemia and lymphoma with T-cells using native receptors or redirected with chimeric antigen receptors (CARs) has not been recapitulated in the treatment of solid tumors. This lack of success is likely related to the paucity of costimulatory and cytokine signaling available in solid tumors, in addition to a range of inhibitory mechanisms.

Areas covered: We summarize the latest developments in engineered T-cell immunotherapy, describe the limitations of these approaches in treating solid tumors, and finally highlight several strategies that may be useful in mediating solid tumor responses in the future, while also ensuring safety of engineered cells.

Expert opinion: CAR-T therapies require further engineering to achieve their potential against solid tumors. Facilitating cytokine signaling in CAR T-cells appears to be essential in achieving better responses. However, the engineering of T-cells with potentially unchecked proliferation and potency raises the question of whether the simultaneous combination of enhancements will prove safe, necessitating continued advancements in regulating CAR-T activity at the tumor site and methods to safely switch off these engineered cells.     

Enhancing adoptive immunotherapy of cancer

Importance of the field: Conventional therapies, including surgery, chemotherapy and radiotherapy have contributed much to cancer treatment. However, these treatment modalities fail in a large proportion of patients, and there is a great need for effective alternate therapies. Adoptive immunotherapy can be effective against some cancers that have failed all other treatment options, even when disease burdens are massive.

Areas covered in this review: This review gives a brief introduction of the historical origins of adoptive immunotherapy and then provides details of strategies for increasing the potency of cell transfer. Approaches for enhancing adoptive immunotherapy include: selecting the right type of cell; providing cytokine support; preconditioning patients and tuning the tumor microenvironment. The review also provides insights into the safety, feasibility and costs of this form of therapy.

What the reader will gain: This article will give the reader an appreciation of the potential of adoptive immunotherapy, as well as an understanding of some limitations and current approaches for optimizing the effectiveness of this approach.

Take home message: With recent developments in knowledge of the interactions between the immune system and tumors, the field of adoptive immunotherapy is now poised to make dramatic contributions to cancer therapy.     

肺癌病人CIK细胞过继免疫治疗的护理

目的 探讨中晚期肺癌病人应用细胞因子诱导的杀伤细胞(CIK)治疗的护理规范.方法 回顾性总结2009年9月～2010年10月接受CIK细胞过继免疫治疗139例肺癌病人从护患沟通、心理护理、标本采集、CIK细胞悬液回输和输注后病情观查等环节的经验.结果 139例中晚期肺癌患者接受CIK细胞过继免疫治疗后有1例出现发热,其...     

Cellular immunotherapy for ovarian cancer

Background: Ovarian cancer is frequently diagnosed at an advanced stage, and although initially responsive to surgery and chemotherapy, has a high rate of recurrence and mortality. Cellular immunotherapy may offer the prospect of treatment to prevent or delay recurrent metastatic disease. Objective: To provide an overview of current innovations in cellular immunotherapy for ovarian cancer, with an emphasis on dendritic cell vaccination and adoptive T-cell immunotherapy. Methods: Three key areas are explored in this review: first, an appraisal of the current state of the art of cellular immunotherapy for treatment of ovarian cancer; second, a discussion of the immunological defenses erected by ovarian cancer to prevent immunological attack, with an emphasis on the role of tumor-associated regulatory T cells; and third, an exploration of innovative techniques that may enhance the ability of cellular immunotherapy to overcome ovarian tumor-associated immune suppression. Results/conclusion: Ovarian cancer is recognized as a paradigm for tumor-associated immune suppression. Innovative approaches for antagonism of tumor-associated regulatory T-cell infiltration and redirection of self antigen-driven regulatory T-cell activation may provide the key to development of future strategies for cellular immunotherapy against ovarian cancer.     

CAR-T在治疗恶性胸膜间皮瘤中的研究进展

恶性胸膜间皮瘤(MPM)是一种具有高度侵袭性的多与石棉接触有关的胸膜疾病。MPM的局部高侵袭性导致其治疗方法的选择有限,虽然手术治疗及化学治疗药物方面的研究进展延长了部分MPM患者的生存期,但是MPM总体生存期仍低,目前仍无新的治疗方法可以改善MPM患者的结局。嵌合抗原受体(CAR)是通过现代分子生物技术构建的融合蛋白,嵌合抗原受体T细胞(CAR-T)疗法在治疗血液系统恶性肿瘤中已获较满意疗效,部分试验证实了CAR-T应用于实体肿瘤的安全性及有效性,该文就CAR-T在治疗MPM中的研究进展做一综述。     

嵌合抗原受体T细胞治疗非霍奇金淋巴瘤的最新研究进展

非霍奇金淋巴瘤(NHL)为一组起源于T或B淋巴细胞的恶性肿瘤,约85％均来源于B淋巴细胞.NHL临床与生物学上具有很高的异质性,并且诊断、治疗及预后亦存在很大的差异.随着诊断与治疗水平的提高,大部分NHL患者均可获得长期缓解,但是部分复发/难治性NHL患者的长期生存率仍然不容乐观.近年来,过继细胞免疫治疗(ACT)发展迅猛,尤其是嵌合抗原受体T细胞(CAR-T)在治疗复发/难治性NHL方面进展迅速,其中靶向针对NHL细胞表面的CD19、CD20、CD30等抗原的CAR-T逐步成为治疗NHL的一种全新治疗手段.本文拟从CAR-T的构建、临床治疗NHL的有效性与安全性、性能优化等方面的最新研究进展进行阐述.     

CAR-T细胞构建技术研究进展

嵌合抗原受体T细胞免疫疗法(CAR-T)被认为是最有潜力的癌症治疗方法,并取得了良好的临床疗效.随着CAR-T大规模应用,该技术的局限性也逐渐暴露出来,如治疗效果差 、疾病复发 、不良反应多等.这使得制造结构更优 、安全性更高 、效能更佳的CAR-T细胞成为临床所需.了解CAR-T的制造过程,掌握技术进展,是构建理想的...     

Current status of adoptive immunotherapy of malignancies

Adoptive immunotherapy involves the transfer of immune effectors with antitumour activity into the tumour bearing host. Early approaches such as lymphokine activator killer (LAK) cells and tumour infiltrating lymphocytes (TILs) have yielded occasional clinical responses. More recently, attempts to stimulate and/or select antigen-specific T-cells in vitro have demonstrated that tumour-specific adoptive immunotherapy is possible. These approaches require complicated and time consuming in vitro stimulation procedures. Therefore, genetic modification of bulk T-cell populations is an attempt to create a large population of T-cells with a single specificity. In addition to work being done to develop the most potent effector, other studies are working on improving T-cell trafficking to tumours and interfering with the tumour-induced immunosuppression that can impair in vivo T-cell activity.     

Facing the future: challenges and opportunities in adoptive T cell therapy in cancer

Introduction: In recent years, immunotherapy for the treatment of solid cancer has emerged as a promising therapeutic alternative. Adoptive cell therapy (ACT), especially T cell-based, has been found to cause tumor regression and even cure in a percentage of treated patients. Checkpoint inhibitors further underscore the potential of the T cell compartment in the treatment of cancer. Not all patients respond to these treatments; however, many challenges remain.

Areas covered: This review covers the challenges and progress in tumor antigen target identification and selection, and cell product manufacturing for T cell ACT. Tumor immune escape mechanisms and strategies to overcome those in the context of T cell ACT are also discussed.

Expert opinion: The immunotherapy toolbox is rapidly expanding and improving, and the future promises further breakthroughs in the T cell ACT field. The heterogeneity of the tumor microenvironment and the multiplicity of tumor immune escape mechanisms pose formidable challenges to successful T cell immunotherapy in solid tumors, however. Individualized approaches and strategies combining treatments targeting different immunotherapeutic aspects will be needed in order to expand the applicability and improve the response rates in future.     

Novel approaches to promote CAR T-cell function in solid tumors

Introduction: Following recent breakthrough developments in the application of CAR T-cell treatments for hematologic cancers, the potential of this approach to achieve meaningful impact against solid tumors now warrants careful consideration.

Areas covered: Effective deployment of CAR T-cell immunotherapy for solid tumors has proven challenging to date, due to a series of formidable hurdles. The first of these is the paucity of safe targets for this highly potent, expensive and potentially toxic form of treatment. Compounding this, the tumor microenvironment (TME) constitutes a nexus of cellular and molecular elements that conspire to suppress effective immunological function at that site, corrupting the physiological reparative processes that operate during wound healing. These obstacles are considered with a view to addressing how next-generation CAR T-cell approaches may be effectively applied to different cancer types.

Expert opinion: A variety of novel synthetic biology and combinatorial strategies are being developed that can improve CAR T-cell specificity and combat immunosuppressive pathways found in the TME. In addition, recent advances in genome editing techniques are paving the way toward the production of universally applicable CAR T cells.     

The rise of human stem cell-derived natural killer cells for cancer immunotherapy

Introduction: Natural killer (NK) cell therapy has been proven to be safe and clinically effective for the treatment of multiple cancers, in particular blood cancers. Most of the clinical trials use primary NK cells from peripheral blood or umbilical cord blood, or NK-92 cells. Each cell source is confined by limitations, such as donor dependence, low persistence in vivo, and its difficulty to genetically modify. Thus, there is an urgent need to explore novel NK cell sources for clinical use.

Areas covered: This article highlights the recent progress in utilizing stem cell-derived NK cells as anticancer therapies and strategies to improve their antitumor activities.

Expert commentary: Stem cell-derived NK cells are homogenous, easy to genetically modify on a clonal level, and can be expanded to clinical scale. They may therefore arise as an ideal population for developing off-the-shelf, standardized adoptive NK cell therapeutic products.     

膀胱腔内过继免疫治疗对膀胱局部免疫功能的影响

目的：观察膀胱腔内细胞过继免疫治疗对膀胱局部免疫功能的影响,以探讨一种有效预防浅表性膀胱癌术后复发的新疗法。方法：采用盐析法,由手术切除的患者自体膀胱肿瘤标本制备膀胱肿瘤可溶性抗原（BTSA）,以卡介苗为佐剂,共同诱导人外周血单个核细胞成为抗膀胱肿瘤效应细胞（BT-BAK）细胞。将BT-BAK细胞应用于肿瘤切除术后浅表性膀胱癌患者的膛胱腔内灌注治疗,定期行膀胱镜复查及膀胱粘膜活检;采用酶联免疫吸附法测定尿液中细胞因子含量的变化。结果：37例治疗后,膀胱粘膜组织学观察显示为轻或中度非特异性炎症性反应,仅1例发现粘膜上皮轻度异型性增生,复发率为2.7%。治疗后患者尿液中IL-2、TNF-α及IFN-γ的水平均较治疗前显著提高。结论：BT-BAK细胞膀胱灌注应用于膀胱癌术后治疗,可以有效进高膀胱局部的免疫反应水平,降低膀胱癌的复发率。     

Recent clinical development of dendritic cell-based immunotherapy for prostate cancer

Dendritic cells (DCs) are the most powerful immune cells that present antigens to T cells, resulting in a T cell response. Therapeutic strategies involving DCs have been explored in many malignancies, including prostate cancer. These strategies are designed to stimulate DC proliferation, promote antigen uptake and processing by DCs, or to directly provide antigen-loaded DCs. All approaches are designed to stimulate an antitumour T cell response leading to clinical benefit. Many approaches in prostate cancer have demonstrated successful induction of the desired immune response. Clinical effect has also been observed, prompting larger definitive trials.     

Dendritic cell fusion vaccines for cancer immunotherapy

The use of tumour vaccines is being explored as a means of generating effective antitumour immune responses in patients with cancer. Dendritic cells (DCs) are the most potent antigen-presenting cells that are essential for initiating primary immune responses. As such, DCs are being studied as a p-latform for the design of cancer vaccines. DCs loaded with tumour antigens or whole tumour cell derivatives stimulate tumour-specific immunity. A p-romising vaccine strategy involves the fusion of DCs with whole tumour cells. DC/tumour fusions express a broad array of tumour antigens, including those yet to be identified, in the context of DC-mediated costimulation. An-imal models have demonstrated that vaccination with fusion cells is p-rotective against tumour challenge and results in the regression of es-tablished metastatic disease. In vitro human studies have demonstrated that DC/tumour fusions potently stimulate antitumour immunity and lysis of autologous tumour cells. Vaccination of cancer patients with DC/tumour fusions is being studied in Phase I/II clinical trials. Preliminary results demonstrate that generation of a vaccine is feasible and that vaccination is associated with minimal toxicity. Immunological and clinical responses have been found in a subset of patients.     

嵌合抗原受体T细胞治疗恶性血液病的研究进展

嵌合抗原受体(CAR)-T细胞治疗是一种新的免疫疗法.该方法是将识别肿瘤细胞相关抗原的受体与T细胞胞内信号域在体外进行基因重组,再将这些质粒转染至T细胞中,而这类表达CAR的T细胞可特异性识别具有靶抗原的肿瘤细胞并发挥杀伤作用.目前,CAR-T细胞在肿瘤治疗,尤其是在恶性血液病治疗上获得良好疗效,但其疗效、安全性、不良反应、质量控制方面均需进一步验证.笔者拟就CAR-T细胞治疗中的CAR设计、细胞制备、临床试验及不良反应进行综述.