Gene Delivery Systems of Carbohydrate Mimotopes to Dendritic Cells

碳水化合物模拟表位至树突细胞的基因递送系统

• 批准号: 7574401
• 负责人: Danuta B Kozbor
• 金额: $ 23.06万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2011-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7574401
• 关键词: Address; Adoptive Cell Transfers; Affinity; Antibodies; Antibody Formation; Antigen-Presenting Cells; Antigens; Autoantigens; Carbohydrates; Cells; Chimeric Proteins; Clinical Trials; Complex; Dendritic Cell Vaccine; Dendritic Cells; Effectiveness; Epitopes; Fc Receptor; Future; Ganglioside GD2; Glioma; Glycols; IgG Receptors; IgG1; IgG3; Immune response; Immunity; Immunization; Immunoglobulin G; Immunoglobulin M; Immunotherapy; Lesion; Liposomes; Modified Vaccinia Virus Ankara; Monoclonal Antibodies; Monoclonal Antibody 14G2A; Mus; Neuroblastoma; Patients; Peptides; Physiologic pulse; Proliferating; Recombinant Fusion Proteins; Recombinants; Reporting; T-Lymphocyte; Therapeutic antibodies; Therapy Clinical Trials; Toxic effect; Treatment Protocols; Tumor Antigens; Tumor-Derived; Vaccination; Vaccines; Viral Vector; base; cancer therapy; design; gene delivery system; immunogenic; immunogenicity; in vivo; melanoma; neoplastic cell; next generation; novel strategies; public health relevance; response; sarcoma; trafficking; tumor; tumor immunology

DESCRIPTION (provided by applicant): The GD2 ganglioside expressed on neuroectodermally derived tumors, including neuroblastoma and melanoma, is weakly immunogenic in tumor-bearing patients and induces predominantly IgM antibody responses in the immunized host. To overcome the intrinsically weak immunogenicity of carbohydrate antigens and tolerance to self/tumor-associated antigens in a tumor-bearing host, we have generated a mimotope of GD2 ganglioside, designated 47-LDA. Our rational for this immunization strategy is that since the 47-LDA mimotope is structurally similar but not identical to GD2 ganglioside, it may stimulate T cell clones that recognize GD2 but have not been deleted during the establishment of self-identity because of their lower affinity for the antigen. We are proposing to express the 47-LDA mimotope together with universal T helper (Th) epitopes in the context of Fc region of IgG antibodies for targeting the antigenic cassettes to activating Fc gamma receptors (Fc?Rs) on antigen presenting cells. For immunization, the 47-LDA-Fc fusion proteins will be delivered by dendritic cell (DC) vaccination or by our newly developed recombinant modified vaccinia Ankara (rMVA) viral vector/liposomal complex. We hypothesize that targeting the 47-LDA-Fc fusion proteins to activating Fc?Rs on DCs will enhance the magnitude of protective immunity against GD2+ tumors. The Specific Aims are: i) We will generate 47-LDA-Fc fusion proteins with murine IgG1, IgG2a, and IgG3 Fc regions to evaluate their abilities to elicit antitumor immune responses in mice and select the most efficacious construct; ii) We will express the most efficacious 47-LDA Fc-fusion protein by rMVA virus covalently attached to tresylmonomethoxypolyethylene glycol (TMPEG)-modified cationic liposomes (rMVA47-LDAFc/ TMPEG/liposomes) for systemic and mucosal immunizations; and iii) We will compare antitumor efficacy of 47-LDA-Fc fusion protein-pulsed DC vaccine with that of rMVA47-LDA-Fc/TMPEG/liposomes using a combination of adoptive cell transfer (ACT) therapy and vaccination in GD2+ tumor-bearing mice. As the next generation of ACT-based immunotherapies might rely on the ability to endow 'fit' tumor-specific cells that are capable of proliferating and trafficking to tumor lesions, the use of potent vaccines to enhance adoptively transferred T cells may represent a promising new approach for cancer treatment. Public Health Relevance: The GD2 ganglioside expressed on neuroectodermally derived tumors, including neuroblastoma and melanoma, is weakly immunogenic in tumor-bearing patients and induces predominantly IgM antibody responses in the immunized host. To overcome the intrinsically weak immunogenicity of carbohydrate antigens and tolerance to self/tumor-associated antigens in a tumor-bearing host, we have generated a mimotope of GD2 ganglioside, designated 47-LDA. We are proposing to express the 47-LDA mimotope together with universal T helper epitopes in the context of Fc region of IgG antibodies for targeting the antigenic cassettes to activating Fc gamma receptors on antigen presenting cells.

描述（由申请人提供）：在神经性衍生的肿瘤上表达的GD2神经苷，包括神经母细胞瘤和黑色素瘤，在肿瘤患者中具有弱免疫原性，并且在免疫宿主中主要诱导IgM抗体反应。为了克服碳水化合物抗原的本质上弱免疫原性，并在肿瘤宿主中对自我/肿瘤相关的抗原的耐受性，我们产生了指定为47-LDA的GD2神经节的模仿。我们对这种免疫策略的理性是，由于47-LDA模拟型在结构上是相似的，但与GD2神经节苷脂不同，因此它可能会刺激识别GD2但在建立自我认同期间由于对抗原的较低亲和力而尚未删除的T细胞克隆。我们提议在IgG抗体的FC区域中表达47-LDA模拟型以及通用T辅助（Th）表位，用于靶向抗原性磁带在抗原呈递细胞上激活FC Gamma受体（FC？rs）。为了进行免疫接种，47-LDA-FC融合蛋白将通过树突细胞（DC）疫苗接种或我们新开发的重组改性疫苗Ankara（RMVA）病毒载体/脂质体复合物进行。我们假设将47-LDA-FC融合蛋白靶向激活DC上的FC？RS将增强针对GD2+肿瘤的保护性免疫的大小。具体目的是：i）我们将与鼠IgG1，IgG2a和IgG3 FC区域生成47-LDA-FC融合蛋白，以评估其在小鼠中引起抗肿瘤免疫反应的能力并选择最有效的构建体； ii）我们将通过RMVA病毒表达最有效的47-LDA FC-融合蛋白，该病毒共同附着于曲甲基摩硫代氧基氧基乙二醇（TMPEG）改性阳离子脂质体（RMVA47-LDAFC/ TMPAFC/ TMPEG/ LIPOSOMES），以实现系统性和MUC和MUC的不受解液；和iii）我们将使用收养细胞转移（ACT）治疗和GD2+肿瘤疫苗的疫苗的组合比较47-LDA-FC融合蛋白脉冲蛋白脉冲DC疫苗的抗肿瘤功效与RMVA47-LDA-LDA-FC/TMPEG/脂质体的抗肿瘤功效。 由于下一代基于ACT的免疫疗法可能依赖于能够增殖和运输到肿瘤病变的“拟合”肿瘤特异性细胞的能力，因此使用有效的疫苗来增强采用的T细胞可以代表一种有希望的新方法进行癌症治疗。 公共卫生相关性：包括神经细胞瘤和黑色素瘤在内的神经模胚衍生的肿瘤表达的GD2神经苷在肿瘤患者中具有弱免疫原性，并且在免疫宿主中主要诱导IgM抗体反应。为了克服碳水化合物抗原的本质上弱免疫原性，并在肿瘤宿主中对自我/肿瘤相关的抗原的耐受性，我们产生了指定为47-LDA的GD2神经节的模仿。我们提议在IgG抗体的FC区域中表达47-LDA模拟物以及通用T辅助表位，用于靶向抗原盒在抗原呈现细胞上激活FC Gamma受体。

项目成果

Targeting a mimotope vaccine to activating Fcgamma receptors empowers dendritic cells to prime specific CD8+ T cell responses in tumor-bearing mice.

• DOI: 10.4049/jimmunol.0900364
• 发表时间: 2009-11-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Gil M;Bieniasz M;Wierzbicki A;Bambach BJ;Rokita H;Kozbor D
• 通讯作者: Kozbor D

Immunization with a mimotope of GD2 ganglioside induces CD8+ T cells that recognize cell adhesion molecules on tumor cells.

• DOI: 10.4049/jimmunol.181.9.6644
• 发表时间: 2008-11-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Wierzbicki A;Gil M;Ciesielski M;Fenstermaker RA;Kaneko Y;Rokita H;Lau JT;Kozbor D
• 通讯作者: Kozbor D