Improved idiotype immunotherapy for lymphoma by RNA vaccine delivery

通过 RNA 疫苗递送改进淋巴瘤的独特型免疫疗法

• 批准号: 7707096
• 负责人: Alison Anne McCormick
• 金额: $ 16.83万
• 依托单位: TOURO UNIVERSITY OF CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-14 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7707096
• 关键词: Adjuvant; Adoption; Antibodies; Antigen Presentation; Antigen Targeting; Antigens; Area; Attention; Autoantigens; Cancer Vaccines; Capsid; Capsid Proteins; Cell Culture Techniques; Cell surface; Characteristics; Chimeric Proteins; Clinical; Clinical Research; Combination Drug Therapy; Communities; Custom; Cytokine Gene; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Disease; Disease remission; Drug Design; Drug Formulations; Enzyme-Linked Immunosorbent Assay; Follicular Lymphoma; Future; Generations; Genes; Genetic; Goals; Gold; Hematologic Neoplasms; Immune; Immune response; Immunity; Immunoglobulin Idiotypes; Immunoglobulin Variable Region; Immunoglobulins; Immunotherapy; In Vitro; Lymphocyte Activation; Lymphoma; Measures; Medical; Medicine; Methods; Modeling; Mus; Natural Immunity; Non-Hodgkin' s Lymphoma; Outcome; Patients; Peptide Vaccines; Peptides; Pharmaceutical Preparations; Preparation; Property; Protein Analysis; Proteins; RNA; RNA Viruses; Relapse; Research Priority; Risk; Scientist; Semliki forest virus; Staging; Surface; System; TNFRSF5 gene; Testing; Tobacco Mosaic Virus; Toxin; Tumor Antigens; United States; Vaccinated; Vaccination; Vaccine Antigen; Vaccine Production; Vaccine Therapy; Vaccines; Viral Antigens; Viral Vaccines; Virus; base; cancer immunotherapy; cytokine; design; immunogenicity; improved; in vivo; novel; novel vaccines; particle; prophylactic; public health relevance; response; self assembly; therapeutic vaccine; tumor; tumor growth; uptake; vaccination strategy; vaccine delivery; viral RNA

DESCRIPTION (provided by applicant): In recent years, Non-Hodgkin's lymphoma (NHL) has risen to be the most common hematologic malignancy in the United States. Aggressive new combination chemotherapy regimes have slowly improved remission rates for most stages of disease, however the risk of relapse is still significant, even if patients achieve remission during therapy, and patients that relapse are characterized by a reduced response to treatment. To improve patient survival outcomes, significant attention has been focused on the generation of an active, tumor specific, immune response through vaccination with a tumor-specific antigen: the cell-surface expressed immunoglobulin (Ig), or idiotype. Clinical studies show that when patients make an immune response to the vaccine, they have improved survival characteristics. Protein Ig, however, is difficult to make for patient specific applications, and may not provide adequate immune stimulation in tumor-bearing patients. Our hypothesis is that RNA based vaccines can improve anti-idiotype immunity by delivering idiotype sequences in the context of viral antigen delivery, in a system that is ideally suited for simple and rapid individualized vaccine production. Our goal is to design and test model antigen expressing RNA constructs to determine the efficacy of RNA based idiotype vaccines in two murine models of NHL (38C13 and A20). These models are ideal, because they require either antibody (38C13) or CTL activation (A20) for optimal tumor protection, characteristics that are also needed for successful patient immune activation. We will use Semliki Forest Virus (SFV) nonstructural genes to drive expression of 38C13 and A20 idiotype sequences, either singly or in tandem with cytokine gene sequences for maximum antigen delivery and immune activation. SFV RNA, rather than encapsidated in cell culture with native capsid, will be encapsidated using the novel self-assembly properties of Tobacco Mosaic Virus coat protein. Preparation of encapsidated RNA vaccines is simple, involving merely mixing coat protein with RNA to generate fully protected pseudovirus particles. Encapsidated RNA pseudovirus vaccines induce both antibody and cytotoxic T lymphocyte (CTL) activation, as well as tumor protective immunity, without additional adjuvants. Vaccine agents can be "cloaked" with surface peptides reduce immune responses to viral coat protein, and are stable for repeated vaccine antigen delivery and boosting. We will establish the best method to co-deliver cytokine genes to promote improved immune activation and reversal of self-antigen tolerance to 38C13 and A20 NHL tumor antigens. Antigen expression level and cytokine activity will be verified in vitro, as well as antibody and CTL reactivity to target antigens in vivo. We will test peptide antigen conjugates that may boost anti-idiotype immunity or improve vaccine potency. Lastly, we will test the most effective idiotype antigen/cytokine encapsidated RNA formulations in vivo and correlate improved immunity with tumor protection in the relevant 38C13 or A20 mouse tumor model. PUBLIC HEALTH RELEVANCE: Improving cancer vaccine therapy by rational drug design is a high priority of research scientists and the medical community. This R21 application seeks to implement improved cancer vaccine characteristics by harnessing innate immunity to RNA viruses. Our hypothesis is that encapsidated RNA vaccines that express non-Hodgkin's lymphoma tumor antigens will provide superior immune activation and protection against lymphoma tumor growth. Unlike current therapies, custom vaccines are easily made, and may facilitate widespread adoption of individualized patient immunotherapy.

描述（由申请人提供）：近年来，非霍奇金淋巴瘤（NHL）已上升为美国最常见的血液恶性肿瘤。积极的新的联合化疗方案已经缓慢地改善了大多数疾病阶段的缓解率，然而复发的风险仍然很大，即使患者在治疗期间达到缓解，并且复发的患者的特征是对治疗的反应降低。为了改善患者的生存结局，人们一直关注通过接种肿瘤特异性抗原（细胞表面表达的免疫球蛋白（IG）或独特型）来产生主动的肿瘤特异性免疫应答。临床研究表明，当患者对疫苗产生免疫反应时，他们的生存特征会得到改善。然而，蛋白质IG难以用于患者特异性应用，并且可能不能在携带肿瘤的患者中提供足够的免疫刺激。我们的假设是，基于RNA的疫苗可以通过在病毒抗原递送的背景下递送独特型序列来提高抗独特型免疫力，该系统非常适合于简单和快速的个体化疫苗生产。我们的目标是设计和测试模型抗原表达RNA构建体，以确定基于RNA的独特型疫苗在两种NHL小鼠模型（38 C13和A20）中的功效。这些模型是理想的，因为它们需要抗体（38 C13）或CTL活化（A20）以获得最佳的肿瘤保护，这些特征也是成功的患者免疫活化所需的。我们将使用塞姆利基森林病毒（SFV）非结构基因驱动38 C13和A20独特型序列的表达，单独或与细胞因子基因序列串联，以实现最大的抗原递送和免疫激活。SFV RNA，而不是在细胞培养物中与天然衣壳结合，将利用烟草花叶病毒外壳蛋白的新的自组装特性进行结合。纯化的RNA疫苗的制备很简单，仅涉及将外壳蛋白与RNA混合以产生完全受保护的假病毒颗粒。包封的RNA假病毒疫苗诱导抗体和细胞毒性T淋巴细胞（CTL）活化，以及肿瘤保护性免疫，而无需额外的佐剂。疫苗剂可以用表面肽“掩盖”，减少对病毒外壳蛋白的免疫应答，并且对于重复的疫苗抗原递送和加强是稳定的。我们将建立最佳的方法来共同递送细胞因子基因，以促进改善的免疫激活和逆转对38 C13和A20 NHL肿瘤抗原的自身抗原耐受。将在体外验证抗原表达水平和细胞因子活性，以及在体内验证抗体和CTL对靶抗原的反应性。我们将测试肽抗原结合物，可能会提高抗独特型免疫力或提高疫苗效力。最后，我们将在体内测试最有效的独特型抗原/细胞因子标记的RNA制剂，并在相关的38 C13或A20小鼠肿瘤模型中将免疫力改善与肿瘤保护相关联。 公共卫生相关性：通过合理的药物设计改善癌症疫苗治疗是研究科学家和医学界的高度优先事项。该R21应用旨在通过利用对RNA病毒的先天免疫来实现改进的癌症疫苗特性。我们的假设是，表达非霍奇金淋巴瘤肿瘤抗原的重组RNA疫苗将提供上级免疫激活和针对淋巴瘤肿瘤生长的保护。与目前的疗法不同，定制疫苗很容易制造，并且可以促进个体化患者免疫疗法的广泛采用。