肿瘤微环境中代谢检查点调节T细胞免疫功能的研究进展

免疫疗法的出现改变了现有的晚期肿瘤治疗模式,为患者带来了希望。然而,许多肿瘤已经显示出对检查点抑制等免疫治疗的显著抵抗机制,导致部分患者的应答率始终不高,甚至超进展。通过对新兴免疫代谢领域的研究发现,靶向代谢途径重塑肿瘤微环境有望重振抗肿瘤免疫反应,并可能与现有免疫疗法产生协同效应。本文着重探讨了代谢检查点调节T细胞代谢在肿瘤免疫治疗中产生的一系列影响,旨在为肿瘤免疫治疗提供新的思路。     

代谢重编程介导肿瘤微环境免疫抑制的研究评述

近十年免疫疗法在肿瘤的治疗中取得了突破性进展,导致肿瘤治疗的范式转变。然而大多数患者并不能从中获益,如何提高患者免疫治疗的应答率是亟待解决的热点问题。免疫疗法的成功有赖于机体免疫效应细胞的活化及杀伤效应。然而,在肿瘤微环境严苛的代谢和营养应激下,免疫细胞的功能常处于紊乱状态,导致抗肿瘤免疫应答受损。因此,通过靶向肿瘤代谢重塑免疫微环境,恢复抗肿瘤免疫应答,有望在与免疫疗法的联合应用中取得协同效应。本文着重探讨代谢重编程及其代谢产物如何调节抗肿瘤免疫应答,旨在为肿瘤免疫治疗提供新的思路和方法。     

代谢重编程介导肿瘤微环境免疫抑制的研究评述

近十年免疫疗法在肿瘤的治疗中取得了突破性进展,导致肿瘤治疗的范式转变。然而大多数患者并不能从中获益,如何提高患者免疫治疗的应答率是亟待解决的热点问题。免疫疗法的成功有赖于机体免疫效应细胞的活化及杀伤效应。然而,在肿瘤微环境严苛的代谢和营养应激下,免疫细胞的功能常处于紊乱状态,导致抗肿瘤免疫应答受损。因此,通过靶向肿瘤代谢重塑免疫微环境,恢复抗肿瘤免疫应答,有望在与免疫疗法的联合应用中取得协同效应。本文着重探讨代谢重编程及其代谢产物如何调节抗肿瘤免疫应答,旨在为肿瘤免疫治疗提供新的思路和方法。     

癌-睾丸抗原在肺癌中的研究进展

肺癌目前全面进入免疫治疗新时代,但是单一的一种免疫疗法仍无法满足免疫微环境的复杂状况,不同免疫联合方案成为克服免疫耐药的有效手段。癌-睾丸抗原(CTA)是一种几乎只在恶性肿瘤中表达的特异性极高的肿瘤抗原,能够产生强大的抗肿瘤免疫反应,是新型免疫治疗中很有希望的靶点。文章就CTA在肺癌中的表达、功能和免疫治疗应用等方面的研究进展进行综述。     

胰腺癌免疫治疗进展

随着分子生物学技术和肿瘤免疫学的发展，免疫治疗已成为肿瘤综合治疗模式的重要组成部分。近年来胰腺癌免疫治疗的研究也日趋增多，可望为胰腺癌的治疗开辟新的途径。现综述胰腺癌特异性主动免疫治疗、单克隆抗体治疗、细胞因子治疗和过继性细胞免疫治疗等进展。     

肠道菌群影响肿瘤免疫治疗的机制及临床应用研究进展

肿瘤免疫治疗是继手术、化疗、放疗后的第四种疗法，在部分上皮性肿瘤和血液性肿瘤的治疗中取得较大突破，但不良反应常见甚至比较严重，在部分实体肿瘤中的应答率也不够理想。随着基因组学和代谢组学技术的成熟，人们逐渐认识到肠道菌群在肿瘤发展与治疗中的作用。菌群可能通过调节宿主免疫系统和肿瘤微环境等方式影响肿瘤免疫，部分细菌通过激活免疫起到协助对抗肿瘤的作用，而有些细菌则介导免疫抑制帮助癌细胞逃避免疫系统的杀伤。越来越多的研究揭示肿瘤免疫治疗的效果和并发症与患者肠道菌群组成有关，对治疗敏感或易发生不良反应的患者肠道菌群组成有一定特征。这些特征可能作为生物标志物来预测免疫治疗的预后，也可能被开发为“免疫增效剂”（如Akk菌和双歧杆菌）来辅助免疫治疗。部分临床和临床前研究已证明包括菌群移植在内的微生物干预能一定程度上提高免疫治疗的敏感性或减轻不良反应。随着基因编辑技术和纳米技术的发展，有助于免疫治疗的工程细菌的设计开发成为了新的研究热点。基于肠道菌群和免疫治疗的关系，正确挖掘微生物信息、开发合理可行的微生物干预手段，有希望在很大程度上优化肿瘤免疫疗法，为肿瘤治疗带来新的突破。     

胰腺癌免疫治疗研究进展

胰腺癌作为一种致命的恶性肿瘤，起病隐匿，对放化疗、靶向治疗等传统治疗不敏感，患者预后极差。免疫治疗是当今多种恶性肿瘤综合治疗的有效手段，以其显著临床疗效而备受瞩目。然而胰腺癌因其较低的肿瘤免疫原性和独特的肿瘤微环境在免疫治疗迅速发展的当今成为难以攻破的一方“免疫荒漠”。目前胰腺癌免疫治疗的研究方向主要包括：肿瘤疫苗、免疫检查点抑制剂、单克隆抗体、溶瘤病毒、T细胞治疗等。本文将对以上相关研究进展作一综述，以期为胰腺癌的免疫治疗提供新思路。     

宫颈癌免疫治疗的耐药机制及应对措施

宫颈癌严重威胁全球女性的生命健康，晚期宫颈癌治疗手段有限，5年生存率不到20%，是妇科肿瘤的巨大挑战。免疫治疗是晚期宫颈癌患者的重要治疗手段之一，包括免疫检查点抑制剂、治疗性疫苗和过继性T细胞免疫疗法等，但免疫治疗耐药性使部分患者无应答而效果不佳。因此，迫切需要深入研究和探讨免疫耐药的机制从而改善耐药，现归纳总结了近年有关宫颈癌中免疫耐药机制的相关研究，主要分为肿瘤内在因素和外在免疫环境改变等因素，并介绍针对免疫耐药提出的应对措施及进展。     

基于肿瘤免疫微环境分型的实体瘤免疫治疗策略的研究进展

肿瘤免疫微环境（TIME）是肿瘤细胞得以生存和发展的复杂环境,其组成成分及相关特征在调节肿瘤的发生和发展中发挥重要作用,并影响不同免疫疗法的临床疗效。TIME的研究为实体瘤诊疗开辟了一条新的路径,因此针对TIME的治疗策略具有发展前景且成为探索方向,以帮助指导和改善实体瘤的治疗。本文基于FOWLER团队确认的TIME四分型理论,进一步阐述不同分型的TIME特征及潜在可适用的免疫治疗方式,对目前基于TIME分型的肿瘤免疫治疗选择提供指导。同时提出在成像引导的测序等新技术协助下,新的生物标志物、TIME分型理论和治疗靶点的涌现,为实体瘤免疫疗法赋予光明前景。在新的疗法不断出现的同时,基于TIME的免疫治疗研究方向仍应尽可能提前关口,以实现肿瘤早诊早治的目的。     

RNA及其衍生体：肿瘤免疫治疗的新策略

RNA在多种生理和病理过程中起着至关重要的作用。在过去的几十年中,研究人员已经设计出多种类型的RNA及 其衍生体,并应用于不同的生物学领域。研究证实,RNA分子在肿瘤的生长、转移、代谢和免疫逃逸等方面发挥着重要作用。基 于肿瘤相关RNA的研究和相关技术的应用,RNA已经被设计应用于肿瘤免疫治疗之中。此外,作为肿瘤免疫治疗的工具,RNA 可以与其他类型的免疫疗法结合使用,例如免疫检查点抑制剂、树突状细胞回输治疗以及嵌合抗原受体T细胞免疫疗法等。在 综述中,论述了各种RNA工具（包括RNA适配体、mRNA疫苗和RNA溶瘤病毒）在肿瘤免疫治疗中应用的研究进展,总结了这些 RNA工具治疗肿瘤的优点和缺点,并展望了RNA及其衍生体未来在肿瘤免疫治疗中的潜在临床应用。     

胰腺癌免疫治疗进展

胰腺癌预后差,对传统的治疗不敏感,大多数患者一经诊断即为晚期.传统的治疗方法,包括紫杉醇、氟尿嘧啶类药物、吉西他滨等常用的化疗药物并没有为胰腺癌患者带来显著的生存获益.因此,我们目前需要急切的探索在免疫方面治疗胰腺癌的新思路.当前关于胰腺癌免疫治疗的研究方向主要在以下几个方面:免疫检查点抑制剂、疫苗、T细胞治疗、单克隆抗体、细胞因子等.本文将近年来以上方面的研究进展做一回顾总结.     

Understanding the immune landscape and tumor microenvironment of pancreatic cancer to improve immunotherapy

Immunotherapy has revolutionized cancer treatment for several hematologic and solid organ malignancies; however, pancreatic cancer remains unresponsive to conventional immunotherapies. Several characteristics of pancreatic cancer present challenges to successful treatment with immunotherapy, including its aggressive biology, poor immunogenicity, and abundant desmoplastic stroma which can impede effector T cell infiltration and promote an immunosuppressive microenvironment. In this review, we evaluate the current understanding of the immune and stromal landscapes of pancreatic cancer, discuss the successes and failures of stroma-targeted therapies, and highlight how stroma-directed therapies may be synergistic with immunotherapy.     

Emerging Immunotherapies in the Treatment of Brain Metastases

Brain metastases account for considerable morbidity and mortality in patients with cancer. Despite increasing prevalence, limited therapeutic options exist. Recent advances in our understanding of the molecular and cellular underpinnings of the tumor immune microenvironment and the immune evasive mechanisms employed by tumor cells have shed light on how immunotherapies may provide therapeutic benefit to patients. The development and evolution of immunotherapy continue to show promise for the treatment of brain metastases. Positive outcomes have been observed in several studies evaluating the efficacy and safety of these treatments. However, many challenges persist in the application of immunotherapies to brain metastases. This review discusses the potential benefits and challenges in the development and use of checkpoint inhibitors, chimeric antigen receptor T‐cell therapy, and oncolytic viruses for the treatment of brain metastases. Future studies are necessary to further evaluate and assess the potential use of each of these therapies in this setting. As we gain more knowledge regarding the role immunotherapies may play in the treatment of brain metastases, it is important to consider how these treatments may guide clinical decision making for clinicians and the impact they may have on patients.Implications for PracticeImmunotherapies have produced clinically significant outcomes in early clinical trials evaluating patients with brain metastases or demonstrated promising results in preclinical models. Checkpoint inhibitors have been the most common immunotherapy studied to date in the setting of brain metastases, but novel approaches that can harness the immune system to contain and eliminate cancer cells are currently under investigation and may soon become more common in the clinical setting. An understanding of these evolving therapies may be useful in determining how the future management and treatment of brain metastases among patients with cancer will continue to advance.     

胰腺癌免疫治疗的现状及前景CSCD

胰腺癌(胰腺导管腺癌)是一种恶性程度较高,诊断和治疗都较困难的消化系统恶性肿瘤。近年来,肿瘤免疫治疗在多种肿瘤中如黑色素瘤、膀胱癌、乳腺癌、非小细胞肺癌和肾癌等均取得了令人振奋的治疗效果,但是胰腺癌的免疫治疗策略尚在不断探索中。目前针对胰腺癌独特的肿瘤微环境设计了多种免疫治疗策略,包括强化/提高自身免疫反应(免疫调节剂、单克隆抗体、肿瘤疫苗和细胞治疗)以及抑制肿瘤免疫逃逸(免疫检查点抑制剂和肿瘤微环境)等。本文就胰腺癌免疫治疗的研究进展进行综述,着重探讨PD-1/PD-L1抑制剂在胰腺癌中的应用,并分析免疫治疗联合其他方式治疗胰腺癌的前景。     

Clinical development of Listeria monocytogenes-based immunotherapies

Active immunotherapy targeting dendritic cells (DCs) has shown great promise in preclinical models and in human clinical trials for the treatment of malignant disease. Sipuleucel-T (Provenge, Dendreon, Seattle, WA), which consists of antigen-loaded dendritic cells (DCs), recently became the first targeted therapeutic cancer vaccine to be approved by the US Food and Drug Administration (FDA). However, ex vivo therapies such as Provenge have practical limitations and elicit an immune response with limited scope. By contrast, live-attenuated Listeria monocytogenes (Lm) naturally targets DCs in vivo and stimulates both innate and adaptive cellular immunity. Lm-based vaccines engineered to express cancer antigens have demonstrated striking efficacy in several animal models and have resulted in encouraging anecdotal survival benefit in early human clinical trials. Two different Lm-based vaccine platforms have advanced into phase II clinical trials in cervical and pancreatic cancer. Future Lm-based clinical vaccine candidates are expected to feature polyvalent antigen expression and to be used in combination with other immunotherapies or conventional therapies such as radiotherapy and chemotherapy to augment efficacy.     

2015 Guidance on cancer immunotherapy development in early‐phase clinical studies

The development of cancer immunotherapies is progressing rapidly with a variety of technological approaches. They consist of “cancer vaccines”, which are based on the idea of vaccination, “effector cell therapy”, classified as passive immunotherapy, and “inhibition of immunosuppression”, which intends to break immunological tolerance to autoantigens or immunosuppressive environments characterizing antitumor immune responses. Recent reports showing clinical evidence of efficacy of immune checkpoint inhibitors and adoptive immunotherapies with tumor‐infiltrating lymphocytes and tumor‐specific receptor gene‐modified T cells indicate the beginning of a new era for cancer immunotherapy. This guidance summarizes ideas that will be helpful to those who plan to develop cancer immunotherapy. The aims of this guidance are to discuss and offer important points in early phase clinical studies of innovative cancer immunotherapy, with future progress in this field, and to contribute to the effective development of cancer immunotherapy aligned with the scope of regulatory science. This guidance covers cancer vaccines, effector cell therapy, and inhibition of immunosuppression, including immune checkpoint inhibitors.     

Antibody-based immunotherapy for ovarian cancer: where are we at?

Cytoreductive surgery and chemotherapy continue to be the mainstay of ovarian cancer treatment. However, as mortality from advanced ovarian cancer remains very high, novel therapies are required to be integrated into existing treatment regimens. Immunotherapy represents an alternative and rational therapeutic approach for ovarian cancer based on a body of evidence supporting a protective role of the immune system against these cancers, and on the clinical success of immunotherapy in other malignancies. Whether or not immunotherapy will have a role in the future management of ovarian cancer is too early to tell, but research in this field is active. This review will discuss recent clinical developments of selected immunotherapies for ovarian cancer which fulfil the following criteria: (i) they are antibody-based, (ii) target a distinct immunological pathway, and (iii) have reached the clinical trial stage. Specifically, the focus is on Catumaxomab (anti-EpCAM × anti-CD3), Abagovomab, Oregovomab (anti-CA125), Daclizumab (anti-CD25), Ipilimumab (anti-CTLA-4), and MXD-1105 (anti-PD-L1). Catumaxomab has reached phase III clinical trials and exhibits promise with reports, showing that it can cause a significant and sustained reduction in ascites. Phase I–III clinical trials continue to be conducted on the other antibodies, some of which have had encouraging reports. We will also provide our perspective on the future of immunotherapy for ovarian cancer, and how it may be best employed in treatment regimens.     

Reevaluation of immunopotentiation therapy for cancer

Various cancer immunotherapies are thought to be insufficient to suppress cancers by themselves. Thus, they are usually applied in cancer therapy as an immunopotentiator in combination with chemotherapy. However, chemotherapy itself seems to be hazardous for activated immune cells. On the other hand, immunotherapy after surgical treatment for cancer patients of stages I through III significantly reduced cancer deaths compared to historical control data for the same surgeon team. Some lymph node metastases are cured by immunotherapy after resection of the main tumors. The potential of immunocancer therapy and problems in the future development of new cancer therapies are discussed.     

卵巢癌的免疫治疗

卵巢癌作为妇女死亡的重要因素,一直受到人们的关注.手术和化学治疗目前都不能达到令人满意的效果.随着免疫学的进展,卵巢癌的免疫治疗将成为临床治疗的可选择手段之一.卵巢癌免疫治疗可分为预防性和治疗性免疫两种,同时还可分为腹腔内与全身两种给药方式.本文对卵巢癌的免疫治疗目前的一些进展,临床试验结果及发展中的一些问题与探索进行了综述.     

Next-generation immunotherapies for lymphoma: one foot in the future

Improved understanding of the interactions between cancer cells and the immune system combined with technological advances has led to the development of novel types of immunotherapies. These include checkpoint inhibitors, T-cell engager antibodies and chimeric antigen receptor T cells which have demonstrated remarkable efficacy in B-cell malignancies, including anti-PD1 antibodies in Hodgkin lymphoma, and T-cell engager antibodies and chimeric antigen receptor T cells in B-cell acute lymphoblastic leukemia, leading to their approval in these indications. Recent clinical data suggest that these immunotherapies may also benefit patients with other types of hematologic malignancies, particularly patients with Hodgkin and non-Hodgkin lymphomas. Here, we review the most recent clinical data regarding these different immunotherapies in patients with lymphoma. Ongoing and future studies should further define which immunotherapy may best apply to a given patient in order to provide a ‘personalized immunotherapy’.