RNA-Based Immunotherapy Targeting Antigens Unique to Brain Tumor Stem Cells

基于 RNA 的免疫疗法靶向脑肿瘤干细胞特有的抗原

基本信息

批准号：
7822434
负责人：
JOHN H. SAMPSON
金额：
$ 40.72万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7822434
关键词：
Accounting Adult Affinity American American Heart Association Animal Experimentation Animal Technicians Antigen Targeting Antigens Area Autoimmunity Award Backcrossings Biological Assay Biology Bone Marrow Brain Neoplasms Cancer Biology Cause of Death Cells Cessation of life Child Clinical Commit Complementary DNA Data Dendritic Cell Vaccine Dendritic Cells Doctor of Philosophy Dose Education Employee Employment Epidermal Growth Factor Receptor Evaluation Experimental Animal Model Face Fellowship Frequencies Funding Future Generations Glioblastoma Goals Grant Harvest Hematopoietic Hematopoietic stem cells Heterogeneity Hour Human Immune response Immunity Immunologic Monitoring Immunology procedure Immunotherapeutic agent Immunotherapy In Vitro Laboratories Laboratory Animal Science Laboratory Animals Length Lymphocyte Lymphocyte Function Lymphopenia Malignant - descriptor Mediating Medical Messenger RNA Microdissection Minority Modeling Molecular Mus Mutation Myelosuppression Natural regeneration Occupations Organ Harvestings Parents Patients Peptide Vaccines Phase Philanthropic Fund Population Positioning Attribute Postdoctoral Fellow Predisposition Primary Brain Neoplasms Procedures Puerto Rico Quality-Adjusted Life Years RNA RNA analysis Radiosurgery Recovery Recruitment Activity Recurrence Research Resistance Risk Safety Scholarship Schools Screening procedure Signal Pathway Signal Transduction Source Specialist Specificity Stem cell transplant Stem cells T-Lymphocyte Techniques Therapeutic Time Training Transgenic Organisms Treatment Efficacy Treatment Protocols Tumor Antigens Tumor Cell Line Tumor Stem Cells United States United States National Institutes of Health Universities Vaccination Vaccines Wages Work base career chemotherapy conventional therapy epidermal growth factor receptor VIII experience immunogenicity implantation in vivo innovation interest intradermal injection meetings melanoma neoplastic cell nerve stem cell novel strategies parent grant pre-clinical pre-doctoral prevent progenitor public health relevance research study response self-renewal stem cell biology symposium temozolomide tumor vaccine efficacy

项目摘要

DESCRIPTION (provided by applicant): NOT-OD-09-058: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications A subset of cells in glioblastoma multiforme (GBM) have been identified that enjoy a unique capacity to regenerate tumors. These brain tumor stem cells (BTSC) have been segregated by the neural stem cell marker, CD133, and are widely believed to be the cells responsible for resistance to conventional therapies. An effective means of specifically eliminating these cells may reduce the need for intensive and non-specific conventional therapy and lower the risk of tumor recurrence. In our original proposal, we offered vaccines consisting of dendritic cells (DCs) loaded with amplified total tumor RNA derived from BTSCs as an innovative strategy to induce cellular and humoral antitumor immune responses against these BTSCs. Recently, temozolomide (TMZ), a myelosuppressive chemotherapy, has shown a survival benefit in patients with GBM. Unfortunately, the lymphopenia induced by TMZ would be predicted to curtail the induction of productive antitumor immune responses by such vaccines. However, following periods of lymphopenia, such as those induced by TMZ, there is a homeostatic proliferation of the host's remaining lymphocytes, which enjoy a lowered threshold for activation. As a result, anti-tumor lymphocytes that encounter their cognate antigen during this recovery phase, perhaps in the form of a vaccine, may have a competitive advantage and become over-represented in the recovering lymphocyte population. Our preliminary data demonstrate that peptide vaccines targeting a tumor-specific antigen, when given during the recovery from TMZ-induced lymphopenia, produced dramatically enhanced humoral responses and increased antigen-specific T-cell frequencies in mice and humans. Furthermore, increasing the dose of TMZ or treating with serial cycles of TMZ generated progressively higher T-cell frequencies in response to vaccination. These results highlight vaccination during hematopoietic recovery from serial TMZ as a novel strategy for enhancing antitumor immunity that needs to be investigated in the context of vaccines targeting BTSCs. Our Competitive Supplement would propose then to investigate the effects of TMZ on the efficacy of vaccines consisting of DCs loaded with TTRNA derived from BTSCs. Consistent with the goals of the American Recovery and Reinvestment Act, this Supplement would accelerate the tempo of our research in this area and allow for job creation and retention. PHS 398/2590 (Rev. 11/07) Page 1 Continuation Format Page PUBLIC HEALTH RELEVANCE: Treatment for malignant primary brain tumors, which are the most common cause of death among children and account for more deaths in adults than melanoma, currently represents the most expensive medical therapy per quality-adjusted life-year saved currently provided in the United States. A subset of malignant primary brain tumor cells (BTSCs), called brain tumor stem cells, enjoy a unique capacity to regenerate tumors and to resist conventional therapies. In this proposal we will see if targeting antigens preferentially or uniquely expressed by BTSCs in the context of chemotherapy-induced myelosuppression will enhance the efficacy of immunotherapy without inducing autoimmunity. PHS 398/2590 (Rev. 11/07) Page 1 Continuation Format Page

描述（由申请人提供）：NOT-OD-09-058：NIH宣布为竞争性修订应用提供恢复ACT资金的可用性，已确定胶质母细胞瘤多形胶体（GBM）中的细胞子集享有具有重生肿瘤的独特能力。这些脑肿瘤干细胞（BTSC）已被神经干细胞标记CD133隔离，被广泛认为是负责对常规疗法抗性的细胞。特异性消除这些细胞的有效手段可能会减少对密集和非特异性常规治疗的需求，并降低肿瘤复发的风险。在我们的原始建议中，我们提供了由树突状细胞（DC）组成的疫苗，这些疫苗载有源自BTSC的扩增总肿瘤RNA，作为一种创新策略，以诱导针对这些BTSC的细胞和体液抗肿瘤免疫反应。最近，一种骨髓抑制性化学疗法的替莫唑胺（TMZ）显示出对GBM患者的生存益处。不幸的是，TMZ诱导的淋巴细胞减少症将被预测会减少这种疫苗诱导生产性抗肿瘤免疫反应。然而，随着淋巴细胞减少症（例如TMZ诱导的淋巴细胞学），宿主剩余的淋巴细胞的体内平稳性扩散，这会降低激活阈值。结果，在此恢复阶段遇到同源抗原的抗肿瘤淋巴细胞，也许是以疫苗的形式具有竞争优势，并在恢复的淋巴细胞种群中变得过分代表。我们的初步数据表明，靶向肿瘤特异性抗原的肽疫苗在从TMZ诱导的淋巴细胞减少症中恢复期间给予，会产生大幅增强的体液反应，并增加小鼠和人的抗原特异性T细胞频率。此外，增加TMZ的剂量或用TMZ的串行周期处理响应疫苗接种而产生的T-Cell频率逐渐产生的较高的T细胞频率。这些结果突出了造血恢复期间从系列TMZ的疫苗接种，作为增强抗肿瘤免疫力的新策略，需要在针对BTSC的疫苗的背景下研究。然后，我们的竞争性补充剂将提议研究TMZ对由BTSC衍生的TTRNA的DC组成的疫苗的功效的影响。与《美国恢复和再投资法》的目标一致，这种补充将加速我们在该领域的研究的节奏，并允许创造就业机会和保留。 PHS 398/2590（Rev. 11/07）第1页延续格式页面公共卫生相关性：针对儿童中最常见的死亡原因的恶性原发性脑肿瘤的治疗方法，其死亡人数比黑色素瘤的死亡人数更多，目前是目前在美国提供的质量调整后的终身疗法最昂贵的药物治疗。一个称为脑肿瘤干细胞的恶性原发性脑肿瘤细胞（BTSC）的子集具有独特的再生肿瘤能力并抵抗常规疗法。在此提案中，我们将看到在化学疗法诱导的骨髓抑制的背景下，BTSC优先或唯一表达抗原的靶向是否会增强免疫疗法的疗效而不会诱导自身免疫性。 PHS 398/2590（Rev. 11/07）第1页延续格式页面