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

描述（由申请人提供）：no - od -09-058: NIH宣布竞争性修订申请恢复法案基金的可用性多形胶质母细胞瘤（GBM）中的细胞亚群已被确定具有独特的肿瘤再生能力。这些脑肿瘤干细胞（BTSC）已经被神经干细胞标记物CD133分离出来，并且被广泛认为是对常规治疗产生耐药性的细胞。特异性清除这些细胞的有效手段可能减少对强化和非特异性常规治疗的需要，并降低肿瘤复发的风险。在我们最初的建议中，我们提供了一种由树突状细胞（dc）组成的疫苗，该疫苗装载了来自BTSCs的扩增的肿瘤总RNA，作为一种创新策略，可诱导针对这些BTSCs的细胞和体液抗肿瘤免疫反应。最近，替莫唑胺（TMZ），一种骨髓抑制化疗，显示出GBM患者的生存获益。不幸的是，预计TMZ诱导的淋巴细胞减少会减少这种疫苗诱导的生产性抗肿瘤免疫反应。然而，在淋巴细胞减少期之后，如TMZ诱导的淋巴细胞，宿主剩余淋巴细胞的稳态增殖，其激活阈值降低。因此，在这个恢复阶段遇到同源抗原的抗肿瘤淋巴细胞（可能以疫苗的形式）可能具有竞争优势，并在恢复的淋巴细胞群中具有过高的代表性。我们的初步数据表明，针对肿瘤特异性抗原的肽疫苗，当在tmz诱导的淋巴细胞减少症恢复期间给予时，在小鼠和人类中产生显著增强的体液反应和抗原特异性t细胞频率增加。此外，增加TMZ剂量或用TMZ连续周期治疗可使免疫应答的t细胞频率逐渐升高。这些结果强调了在一系列TMZ造血恢复期间接种疫苗作为一种增强抗肿瘤免疫的新策略，需要在针对BTSCs的疫苗背景下进行研究。因此，我们的竞争补充将提出研究TMZ对由载有来自btsc的TTRNA的dc组成的疫苗的效力的影响。与《美国复苏与再投资法案》的目标一致，这一补充将加快我们在这一领域的研究节奏，并允许创造和保留就业机会。PHS 398/2590 （Rev. 11/07）第1页延续格式页

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