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，非霍奇金的淋巴瘤（NHL）已成为美国最常见的血液系统恶性肿瘤。积极的新组合化疗方案在大多数疾病阶段都缓慢提高了缓解率，但是即使患者在治疗期间患者达到缓解，复发的风险仍然很大，而复发的患者的特征是减少了对治疗的反应。为了改善患者的生存结果，通过使用肿瘤特异性抗原疫苗接种活性，肿瘤特异性，免疫反应的产生：细胞表面表达的免疫球蛋白（Ig）或白痴型。临床研究表明，当患者对疫苗做出免疫反应时，他们的生存特征提高了。然而，蛋白质IG很难针对患者特定的应用，并且可能无法在肿瘤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传递偶像型序列来改善抗IDITYPE型免疫，该系统非常适合简单且快速的个性化疫苗生产。我们的目标是设计和测试模型表达RNA构建体的抗原，以确定基于RNA的异常型疫苗在NHL的两个鼠模型中的功效（38C13和A20）。这些模型是理想的，因为它们需要抗体（38C13）或CTL激活（A20）才能提供最佳的肿瘤保护，这是成功的患者免疫激活所需的特征。我们将使用Semliki Forest病毒（SFV）非结构基因来驱动38C13和A20惯用型序列的表达，无论是单独或与细胞因子基因序列串联，以最大程度地抗原递送和免疫激活。 SFV RNA，而不是用天然衣帽封装在细胞培养物中，将使用烟草镶嵌病毒外套蛋白的新型自组装特性封装。封装的RNA疫苗的制备很简单，仅涉及将外套蛋白与RNA混合以产生完全保护的假病毒颗粒。封装的RNA伪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，而无需其他辅助剂。疫苗剂可以用表面肽“掩盖”降低对病毒外套蛋白的免疫反应，并且可以稳定，用于重复的疫苗抗原递送和增强。我们将建立最佳方法来共同使用细胞因子基因，以改善自我抗原耐受性至38C13和A20 NHL肿瘤抗原的免疫激活和逆转。抗原表达水平和细胞因子活性将在体外得到验证，以及对靶抗原在体内的抗体和CTL反应性。我们将测试可能提高抗二动型免疫或提高疫苗效力的肽抗原结合物。最后，我们将在体内测试最有效的白痴抗原/细胞因子封装的RNA配方，并在相关的38C13或A20小鼠肿瘤模型中与肿瘤保护的改善相关性。 公共卫生相关性：通过理性药物设计改善癌症疫苗疗法是研究科学家和医学界的高优先事项。该R21应用程序旨在通过利用对RNA病毒的先天免疫力来实施改善的癌症疫苗特征。我们的假设是，表达非霍奇金淋巴瘤肿瘤抗原的封装的RNA疫苗将提供优质的免疫激活和防止淋巴瘤肿瘤生长的保护。与当前的疗法不同，可以轻松地进行定制疫苗，并可能有助于广泛采用个性化的患者免疫疗法。