非小细胞肺癌的免疫治疗进展

肺癌是最致命的恶性肿瘤之一,也是男性肿瘤患者致死率最高的,5年生存率低于18%。尽管非小细胞肺癌(non-small cell lung cancer,NSCLC)在手术治疗、化疗、放疗以及靶向治疗方面均取得了一定的成果,但晚期NSCLC的预后依然很差。免疫治疗为NSCLC患者提供了一个新的治疗方向。免疫治疗目前主要研究方向在免疫检查点抑制剂(Ipilimumab、Nivolumab、MK-3475)和肿瘤疫苗(MAGE-A3,L-BLP25,TG4010,Belagenpumatucel-L)等。免疫治疗具有针对性强、副作用少、效率高的特点,并在Ⅱ、Ⅲ期临床试验中取得了较好的疗效,成为在手术、化疗、放疗以及靶向治疗后一种新的重要治疗手段。本文就当前非小细胞肺癌免疫治疗原理、临床试验及待解决问题作一综述。     

Interleukin-8 has antitumor effects in the rat which are not associated with polymorphonuclear leukocyte cytotoxicity

The antitumor effect of lipopolysaccharides (LPS) has been observed in several experimental models and is likely to be mediated by macrophages. Stimulation of macrophages with LPS results in the release of several cytokines, including tumor necrosis factor, interleukin-1 and neutrophil-activating peptide-1/interleukin-8 (IL-8), which activates polymorphonuclear leukocytes (PMN) in vitro. Since PMN have an antitumor activity, we tested the in vivo effect of IL-8 on the growth of peritoneal carcinomatoses induced by PROb colon cancer cells in syngeneic rat. IL-8 induced a significant regression of tumors measuring 1–5 mm, and a complete regression was observed in 8 out of 40 rats in four independent experiments. IL-8 was not directly cytotoxic in vitro for tumor cells and was effective in vivo in a narrow range of doses. IL-8 had a significant chemotactic effect for peritoneal PMN in both normal and tumor-bearing rats. PMN taken from the peritoneum of tumor-bearing rats during IL-8 treatment had the same cytotoxic activity against PROb tumor cells as PMN from untreated control rats. Microscopic examinations of tumors during the treatment showed poor infiltrating by PMN. We conclude that the antitumor activity of IL-8 in this model is not mediated by PMN cytotoxicity.     

Pilot study of mutant ras peptide-based vaccine as an adjuvant treatment in pancreatic and colorectal cancers

INTRODUCTION: There is mounting evidence describing the immunosuppressive role of bulky metastatic disease, thus countering the therapeutic effects of tumor vaccine. Therefore, adjuvant immunotherapy may have a better impact on clinical outcome. In this phase II clinical trial, we aimed to test the feasibility of using a specific mutant ras peptide vaccine as an adjuvant immunotherapy in pancreatic and colorectal cancer patients. MATERIALS AND METHODS: Twelve patients with no evidence of disease (NED), five pancreatic and seven colorectal cancer patients were vaccinated subcutaneously with 13-mer mutant ras peptide, corresponding to their tumor's ras mutation. Vaccinations were given every 4 weeks, up to a total of six vaccines. RESULTS: No serious acute or delayed systemic side effects were seen. We detected specific immune responses to the relevant mutant ras peptide by measuring IFN-gamma mRNA expression by quantitative real-time PCR. Five out of eleven patients showed a positive immune response. Furthermore, the five pancreatic cancer patients have shown a mean disease-free survival (DFS) of 35.2+ months and a mean overall survival (OS) of 44.4+ months. The seven colorectal cancer patients have shown a mean disease-free survival (DFS) of 27.2+ months and a mean overall survival (OS) of 41.5+ months. CONCLUSION: In this study, we found that it is feasible to use mutant ras vaccine in the adjuvant setting. This vaccine is safe, can induce specific immune responses, and it appears to have a positive outcome in overall survival. Therefore, we believe that such an approach warrants further investigation in combination with other therapies.     

结直肠癌与肠道微生物群研究进展

肠道微生物群是人体内环境的重要组成部分,与宿主共进化、共代谢、共发育,并与宿主之间相互调控,影响宿主健康。近年研究显示,肠道微生物群参与了结直肠癌的发生和发展。了解肠道微生物群的特征性变化及其诱发结直肠癌的机制对于结直肠癌的防治有着重要意义。目前以肠道微生物群为靶点的干预性基础研究也取得了一些突破性的研究进展。本文主要对结直肠癌患者肠道微生物群的变化、其可能的致病机制及临床相关研究进展等进行综述。     

肠道菌群与胃肠肿瘤关系的研究进展

随着人们对肠道菌群认识的深入,其在胃肠肿瘤发生、发展和防治中的作用越来越受到重视。大量研究表明:失调的肠道菌群可通过产生促肿瘤代谢产物及毒素、影响宿主免疫等促进胃肠肿瘤的发生发展;相反,健康且平衡的肠道菌群可增强宿主的抗肿瘤效应而抑制胃肠肿瘤发生发展、改善其预后。本文从肠道菌群与胃肠肿瘤的相关性、肠道菌群对胃肠肿瘤的影响机制及防治应用等角度,对二者关系的最新研究进展作一综述,旨在为胃肠肿瘤的预防、早诊和治疗提供新的思路。     

腹腔镜手术与开腹手术治疗结直肠癌的临床疗效对比分析

目的:探讨腹腔镜手术治疗结直肠癌的临床效果,比较腹腔及与传统开腹术的优势,为临床研究提供可借鉴的方法。方法:对2008年5月至2012年7月在我院接受肠癌切除术的62例患者的临床资料进行回顾性分析,根据手术方式的不同,将患者分为腹腔镜组(33例)和开腹组(29例),分别采取腹腔镜手术和传统开腹手术治疗。比较两组患者的手术时间、出血量、术后排气时间、并发症、平均住院时间及住院费用等。结果:腹腔镜组患者的手术时间、术中出血量、术后排气时间、平均住院时间均明显优于开腹组患者(P0.05);腹腔镜组术后无并发症,开腹组11例出现并发症,差异具有统计学意义(P0.05);两组患者的住院费用无明显差异(P0.05)。结论:腹腔镜结直肠癌根治术具有很好的临床效果,术中出血少、术后恢复快,能够减少手术对患者机体造成的损伤,值得临床推广应用。     

腹腔镜结直肠癌根治术与传统开腹手术比较分析

目的:分析腹腔镜结直肠癌根治手术与传统开腹术治疗结直肠癌的临床效果,探讨腹腔镜手术的特点及优势,为临床外科手术提供参考。方法:选择2009年7月至2013年5月在我院进行腹腔镜手术的186例结直肠癌患者的临床资料进行分析,并与择期接受开腹手术的181例结直肠癌患者的临床效果进行对比。比较两组患者的平均手术时间、平均术中出血量、术后肛门排气时间、下床活动时间、平均住院时间及并发症的发生率等。结果:与传统手术组相比,腹腔镜组患者的平均手术时间短、平均术中出血量少、术后肛门排气时间早、平均住院时间短,差异显著且具有统计学意义(P0.05);腹腔镜组患者术后出现下肢静脉血栓1例、皮下气肿9例、高碳酸血症8例,并发症的发生率为7.14%;传统手术组术后出现切口感染10例、消化道出血13例,吻合口漏11例、并发症的发生率为12.90%。腹腔镜根治术患者术后并发症的发生率明显低于传统开腹手术组,差异具有统计学意义(P0.05);腹腔镜组患者的平均住院时间为(8.34±2.12)天,明显短于传统开腹手术组的(11.58±1.98)天,差异具有统计学意义(P0.05)。结论:腹腔镜结直肠癌根治术具有很好的临床效果,术中出血少、术后恢复快,能够减少手术对患者机体造成的损伤,值得临床推广应用。     

Targeting unique tumor antigens and modulating the cytokine environment may improve immunotherapy for tumors with immune escape mechanisms

Cytotoxic T-cell responses to shared tumor antigens have been characterized for several tumor types, and the MHC-associated peptides that comprise these antigens have been defined at a molecular level. These provide new tools to determine whether immune responses can be generated with these tumor antigens, and there are data to suggest that such immune responses can be generated. However, it is also clear that tumor cells can evade immune responses directed against some shared antigens, by downregulating expression of MHC or of the antigenic protein(s), as well as by more active methods such as secretion of immunosuppressive cytokines. Awareness of these mechanisms of immune escape will help to direct development of the next generation of tumor vaccines. Targeting unique antigens and modulating the cytokine environment likely will be critical to comprehensive vaccine systems in the future. Received: 20 March 1999 / Accepted: 3 May 1999     

Immuno-gene therapy of melanoma by tumor antigen epitope modified IFN-γ

Cytokine-based vaccines play a major part in tumor immuno-gene therapy. However, down-regulated antigen expression on tumor cells may diminish the immuno-potentiating aspects of cellular vaccines. In this study, we coexpressed a tumor antigen epitope with IFN- in the same gene by replacing the IFN- signal peptide with an antigen epitope-expressing signal peptide. We then investigated the effect of the antigen epitope-incorporated IFN- on the immunotherapy of murine melanoma B16 tumors. Results showed that TRP-2 epitope-expressing IFN- decreased B16 tumorigenicity and enhanced its immunogenicity after gene transfer. Protective immunity against wild type B16 tumors was induced by vaccination with IFN- transiently gene-modified tumor cells. These data suggest that cellular vaccines engineered to express an antigen epitope within an immunostimulatory cytokine could potentiate the immunization effect.     

免疫治疗背景下提高临床肿瘤教学水平的探讨

肿瘤发病率的日益攀升以及临床肿瘤学的迅速发展,对培养专业的临床肿瘤学人才提出了更高的要求。随着第一个细胞免疫治疗药物Sipuleucel-T被美国FDA批准用于晚期前列腺癌的治疗,肿瘤治疗进入免疫治疗的新时代,现有传统临床肿瘤学教学方法及观念已经不能适应目前的要求,因此必须提高临床教学水平。本文在肿瘤免疫治疗迅速发展背景下,对如何提高临床肿瘤教学水平进行思考与探讨,通过加强肿瘤分子生物学及细胞分子免疫学理论教学,以及在教学过程中贯穿循证医学与个体化治疗相结合的理念、引入多学科参与的肿瘤综合治疗模式,并强调心理干预和人文关怀的重要性,兼顾教学理论和临床实践最新进展及趋势,有效地帮助学生树立全面、科学的临床肿瘤治疗理念,掌握改善临床肿瘤治疗的有效方法,切实提升临床肿瘤学的教学质量和水平,培养出能胜任现代临床肿瘤学实践需求的专业人才。     

ImmTher, a lipophilic disaccharide derivative of muramyl dipeptide, up-regulates specific monocyte cytokine genes and activates monocyte-mediated tumoricidal activity

ImmTher, a liposome-encapsulated lipophilic disaccharide tripeptide derivative of muramyl dipeptide, previously showed activity against liver and lung colorectal metastases in a phase I trial. The purpose of the current studies was to investigate whether ImmTher could up-regulate specific cytokine gene expression and protein production, as well as activate the tumoricidal or cytostatic activity of human monocytes. ImmTher induced the expression and production of interleukin(IL)-1α IL-1β, IL-6, IL-8, IL-12, macrophage chemotactic and activating factor, and tumor necrosis factor α but not IL-2 or IL-10. Cytostatic or cytotoxic monocyte activity was stimulated against human Ewing's sarcoma, osteosarcoma, and melanoma cells but not breast cancer cells. Production and secretion of these cytokine proteins may play a role in the antitumor activity of ImmTher. Received: 15 December 1998 / Accepted: 18 March 1999     

Selective Expansion of Chimeric Antigen Receptor-targeted T-cells with Potent Effector Function using Interleukin-4

Polyclonal T-cells can be directed against cancer using transmembrane fusion molecules known as chimeric antigen receptors (CARs). Although preclinical studies have provided encouragement, pioneering clinical trials using CAR-based immunotherapy have been disappointing. Key obstacles are the need for robust expansion ex vivo followed by sustained survival of infused T-cells in patients. To address this, we have developed a system to achieve selective proliferation of CAR⁺ T-cells using IL-4, a cytokine with several pathophysiologic and therapeutic links to cancer. A chimeric cytokine receptor (4αβ) was engineered by fusion of the IL-4 receptor α (IL-4Rα) ectodomain to the β_c subunit, used by IL-2 and IL-15. Addition of IL-4 to T-cells that express 4αβ resulted in STAT3/STAT5/ERK phosphorylation and exponential proliferation, mimicking the actions of IL-2. Using receptor-selective IL-4 muteins, partnering of 4αβ with γ_c was implicated in signal delivery. Next, human T-cells were engineered to co-express 4αβ with a CAR specific for tumor-associated MUC1. These T-cells exhibited an unprecedented capacity to elicit repeated destruction of MUC1-expressing tumor cultures and expanded through several logs in vitro. Despite prolonged culture in IL-4, T-cells retained specificity for target antigen, type 1 polarity, and cytokine dependence. Similar findings were observed using CARs directed against two additional tumor-associated targets, demonstrating generality of application. Furthermore, this system allows rapid ex vivo expansion and enrichment of engineered T-cells from small blood volumes, under GMP-compliant conditions. Together, these findings provide proof of principle for the development of IL-4-enhanced T-cell immunotherapy of cancer.     

Cancer vaccines as a therapeutic modality: the long trek

The development of cancer vaccines has been one of the several false dawns in which initial promising Phase I and Phase II clinical data have not been followed up with conclusive Phase III trials. In this review, we describe some of the successes and failures, and review the most likely reasons for Phase III failure, such as protocol changes, which are common between Phase II and III, and poorly defined patient groups. Nevertheless, significant survival results have been reported with autologous vaccines for colorectal, renal and, more recently, prostate cancer. In addition, it is becoming evident that immunotherapy is potentially synergistic with other treatment modalities, such as chemotherapy, which can reduce T-regulatory activity that inhibits the immune response to cancer vaccines. This potential for synergy should allow cancer vaccines to become part of the standard treatment regimen for many common tumours.This article is a symposium paper from the “Robert Baldwin Symposium: 50 years of Cancer Immunotherapy”, held in Nottingham, Great Britain, on 30 June 2005.