肿瘤疫苗研究进展

随着肿瘤发生率及死亡率的日益提高,肿瘤治疗的手段不断改进和完善,采用疫苗治疗的方法成为肿瘤治疗的新途径。目前,针对肿瘤治疗的疫苗主要包括以下几种类型：细胞载体疫苗,单克隆抗体疫苗,肿瘤基因疫苗以及肿瘤多肽疫苗等,尤其是肿瘤多肽疫苗,在肿瘤治疗中具有广泛的应用前景。本综述对目前肿瘤相关疫苗的类型及研究进展情况进行了总结和分析,从而为进一步的研究提供一定的参考和借鉴。     

脂质体佐剂疫苗研究进展

脂质体作为蛋白质及多肽抗原的佐剂和载体已被广泛应用。通过综述脂质体在细菌、病毒、寄生虫和肿瘤疫苗中的研究应用 ,提示脂质体在疫苗的研制中具有广阔的应用前景     

脂质体佐剂疫苗研究进展

脂质体作为蛋白质及多肽抗原的佐剂和载体已被广泛应用。通过综述脂质体在细菌、病毒、寄生虫和肿瘤疫苗中的研究应用，提示脂质体在疫苗的研制中具有广阔的应用前景。     

药理学名词解释

肿瘤疫苗　　肿瘤疫苗是应用特异性的、具有免疫原性的肿瘤抗原,激活、恢复或加强机体抗肿瘤的免疫反应,清除残存的和转移的肿瘤细胞。肿瘤疫苗包括很多肿瘤抗原制剂,从整体肿瘤、肿瘤细胞的裂解物,纯化或合成的肿瘤多肽、肿瘤抗原的cDNA密码,或抗个体型抗体。肿瘤疫苗目前尚未     

肿瘤疫苗

肿瘤疫苗是应用特异性的、具有免疫原性的肿瘤抗原，激活、恢复或加强机体抗肿瘤的免疫反应，清除残存的和转移的肿瘤细胞。肿瘤疫苗包括很多肿瘤抗原制剂，从整体肿瘤、肿瘤细胞的裂解物，纯化或合成的肿瘤多肽、肿瘤抗原的cDNA密码，或抗个体型抗体。肿瘤疫苗目前尚未用于健康人的肿瘤预防，主要用于恶性肿瘤的辅助治疗。目前可将肿瘤疫苗的发展分为两个阶段。     

基于骨髓瘤抗原sp17的伪病毒肿瘤疫苗的制备和鉴定

目的：探讨制备、鉴定基于sp17的伪病毒肿瘤疫苗,为肿瘤的生物治疗策略提供新的方法。方法：在特定的条件下将肿瘤抗原多肽和DNA制备成模拟病毒样结构的颗粒,并以电镜、DNA阻滞试验、DNaseⅠ保护试验和免疫印迹（Westem blot）对该疫苗进行制备鉴定。结果：在一定浓度的氯化钠溶液中,电荷比为2的制备条件下,该疫苗能形成均匀的颗粒样结构。并可有效介导瘤苗所携带基因的表达。结论：该研究成功制备了基于sp17的伪病毒肿瘤疫苗,为新型的肿瘤疫苗的设计提供了新的思路。     

多肽疫苗的设计

本文介绍近年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.     

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。     

信使

[研发]抗肝癌NY-ESO-1b多肽疫苗获准临床试验在近日召开的北京大学人民医院科研年会上,该院肝病研究所陈红松报告称,经过9年的临床前研究,肿瘤抗原NY-ESO-1b多肽疫苗终于     

食管癌可溶性抗原和超抗原构建肿瘤疫苗的免疫活性成分分析

目的对食管癌可溶性抗原和超抗原SEC构建的肿瘤疫苗中的免疫活性成分进行分析,从而为探讨其抗癌机制打下理论基础。方法提取食管癌抗原,和超抗原SEC构建成肿瘤疫苗;分离人外周血单个核细胞（peripheral blood mononuclear cells,PBMC）,经肿瘤疫苗联合作用,进行体外培养,观察其增殖活性;流式细胞术FCM和细胞毒试验测定效应细胞表型和杀伤活性;提取食管癌细胞中的细胞膜抗原（mAg）、热休克蛋白70（HSP70）、DNA、RNA和细胞内多肽（Peptides）,用于诱导PBMC增殖,培养6d,用3H-Tdr掺入法测定细胞增值,确定其有效成分。结果经肿瘤疫苗刺激的PBMC组增殖活性最强,于72h达到高峰,并且特异性刺激CD8＋T细胞群增值。肿瘤疫苗刺激的PBMC组诱导的CTLs对靶细胞杀伤活性显著高于单纯PBMC组（P〈0.01）。食管癌细胞中的膜抗原和细胞内多肽能显著刺激PBMC增殖。结论食管癌抗原与超抗原构建的肿瘤疫苗能诱导效应细胞明显增殖、活化、并产生高效、特异的抗肿瘤效果,具有免疫活性的成分是细胞中的mAg和细胞内多肽。     

Development of WT1 peptide cancer vaccine against hematopoietic malignancies and solid cancers

Wild-type Wilms' tumor gene WT1 is highly expressed not only in hematopoietic malignancies, including leukemia and myelodysplastic syndromes (MDS), but also in various kinds of solid tumors. Human cytotoxic T lymphocytes (CTLs) which could specifically lyse WT1-expressing tumor cells with HLA class I restriction were generated in vitro. We have also demonstrated that mice immunized with the WT1 peptide or WT1 cDNA rejected challenges by WT1-expressing tumor cells and survived with no signs of auto-aggression to normal organs which physiologically expressed WT1 in prophylactic and therapeutic models. Furthermore, we and others detected IgM and IgG WT1 antibodies in the patients with hematopoietic malignancies, indicating that WT1 protein was highly immunogenic, and that immunoglobulin class-switch-inducing WT1-specific cellular immune responses were elicited in the patients. CD8+ WT1-specific CTLs were also detected in peripheral blood or tumor-draining lymph nodes of cancer patients. These results provided us with the rationale for elicitation of CTL responses targeting the WT1 product for cancer immunotherapy. On the basis of the findings mentioned above, we performed a phase I clinical trial of WT1 peptide cancer vaccine for the patients with malignant neoplasms. These results strongly suggested that WT1 peptide cancer vaccine had efficacy in the clinical setting, because clinical responses, including reduction of leukemic blast cells or regression of tumor masses, were observed after the WT1 vaccination in patients with hematopoietic malignancies or solid cancers. The power of TAA-derived cancer vaccine may be enhanced by combination with stronger adjuvants, helper peptide, or conventional treatments such as molecular-target-based drugs.     

Antiidiotypic antibodies carrying the "internal image" of peptide YIGSR inhibit spontaneous metastasis of Lewis lung carcinoma in mice

BACKGROUND: It has been reported that the laminin derivative synthetic peptide YIGSR can bind to a metastasis-associated laminin receptor and inhibit experimental metastasis. Several antiidiotypic antibody (anti-Id) vaccines have been used in clinical trials with promising results. We used an anti-Id vaccine based on peptide YIGSR for the inhibition of spontaneous metastasis in Lewis Lung carcinoma-bearing mice. MATERIALS AND METHODS: High titer anti-YIGSR serum from immunized rabbits was used to immunize sixteen Lewis Lung Carcinoma (LLC)-bearing mice. Another group of sixteen mice (controls) inoculated with LLC was immunized with control rabbit serum. After 24 days of tumor growth, the volume of the tumor was estimated, a blood sample was collected and the lungs were examined macroscopically and microscopically for metastasis. The presence of anti-Id antibodies was detected by Western blotting, ELISA and inhibition of cell attachment assays. RESULTS: Tumor growth was limited and metastasis was inhibited in the mice that received the anti-Id YIGSR vaccine as compared to controls. Both groups of mice developed anti-rabbit antibodies as indicated by Western blotting. However only the serum of mice immunized with high titer anti-YIGSR rabbit serum (anti-Id YIGSR vaccine) could inhibit the binding of the anti-YIGSR rabbit serum to the peptide YIGSR in ELISA assays. In addition the serum of mice that received the anti-Id YIGSR vaccine but not the controls inhibited cell attachment to the peptide on solid face assays. CONCLUSION: An anti-Id antimetastatic vaccine may be developed based on YIGSR.     

抗CD40抗体增强宫颈癌肽疫苗的治疗作用

目的：探讨抗CD40抗体对宫颈癌肽疫苗治疗作用的影响。方法将乳头状病毒结构性蛋白 E7表位肽（ E749－57,H－2Db限制性,CD8 T细胞表位）与Toll样受体7配体（Gardiquimod）组成疫苗,C57BL／6小鼠给予疫苗及抗CD40抗体免疫后取得外周血及脾组织CD8 T细胞,利用流式细胞仪分析特异性CD8 T细胞数量,Elisa检测CD8 T细胞与TC－1细胞（表达HPV E7蛋白的小鼠宫颈癌细胞）共孵育后干扰素（ INF－γ）表达水平。另取15只皮下荷瘤小鼠,监测免疫后肿瘤生长速度。结果与单用疫苗组相比,抗 CD40抗体明显增加小鼠外周血肿瘤特异性 CD8 T细胞数量（16．50±0．8185％ vs 9．747±1．834％,P＝0．0282）,且内源性CD8 T细胞体外与TC－1细胞共孵育可以分泌INF－γ,体内显著抑制皮下肿瘤生长（ P＜0．001）。结论抗CD40抗体增强肽疫苗诱发的免疫应答,有潜力成为一种良好的佐剂。     

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。     

多免疫途径对肝癌治疗的研究进展

作为我国最常见的恶性肿瘤——肝癌,其"隐匿性"的病情特点增加了临床发现、治疗的难度,使得临床总体治疗效果不理想。生物免疫治疗是继传统治疗后的一种新兴治疗方法,特别是多细胞因子的联合治疗已经取得了初步成效,多免疫途径的治疗措施主要体现在外源性引入细胞因子发挥被动免疫、调节免疫微环境、肿瘤细胞疫苗及多肽疫苗的诱导、过继性细胞免疫治疗等。这些治疗方法既能上调免疫效应细胞发挥特异性免疫应答的作用,又能保护肿瘤效应细胞,使之免受肿瘤细胞的诱导而发生免疫逃逸现象。     

Multi-Compartmental Vaccine Delivery System for Enhanced Immune Response to gp100 Peptide Antigen in Melanoma Immunotherapy

Purpose

To develop a multi-compartmental vaccine delivery system for safe and efficient delivery of the gp100 peptide antigen in melanoma immunotherapy.

Methods

Water-in-oil-in-water (W/O/W) multiple emulsion-based multi-compartmental vaccine delivery system containing the gp100 peptide was prepared by a two-step emulsification method. In vivo prophylactic and active immunization effectiveness of the novel squalane oil-containing gp100 vaccine was evaluated in the murine B16 melanoma model and compared with that of an incomplete Freund’s adjuvant (IFA)-based vaccine.

Results

Morphological evaluation of the W/O/W multiple emulsions showed that the oil-droplets were homogenously dispersed with the gp100 peptide encapsulated in an inner aqueous phase. Immunization with the gp100 peptide delivered in the W/O/W multiple emulsions-based vaccine resulted in increased protection against tumor challenge compared to IFA-based vaccine (p?<?0.05, n?=?8) signifying induction of enhanced anti-tumor immunity. In addition, serum Th1 cytokine levels and immuno-histochemistry of excised tumor tissues indicated activation and local infiltration of antigen specific cytotoxic T-lymphocytes into and/or surrounding the tumor mass. Moreover, the newly developed vaccine formulation did not induce any overt systemic toxicity.

Conclusion

Novel W/O/W multiple emulsions-based vaccine efficiently delivers the gp100 peptide antigen to induce cell-mediated anti-tumor immunity and offers an alternate, safe vaccine delivery system.     

抗肿瘤DNA疫苗的研究近况

DNA疫苗技术在近十年来取得了显著的进步,而它在肿瘤预防和治疗领域的优势,使得抗肿瘤的DNA疫苗成为当前医药界的一个研究热点。文章主要介绍了一些作为DNA疫苗免疫靶点的肿瘤抗原,包括已经鉴定并进入临床试验研究和潜在的.可作为治疗靶点的肿瘤抗原,并着重介绍了如何解决由于肿瘤抗原作为一种自身抗原而导致的抗肿瘤DNA疫苗所面临的免疫原性较弱和抗肿瘤效果不理想这两个主要的问题.包括: 加入分子佐剂.主要是一些细胞因子而有效提高抗肿瘤DNA疫苗的免疫原性;通过使用与肿瘤抗原基因种属不同,但具有一定同源性的基因而打破肿瘤抗原的外周免疫耐受。最后主要从肿瘤疫苗免疫的靶点入手.介绍了能够有效增强DNA疫苗抗肿瘤作用的几种新的策略。     

Intracellular delivery of a novel multiepitope peptide vaccine by an amphipathic peptide carrier enhances cytotoxic T‐cell responses in HLA‐A*201 mice

Abstract: Cytotoxic T lymphocytes (CTL) are key players in the neutralization of viruses and killing of tumor cells. However, for generating an optimal CTL response by vaccination, the antigen has to be delivered directly into the cytoplasm for presentation by the conventional MHC class I pathway. To mimic the presentation of multiple epitopes by a tumor or virus infected cell, we have designed a multiepitope peptide vaccine incorporating thee CTL epitopes in tandem with double arginine spacers to facilitate efficient cleavage of the individual epitopes. To deliver the multiepitope peptide vaccine into the cytoplasm of mature dendritic cells for presentation by the MHC class I pathway we made use of an amphipathic peptide carrier. Direct injection of a non‐covalent complex of the multiepitope peptide vaccine and amphipathic peptide carrier in an aqueous formulation into HLA‐A*0201 (HHD) transgenic mice enhanced the cytotoxic T‐cell responses by two to sixfold compared with multiepitope peptide vaccination alone. This novel antigen delivery strategy may find general application in the development of more effective vaccines for the treatment of cancer and infectious disease.     

肿瘤疫苗临床研究的最新进展

目的:了解肿瘤疫苗临床研究的最新进展,为肿瘤疫苗的研发提供参考。方法:依据国内、外研究文献和临床试验注册平台及相关专利等信息,对已上市和进入Ⅲ期临床试验的肿瘤疫苗的临床研究最新进展进行综述。结果与结论:目前已上市或进入Ⅲ期临床试验的肿瘤疫苗以树突细胞疫苗、抗原佐剂疫苗和肿瘤细胞疫苗为主,多用于宫颈癌、黑色素瘤、肺癌、乳腺癌、前列腺癌等的预防和治疗。     

T-cell epitope analogues from carcinoembryonic antigen for vaccination against cancer: WO2009002418

Background: Cancer is one of the leading causes of death in the Western world. Therapeutic vaccination to target minimal residual disease or prevent tumor recurrence represents an interesting and novel alternative for treatment of tumor diseases. T-cell peptide epitopes are commonly used as vaccine candidates for the induction of antitumor immune responses. By modifying the amino-acid sequence of the peptide at certain, so-called anchor positions, the binding affinity to MHC class I and the immunogenicity of the peptide can be improved. Vaccination with the modified peptide analogue can then be used to induce an immune response to the wild-type epitope. Method: The present application concerns the use of peptides representing wild-type T-cell epitopes and analogues from carcinoembryonic antigen for vaccination against cancer. The stated claims also include the use of these epitopes in several other vaccine modalities, including RNA, DNA and adenoviral vector vaccines. Conclusion: Although the available data clearly support the basic claims that some of the peptide analogues indeed are able to induce a potent immune response in mice to the corresponding wild-type epitopes, the lack of in vivo antitumor data for any of the covered vaccine modalities prevents a thorough evaluation of the stated claims.