个体化新抗原疫苗临床转化的机遇与挑战

[摘要] 肿瘤疫苗（tumor vaccine）作为一种举足轻重的免疫疗法,已日益在恶性肿瘤治疗中显示其重要价值。然而,针对肿瘤相关抗原（tumor associated antigen,TAA）的传统疫苗由于免疫耐受、诱发自身免疫疾病的风险,难以在临床大规模推广。来源于肿瘤体细胞突变、异于正常细胞的新抗原（neoantigen）近年来被认为是理想的疫苗靶点。在测序的基础上发展而来的个体化新抗原疫苗（personalized neoantigen vaccine）特异性靶向新抗原,有望成为精准治疗肿瘤的重要突破口。本文围绕个体化新抗原疫苗的概念、特点、制备流程及临床试验等方面的研究进展进行详细阐述,并对其临床转化面临的机遇与挑战作一展望。     

肿瘤疫苗与肿瘤免疫治疗研究进展

免疫系统是人体最重要的防御系统之一 ,正常的免疫应答赋予人体抗御感染 ,识别自我与非我 ,及时清除体内衰老、变性的细胞 ,监视突变细胞并将之消灭。肿瘤细胞是人体的变异细胞 ,只要充分调动人体的免疫功能 ,尤其是肿瘤特异性免疫功能 ,就能将肿瘤细胞清除。免疫治疗学的本质就是通过各种手段 ,提高、抑制或调节机体的免疫应答能力 ,最终达到纠正紊乱、治疗疾病的目的 ,其中包括特异性免疫和非特异性免疫。非特异性免疫应答是与生俱来的 ,它的形成并不需要抗原刺激 ,能广泛地针对多种抗原 ,是免疫应答的基础 ,但特异性不强 ,对某种特定抗原…     

肿瘤疫苗研究的回顾与展望

190 2年利用肿瘤疫苗 (tumor vaccine,简称瘤苗 )对癌症患者进行免疫治疗的尝试标志着肿瘤免疫学的开端。近一个世纪来有关瘤苗的研究始终是围绕着肿瘤的抗原性及机体的抗肿瘤免疫应答这个肿瘤免疫学的核心问题展开的。在世纪之交对肿瘤疫苗的研究、应用与开发作一回顾与展望可能是有益的。1　百年历史回顾1 .1　早期阶段 (上世纪初～中叶 ) :盲目尝试在基础免疫学 (P.Ehrlich,E.Metchinikoff等 )特别是抗感染免疫治疗成就 (von Behring对白喉的抗毒素血清治疗获首届诺贝尔生理学及医学奖 ,1 90 1 )的启发与推动下 ,1 90 2年 Leyden和 Bl…     

肿瘤疫苗研究的现状

随着分子免疫学、分子生物学及基因工程技术的迅速发展,肿瘤疫苗的研究取得了令人鼓舞的成果.目前,肿瘤疫苗类型主要有以下几种.     

肿瘤相关抗原在乳腺癌治疗性疫苗中的应用

 近年来,多种乳腺癌治疗性疫苗进入临床试验阶段,为乳腺癌治疗带来了新的希望。乳腺癌治疗性疫苗的研究,展现了肿瘤相关抗原的优点及其应用特点,同时也提出有待解决的问题。     

肿瘤疫苗及其应用研究

随着肿瘤免疫学、疫苗新技术及分子医学等学科的不断发展，肿瘤疫苗研究与应用倍受关注。目前已有多种形式肿瘤疫苗进行了动物实验和临床研究，并取得了可喜成果。本文就近年来肿瘤疫苗的制备方法、作用机制及临床应用现状进行综述。     

癌症mRNA疫苗的研究现状、挑战及展望

经过多年发展，癌症疫苗逐渐成为肿瘤免疫治疗的重要组成部分，并且在当今时代的背景下呈现出更加迅猛的发展势头。随着信使RNA(messenger RNA,mRNA)技术在新型冠状病毒疫苗中取得的成功，癌症mRNA疫苗的研发与应用也重新成为科研人员和临床医师关注的焦点。近年来，基于癌症m RNA疫苗的临床研究更是层出不穷，并且在许多肿瘤患者中证明了其可行性与有效性。本文将从癌症mRNA疫苗的优势、研究与应用现状、局限及挑战这几个方面进行评述。     

肿瘤疫苗的研究进展

随着肿瘤免疫学的不断发展,肿瘤疫苗已成为肿瘤免疫治疗研究的热点。目前,肿瘤细胞疫苗在多项临床试验中的效果较为明显,在患者体内可检测出有意义的免疫应答反应, 且患者有很好的耐受性;基因疫苗在动物实验和临床试验中显示出靶向性和充分激活抗肿瘤免疫等优点;肿瘤多肽疫苗,因其化学性质稳定、易于制备、无潜在致癌性等优点, 更是受到广泛关注;以现代分子生物学技术将肿瘤细胞、裂解的肿瘤细胞成分或肿瘤细胞的凋亡产物、肿瘤mRNA或DNA等修饰树突状细胞制成瘤苗, 则为肿瘤治疗开辟了一种新的途径;细胞毒性T淋巴细胞表位肽疫苗通过在体内、外激发特异性CTL抗肿瘤免疫应答, 部分多肽表位疫苗已进入临床Ⅰ期和Ⅱ期试验, 并取得较好的疗效。本文将对这些肿瘤疫苗的作用特点、研究进展及应用现状作一综述。     

抗肿瘤糖疫苗的研究进展

肿瘤相关糖抗原（tumor-associated carbohydrate antigens, TACAs）是肿瘤表面重要的分子标记物,基于TACAs的肿瘤疫苗已成为肿瘤免疫治疗的热点。寻找合适的糖抗原与大分子载体连接,或者在免疫过程中添加免疫佐剂,是目前抗肿瘤糖疫苗设计的主要思路,如将TACAs与蛋白载体共价结合制备糖结合物疫苗,或与T细胞肽表位或免疫刺激表位连接制备多组分糖疫苗。从天然糖抗原疫苗,到半合成和全合成的糖抗原疫苗,抗肿瘤糖疫苗的发展十分迅速,并有一些疫苗进入了临床研究。近年来,联合应用TACAs类似物糖疫苗和肿瘤细胞糖质工程在肿瘤免疫治疗中也取得了可喜的结果,更多有效的TACAs相关肿瘤免疫策略也在积极研究中,相信在不久的将来会取得重大的突破。     

肿瘤免疫与免疫治疗：机遇与挑战

随着新技术的发展以及研究模式的创新,肿瘤免疫的研究迎来了飞速发展,肿瘤免疫治疗也取得了令人瞩目的临床疗效,共同推动了肿瘤免疫学从机制研究到临床转化、从单一学科到多学科融合的整体提升。然而,肿瘤免疫学研究依然面临着诸多挑战,如临床肿瘤的动物模型复制、肿瘤内在调控的复杂性及其与宿主微环境的关系、免疫治疗靶点的筛选及疗效预测,这些问题限制了肿瘤免疫的深入发展及进一步应用,但也给基础与临床免疫学研究者带来了新的研究机遇。因此,本文从研究模式的转变、研究机制的创新、研究方向的拓展、治疗靶点的筛选与评估、研究技术的革新与应用等五个方面,总结并展望了肿瘤免疫与免疫治疗的研究现状及面临的挑战。     

肿瘤免疫治疗的研究进展和发展趋势

随着免疫学技术的进步,大量肿瘤抗原不断被发现。DC摄取肿瘤抗原诱导免疫激活还是抑制,取决于肿瘤细胞释放危险信号（GMCSF、单核趋化蛋白1、MCP1及热休克蛋白等）还是抑制性信号（TGFβ、IDO和iNOS等）。在危险信号的调节下,激活Th1细胞免疫应答清除肿瘤;而在抑制性信号的作用下,激活Th2应答,不能有效清除肿瘤。肿瘤免疫治疗方面的进展主要表现在抗体疗法、T细胞疗法及肿瘤疫苗。目前至少有7种抗体与化疗药物合用的临床效果已经被证实;尽管抗不同种癌症的抗体种类在逐渐增加,但还需进一步探讨用于抗体治疗的新靶点、开发新抗体及扩大抗体应用的抗肿瘤范围。而T细胞疗法治疗效果不十分理想。大多数肿瘤疫苗处于Ⅰ期和Ⅱ临床试验,但为数不多的Ⅲ期临床试验结果不理想,尚需进一步完善。抗体在免疫监视中的重要作用被逐渐认识,肿瘤免疫预防最终可能成为现实。     

Breast cancer immunobiology driving immunotherapy: vaccines and immune checkpoint blockade

Breast cancer is immunogenic, and infiltrating immune cells in primary breast tumors convey important clinical prognostic and predictive information. Furthermore, the immune system is critically involved in clinical responses to some standard cancer therapies. Early breast cancer vaccine trials have established the safety and bioactivity of breast cancer immunotherapy, with hints of clinical activity. Novel strategies for modulating regulators of immunity, including regulatory T cells, myeloid-derived suppressor cells and immune checkpoint pathways (monoclonal antibodies specific for the cytotoxic T-lymphocyte antigen-4 or programmed death), are now available. In particular, immune checkpoint blockade has enormous therapeutic potential. Integrative breast cancer immunotherapies that strategically combine established breast cancer therapies with breast cancer vaccines, immune checkpoint blockade or both should result in durable clinical responses and increased cures.     

Tumor vaccines

Melanoma vaccines are an exciting and increasingly attractive immunotherapeutic approach for malignant melanoma. Vaccines can be used for patients with high risk primary melanoma and regional disease, stages in the progression of melanoma for which there is presently no treatment. They are unique in their potential to prevent cancer in high risk individuals.Multiple approaches are being followed to develop effective vaccines. It is too early to judge whether any of them effectively slow the progression of melanoma. However, it is clear that vaccines are safe to use, and that they can stimulate immune responses to melanoma in some patients. The specificity of these responses needs to be clarified, and multiple challenges remain to be overcome before effective vaccines to melanoma become available. We must first identify the antigens on melanoma that stimulate immune responses, define the immune effector mechanisms that are stimulated by vaccine immunization and identify those responsible for increasing resistance to tumor growth, devise appropriate ways of constructing vaccines that will induce such responses, and find adjuvants and/or immunodulators that will potentiate desirable immune responses.     

The differentiation antigen NY-BR-1 is a potential target for antibody-based therapies in breast cancer

Antibody-based cancer immunotherapy relies on the identification and characterization of target antigens and the development of potent antibodies recognizing the target. Here we report the expression analysis and molecular characterization of the differentiation antigen NY-BR-1, which we previously identified by using the SEREX (serological analysis of recombinant cDNA expression libraries) method. Corroborating methodologies, including mRNA quantitation and immunoblotting show that NY-BR-1 is strongly expressed in >70% of 129 breast tumors. Application of a NY-BR-1 specific antibody demonstrated NY-BR-1 expression in primary and metastastic breast cancers. In contrast, most of the breast cancer cell lines tested, expressed only low NY-BR-1 levels. Importantly, confocal microscopy revealed that ectopically expressed NY-BR-1 localizes to the cytoplasm and the cell membrane. NY-BR-1 localization in breast cancer specimens was also confirmed by immunohistochemistry. Bioinformatic analysis and deletion mutagenesis further show that NY-BR-1 membrane localization is mediated by 2 cis-active membrane targeting domains. Biochemical surface labeling and FACS analysis of live cells further characterize NY-BR-1 as a transmembrane protein, which can be specifically recognized by the anti-NY-BR-1 antibody on the surface of vital cells. The strong expression of NY-BR-1 in breast tumors, its cytoplasmic and membrane localization and accessibility to an ectopically applied antibody now suggest to pursue NY-BR-1 as a potential target for antibody-based therapies in breast cancer patients.     

Molecular cancer vaccines: Tumor therapy using antigen-specific immunizations

Vaccination against tumors promises selective destruction of malignant cells by the host's immune system. Molecular cancer vaccines rely on recently identified tumor antigens as immunogens. Tumor antigens can be applied in many forms, as genes in recombinant vectors, as proteins or peptides representing T cell epitopes.Analysis of various aspects indicates some advantage for peptide-based vaccines over the other modalities. Further refinements and extensively monitored clinical trials are necessary to advance molecular cancer vaccines from concepts into powerful therapy.     

Tumor mutational burden as a predictor of immunotherapy response in breast cancer

Tumor mutational burden (TMB) is a promising tool to help define patients with triple-negative breast cancer (TNBC) most likely to benefit from immune checkpoint blockade (ICB) therapies. Roughly reflecting the degree of neo-antigens that tumors present to immune cells, TMB associates with multiple measures of tumoral immunogenicity and has proven clinically useful in cancers with relatively high mutation burden. TNBC carries higher TMB than other breast cancer subtypes, and recent data suggest that high-TMB TNBC cases may derive particular benefit from ICB in combination with chemotherapy (GeparNuevo, IMpassion130) or even ICB alone (KEYNOTE-119, TAPUR). Given the recent approval of pembrolizumab and atezolizumab in combination with chemotherapy for PD-L1-positive, metastatic TNBC, standardizing TMB calculation methods and cut-off values is of critical importance to deploy this clinical biomarker.     

抑癌基因PTEN与乳腺癌

目的:总结国内外在乳腺癌中关于PTEN的研究进展,探索其对于乳腺癌治疗的指导作用。方法:利用PubMed数据库检索系统,以乳腺癌、PTEN、AKT为关键词,检索近5年的相关文献,共检索到英文文献104篇。纳入标准:1)PTEN来源和分子结构特征;2)PTEN发挥功能的几种途径,特别是PI3K/AKT途径;3)PTEN与乳腺癌治疗的关系。根据纳入标准,最后精选了43篇文章分析。结果:SHIP2、PIK3CA和BRCA1对PTEN的抑癌作用起负性作用,而BMP2、E-钙黏蛋白和p27kip1能促进PTEN的抑癌作用。PTEN表达决定乳腺癌细胞对于化疗药物doxo-rubicin、tamoxifen、ZD1839和trastuzumab的敏感性,却降低了对rapamycin的反应性。结论:虽然已经知道抑癌基因PTEN与乳腺癌密切相关,但其具体机制仍不清楚,需要进一步研究。     

Brain Tumor Immunotherapy: An Immunologist's Perspective

Key concepts in brain tumor immunotherapy are reviewed. "Immunotherapy" can refer to a fully-developed, tumor-specific immune response, or to its individual cellular or molecular mediators. The immune response is initiated most efficiently in organized lymphoid tissue. After initiation, antigen-specific T lymphocytes (T cells) survey the tissues – including the brain. If the T cells re-encounter their antigen at a tumor site, they can be triggered to carry out their effector functions. T cells can attack tumor in many ways, directly and indirectly, through cell-cell contact, secreted factors, and attraction and activation of other cells, endogenous or blood-borne. Recent work expands the list of candidate tumor antigens: they are not limited to cell surface proteins and need not be absolutely tumor-specific. Once identified, tumor antigens can be targeted immunologically, or in novel ways. The immune response is under complex regulatory control. Most current work aims to enhance initiation of the response (for example, with tumor vaccines), rather than enhancing the effector phase at the tumor site. The effector phase includes a rich, interactive set of cells and mediators; some that are not usually stressed are of particular interest against tumor in the brain. Within the brain, immune regulation varies from site to site, and local neurochemicals (such as substance P or glutamate) can contribute to local control. Given the complexity of a tumor, the brain, and the immune response, animal models are essential, but more emphasis should be given to their limitations and to step-by-step analysis, rather than animal "cures".