肿瘤免疫治疗中新生抗原预测与筛选技术研究进展

肿瘤新生抗原是由体细胞突变产生的能诱导肿瘤特异性T细胞识别的多肽,是一种肿瘤特异性抗原,是肿瘤免疫治疗的理想靶点.靶向肿瘤新生抗原的疫苗、T细胞受体嵌合T细胞疗法和肿瘤浸润淋巴细胞疗法均已进入临床研究阶段.准确快速地鉴定肿瘤新生抗原对于成功的免疫治疗至关重要,也是目前个性化免疫治疗中的一个难点.近年来有大量肿瘤新生抗原...     

新生抗原免疫治疗的研究进展与监管现状

新生抗原是由肿瘤细胞基因突变而产生的一类特异性多肽,可在细胞内表达和加工,随后被主要组织相容性复合物呈现至细胞表面,并被T细胞识别,从而激活机体的免疫系统,引起一系列免疫应答反应。随着测序技术和人工智能预测方法的快速发展,新生抗原疗法已成为未来肿瘤治疗的重要发展方向。在精准医疗的时代背景下,基于新生抗原的个体化肿瘤疫苗和过继性T细胞转移疗法在恶性黑色素瘤、脑胶质瘤等肿瘤治疗领域显示出鼓舞人心的结果,并且新生抗原联合其他免疫治疗的方案也展现出广阔的应用前景。然而,这种新兴的个体化治疗方法在充满医学前景的同时也伴随着复杂的研发、监管等挑战。本文将简要介绍新生抗原的研究进展和监管现状,以期为我国新生抗原的研发、监管等提供参考。     

肿瘤新生抗原疫苗研究新进展

肿瘤新生抗原是指由肿瘤细胞基因突变产生的特异性抗原,可激活CD4+T和CD8+T细胞产生免疫反应,抑制肿瘤生长.因肿瘤新生抗原未经历中枢性免疫耐受,故其免疫原性高.肿瘤新生抗原疫苗种类有DNA疫苗、RNA疫苗、树突状细胞疫苗及纳米疫苗等,是高度个体化疫苗,相对安全且副作用小.利用新一代测序技术和生物信息学技术鉴定和筛选...     

抗肿瘤重组蛋白疫苗的研究进展

肿瘤疫苗包括肽或蛋白疫苗、肿瘤细胞疫苗、抗独特型疫苗、树突状细胞疫苗、DNA疫苗及病毒载体类疫苗等。重组蛋白疫苗是通过对目的抗原基因的重组、构建、表达得到抗原蛋白,最终制备成的疫苗。随着重组技术及表达纯化技术的日益成熟,重组蛋白疫苗为肿瘤免疫治疗研究提供了一种研发思路。此文针对肿瘤抗原的重组蛋白疫苗做一综述。     

个体化的癌症疫苗有望使肿瘤缓解

近年来曾应用整个细胞、肽、经遗传工程修饰的及发生凋亡的肿瘤细胞来制作癌症疫苗，用以刺激宿主的免疫系统而应答肿瘤细胞特征性的抗原。不过美国康涅狄格大学医学院癌症及传染病免疫治疗中心主任Srivastava强调：癌症都像指纹那样具有独特性，因此癌症疫苗必须个体化。他与俄勒冈州的Druker等合作成立了一家Antigenic公司研制这类疫苗。     

双特异性抗体在恶性肿瘤临床治疗中的研究进展

肿瘤免疫治疗包括免疫检查点抑制剂、单克隆抗体疗法、过继细胞疗法、溶瘤病毒疗法和肿瘤疫苗等。其机制为免疫治疗可激活体内T细胞识别肿瘤细胞的特异性抗原,诱发免疫细胞激活、克隆性增殖/扩增和靶细胞溶解反应,发挥杀伤肿瘤效应。相比于单克隆抗体,双特异性单克隆抗体可以通过靶向多个抗原或抗原表位发挥协同抗肿瘤作用,介导多种特定生物学效应,后者包括连接免疫细胞与肿瘤细胞,募集并激活免疫细胞来消灭肿瘤细胞;作用于多个信号通路,协调肿瘤杀灭生物过程;通过抗体双价结构来介导蛋白复合物形成。目前双特性抗体用于治疗晚期肺癌,乳腺癌,胃癌,结直肠癌和CD20阳性淋巴瘤等。本文就双特异性抗体在肿瘤临床治疗中的研究进展和应用综述。     

树突状细胞在肿瘤免疫治疗领域的研究进展

树突状细胞具有摄取、加工及呈递抗原至T淋巴细胞的能力,在机体的抗肿瘤免疫过程中具有重要作用.本文对肿瘤抗原肽、肿瘤细胞蛋白提取物或肿瘤相关基因等致敏的树突状细胞疫苗以及肿瘤细胞与树突状细胞的融合疫苗等介导的抗肿瘤免疫治疗在动物试验与临床试验的研究进行综述.     

合理设计基于肽的肿瘤疫苗

体内摄入人工合成的肿瘤细胞所专有的或过表达的肿瘤相关抗原(TAA)肽，就能引发肿瘤特异性免疫应答。但与病毒性抗原的肽不同，TAA肽与主要组织相容性复合体(MHC)分子的结合力一般都较弱。因此，设法通过提高MHC的结合力来上调对抗原的识别，就有可能使低亲和力的TAA肽制备成疫苗而用于肿瘤免疫治疗。本文叙述了迄今为止对TAA肽进行修饰所采取的路线和临床试验的初步结果，以及今后在这一方面探索的努力方向。     

多肽疫苗的设计

本文介绍了近来代表肿瘤相关抗原，病毒和寄生虫保护性表位的多肽疫苗的研究进展，主要是多价抗原肽，分支多肽，融合或重组多肽，Ｔ细胞表位和肿瘤抗原肽疫苗设计方面的进展，它们虽然尚未实际使用，但目前正在探索其潜力。     

新生抗原癌症疫苗研究进展

新生抗原是癌细胞上存在的蛋白质片段,具有特异性,是肿瘤免疫治疗的理想靶标.靶向新生抗原的癌症疫苗不仅能够有效诱导体内的免疫应答,而且具有安全性高、副作用小等优势,已逐渐成为研究的热点.本篇综述主要对新生抗原癌症疫苗的发展历程、制备形式、递送策略及临床进展作一概述,以期为后续的研究提供参考.     

姜黄素的免疫调节作用及其肿瘤免疫治疗的研究进展

癌症发病率逐年增长,且死亡率居高不下。肿瘤免疫治疗作为目前肿瘤治疗领域中最具前景的研究方向之一,其治疗手段主要包括过继性细胞治疗、免疫调节治疗、肿瘤疫苗治疗、分子靶向治疗等。姜黄素是姜黄中主要活性成分,主要通过抑制细胞增殖、诱导细胞凋亡、抑制肿瘤侵袭等机制发挥抗肿瘤功效。在免疫治疗领域,姜黄素通过调节机体的固有免疫系统、获得性免疫系统以及肿瘤相关分子的表达和活性达到抗肿瘤作用,并联合免疫检查点抑制剂、其他肿瘤免疫治疗方法用于肿瘤治疗。总结了姜黄素的免疫调节作用及其用于肿瘤免疫治疗的研究进展。     

恶性黑色素瘤的基因靶向治疗及生物免疫治疗的研究现状

恶性黑色素瘤是一种很难有效治疗的侵袭性恶性肿瘤,其对放化疗的敏感性很低。对于手术后或者已经失去手术时机的患者,基因靶向治疗及生物免疫治疗可以巩固治疗,延长患者生存期或者改善患者生存质量。基因靶向治疗具有一定特异性与靶向性,能切断突变基因诱导的信号传导,抑制肿瘤细胞的增殖。生物免疫治疗通过增强或者诱导患者自身的免疫应答来对抗、抑制和杀灭肿瘤细胞。本文就目前基因靶向治疗及生物免疫治疗的研究现状进行综述。     

Self-assembling peptides-based nano-cargos for targeted chemotherapy and immunotherapy of tumors: recent developments,challenges, and future perspectives

Self-assembling peptides (SAPs) have enormous potential in medical and biological applications, particularly noninvasive tumor therapy. SAPs self-assembly is governed by multiple non-covalent interactions and results in the formation of a variety of morphological features. SAPs can be assembled in a variety of ways, including chemical conjugation and physical encapsulation, to incorporate multiple bioactive motifs. Peptide-based nanomaterials are used for chemotherapy, delivery vehicles, immunotherapy, and noninvasive tumor therapies (e.g. photodynamic therapy) by employing the self-assembling properties of peptides. The recent increase of SAPs is almost entirely due to their excellent biocompatibility, responsiveness toward tumor microenvironment, multivalency, and structural versatility. Synergistic therapy is a more effective and powerful approach to treat the tumor. Notably, SAPs can be used to subtly combine various treatments. Importantly, SAPs are capable of subtly making the combination of various treatments. This review describes mechanisms of peptides self-assemble into various structures and their biomedical applications with a focus on possible treatments.     

细胞治疗产品安全性的研究进展

目前肿瘤免疫治疗方案包括治疗性肿瘤疫苗、免疫检查点抑制剂(PD1、PDL1、CTLA-4)、过继性细胞免疫治疗(CAR-T、TCR-T、CAR-NK)、溶瘤病毒等,过继性免疫治疗技术主要是弥补经过主动免疫治疗(治疗性肿瘤疫苗、免疫检查点抑制剂)的无进展生存(PFS)的肿瘤人群。随着FDA批准的诺华和Kite细胞制品CAR-T的上市,国内外过继性细胞免疫治疗肿瘤的技术发展迅速,但是针对过继性细胞免疫治疗技术生产的细胞治疗产品的质量安全风险凸显出来。文章主要针对国内外细胞治疗产品质量安全性的研究进行综述。     

Drug-induced immunotoxicity.

Immune-related drug responses are one of the most common sources of idiosyncratic toxicity. A number of organs may be the target of such reactions; however, this review concentrates mostly on the liver. Drug-induced hepatitis is generally divided into two categories: acute hepatitis in which the drug or a metabolite destroys a vital target in the cell; immunoallergic hepatitis in which the drug triggers an adverse immune response directed against the liver. Their clinical features are: a) low frequency; b) dose independence; c) typical immune system manifestations such as fever, eosinophilia; d) delay between the initiation of treatment and onset of the disease; e) a shortened delay upon rechallenge; and f) occasional presence of autoantibodies in the serum of patients. Such signs have been found in cases of hepatitis triggered by drugs such as halothane, tienilic acid, dihydralazine and anticonvulsants. They will be taken as examples to demonstrate the recent progress made in determining the mechanisms responsible for the disease. The following mechanisms have been postulated: 1) the drug is first metabolized into a reactive metabolite which binds to the enzyme that generated it; 2) this produces a neoantigen which, once presented to the immune system, might trigger an immune response characterized by 3) the production of antibodies recognizing both the native and/or the modified protein; 4) rechallenge leads to increased neoantigen production, a situation in which the presence of antibodies may induce cytolysis. Toxicity is related to the nature and amount of neoantigen and also to other factors such as the individual immune system. An effort should be made to better understand the precise mechanisms underlying this kind of disease and thereby identify the drugs at risk; and also the neoantigen processes necessary for their introduction into the immune system. An animal model would be useful in this regard.     

Macrophage-mediated tumor-targeted delivery of engineered Salmonella typhimurium VNP20009 in anti-PD1 therapy against melanoma

Bacterial antitumor therapy has great application potential given its unique characteristics, including genetic manipulation, tumor targeting specificity and immune system modulation. However, the nonnegligible side effects and limited efficacy of clinical treatment limit their biomedical applications. Engineered bacteria for therapeutic applications ideally need to avoid their accumulation in normal organs and possess potent antitumor activity. Here, we show that macrophage-mediated tumor-targeted delivery of Salmonella typhimurium VNP20009 can effectively reduce the toxicity caused by administrating VNP20009 alone in a melanoma mouse model. This benefits from tumor-induced chemotaxis for macrophages combined with their slow release of loaded strains. Inspired by changes in the tumor microenvironment, including a decrease in intratumoral dysfunctional CD8⁺ T cells and an increase in PDL1 on the tumor cell surface, macrophages were loaded with the engineered strain VNP-PD1nb, which can express and secrete anti-PD1 nanoantibodies after they are released from macrophages. This novel triple-combined immunotherapy significantly inhibited melanoma tumors by reactivating the tumor microenvironment by increasing immune cell infiltration, inhibiting tumor cell proliferation, remodeling TAMs to an M1-like phenotype and prominently activating CD8⁺ T cells. These data suggest that novel combination immunotherapy is expected to be a breakthrough relative to single immunotherapy.     

The progress and perspective of nanoparticle-enabled tumor metastasis treatment

As one of the most serious threats to human being, cancer is hard to be treated when metastasis happens. What's worse, there are few identified targets of metastasis for drug development. Therefore, it is important to develop strategies to prevent metastasis or treat existed metastasis. This review focuses on the procedure of metastasis, and first summarizes the targeting delivery strategies, including primary tumor targeting drug delivery, tumor metastasis targeting drug delivery and hijacking circulation cells. Then, as a promising treatment, the application of immunotherapy in tumor metastasis treatment is introduced, and strategies that stimulating immune response are reviewed, including chemotherapy, photothermal therapy, photodynamic therapy, ferroptosis, sonodynamic therapy, and nanovaccines. Finally, the challenges and perspective about nanoparticle-enabled tumor metastasis treatment are discussed.     

Selecting immuno-oncology–based drug combinations – what should we be considering?

ABSTRACT

Introduction: Checkpoint inhibitor immunotherapy has revolutionized the treatment of many advanced stage cancers. Preexisting immunity is necessary for a response to these agents, which are most effective in inflamed tumors since they principally act by reinforcing preexisting antitumor T-cell responses. An important goal of therapy is to convert the tumor environment from non-inflamed to inflamed in order to facilitate subsequent response to checkpoint inhibitors. Clinical trials are underway to identify checkpoint inhibitor-based combination approaches, which may help to achieve this goal.

Areas covered: Anti-PD-1 agents are being assessed in combination with different treatments (e.g. TLR9 agonists, oncolytic peptides, oncolytic vaccines, LAG-3, HDAC inhibitors, GITR, recombinant human interleukin-2) with promising results. PD-1 agents are also being assessed in combination with other locoregional or systemic treatment modalities, including ECT, radiotherapy, chemotherapy, and targeted therapy, with promising results being achieved.

Expert commentary: Emerging approaches based on combinations with anti-PD-1 agents seem to offer increased efficacy compared to anti-PD-1 monotherapy. Such combinations also appear to be well tolerated, with safety profiles often comparable to those seen with anti-PD-1 monotherapy. These combination approaches are likely to become an increasing focus of research. There is also the potential for triplet anti-PD-1 combinations.