Molecularly targeted, multidisciplinary glioma vaccine approaches

分子靶向、多学科神经胶质瘤疫苗方法

• 批准号: 8377644
• 负责人: Hideho Okada
• 金额: $ 24.54万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8377644
• 关键词: Address; Antigens; Apoptotic; Astrocytes; Biological Response Modifiers; Brain Neoplasms; CD8B1 gene; CNS autoimmunity; CXC Chemokines; CXC chemokine IP-10; Cancer Vaccines; Carboxymethylcellulose; Central Nervous System Neoplasms; Cessation of life; Clinical; Clinical Trials; Collaborations; Cytotoxic T-Lymphocytes; Development; Dioxygenases; Effector Cell; Encephalitis; Environment; Funding; Future; Generations; Genetic; Glioma; Goals; Homing; Human; Immune; Immune response; Immune system; Immunity; Immunosuppression; Immunotherapy; Interferon Inducers; Interferon Type II; Interferon-alpha; Interferons; Interleukin-10; Interleukin-6; Intramuscular; Ligands; Lysine; Malignant Glioma; Malignant Neoplasms; Mediating; Microglia; Modality; Modeling; Molecular; Molecular Target; Participant; Patients; Peptides; Peripheral; Phase; Phenotype; Poly I-C; Production; Property; Proteins; Recurrence; Regimen; Role; STAT3 gene; Safety; Shapes; Signal Transduction; Simplexvirus; Site; Stat3 protein; Surrogate Markers; T-Lymphocyte; T-Lymphocyte Epitopes; TLR3 gene; Therapeutic; Therapeutic Effect; Treatment Efficacy; Tumor Escape; Tumor Immunity; Tumor-Derived; Vaccination; Vaccine Antigen; Vaccines; base; cell growth; chemokine; chemokine receptor; cytokine; design; human TLR3 protein; improved; indoleamine; inhibitor/antagonist; multidisciplinary; neoplastic cell; novel strategies; peptide based vaccine; tumor

The long term goal of Project 2 is to develop safe and effective immunotherapy strategies for CNS tumors incorporating multi-disciplinary approaches that are being pursued in Projects 1 and 3. Despite the feasibility and safety of cancer vaccine-approaches, current evidence suggests that the systemic induction of anti-tumor immune responses by peripheral vaccines should be combined with modalities that enhance the homing and function of vaccine-induced effector cells within CNS tumor sites. Indeed, our studies from the prior funding period have indicated that genetic delivery of interferon (IFN)-alpha into CNS tumors facilitates the tumor-homing and therapeutic efficacy of Type-1 cytotoxic T-lymphocytes (CTLs) in an IFN-inducible protein (IP)-10 dependent manner. More relevant, underlying "prime-boost" regimen may be achieved in a more clinically feasible manner via administration of a "natural" inducer of IFN-alpha within the CNS-environment, such as a toll-like receptor (TLR)3 ligand, polyinosinic-polycytidylic acid (poly-IC), stabilized with poly-lysine and carboxymethylcellulose (poly-ICLC). Our preliminary studies with the GL261 glioma model have demonstrated that intramuscular (i.m.) administration of poly-ICLC improves the therapeutic effect of vaccinations with GL261-derived glioma-associated antigen (GAA) CTL epitopes by enhancing the homing of IFN-gamma expressing antigen-specific CTLs to the CNS tumor site. Based on the property of poly-ICLC to induce IFNs as well as IP-10, we hypothesize that administration of poly-ICLC effectively induces Type-1 GAA-specific effector cells as well as IP-10 at the tumor site, both of which are responsible for the enhanced efficacy of poly-ICLC-assisted vaccines. In Specific Aim (SA)1, we will determine whether promotion of Type-1 phenotype is the critical factor for the efficacy of poly-ICLC assisted GAA vaccines. Findings from these studies will allow us to determine the critical surrogate markers in our clinical trial proposed in SA3. In collaboration with Project 1 and 3, in our SA2, we will evaluate our hypothesis that inhibition of STATS signals may improve the efficacy of poly-ICLC assisted GAA-based vaccines. In addition, enhanced local IFN expression by tumor-infiltrating effector cells, may induce Indoleamine 2,3 dioxygenase (IDO), which inhibits proliferation of both T cells and Herpes-Simplex Viruses (HSV). We will determine whether poly-ICLC-assisted GAA-vaccines can be efficiently combined with HSV-therapy under the inhibition of IDO in collaboration with Project 3. We will implement a phase I/I I trial of vaccinations with human GAA-peptides identified during the initial funding period in conjunction with poly-ICLC in participants with recurrent malignant glioma. These proposed studies will provide a strong basis for a near future development of effective combination therapeutic strategies using vaccination with signal transduction modulation and/or HSV therapy.

项目2的长期目标是开发安全有效的中枢神经系统肿瘤免疫治疗策略 纳入项目 1 和 3 中正在推行的多学科方法。尽管具有可行性 和癌症疫苗方法的安全性，目前的证据表明，系统性诱导抗肿瘤疫苗 外周疫苗的免疫反应应与增强归巢和免疫的方式相结合。 中枢神经系统肿瘤部位内疫苗诱导的效应细胞的功能。事实上，我们的研究来自先前的资助 时期的研究表明，将干扰素（IFN）-α基因传递到中枢神经系统肿瘤中可以促进 IFN 诱导蛋白中 1 型细胞毒性 T 淋巴细胞 (CTL) 的肿瘤归巢和治疗功效 (IP)-10 依赖方式。更相关的、潜在的“启动-加强”方案可以通过更有效的方法来实现。 临床上可行的方式是通过在中枢神经系统环境内施用“天然”IFN-α诱导剂， 例如 Toll 样受体 (TLR)3 配体、聚肌苷-聚胞苷酸 (poly-IC)，用聚赖氨酸稳定 和羧甲基纤维素（聚-ICLC）。我们对 GL261 神经胶质瘤模型的初步研究 证明肌肉注射（i.m.）聚-ICLC 可提高治疗效果 通过增强 GL261 衍生的神经胶质瘤相关抗原 (GAA) CTL 表位的归巢来接种疫苗 IFN-γ 表达针对中枢神经系统肿瘤部位的抗原特异性 CTL。基于poly-ICLC的特性 诱导 IFN 以及 IP-10，我们假设给予聚 ICLC 可有效诱导 1 型 GAA 特异性效应细胞以及肿瘤部位的 IP-10，两者均负责增强 聚 ICLC 辅助疫苗的功效。在特定目标（SA）1中，我们将确定是否推广Type-1 表型是聚 ICLC 辅助 GAA 疫苗功效的关键因素。从这些结果中得出的结论 研究将使我们能够确定 SA3 中提出的临床试验中的关键替代标志物。 与项目 1 和 3 合作，在我们的 SA2 中，我们将评估我们的假设，即抑制 STATS 信号可能会提高多聚 ICLC 辅助的基于 GAA 的疫苗的功效。此外，增强局部干扰素 肿瘤浸润效应细胞的表达，可能会诱导吲哚胺 2,3 双加氧酶 (IDO)，从而抑制 T 细胞和单纯疱疹病毒 (HSV) 的增殖。我们将确定是否有聚 ICLC 辅助 在 IDO 的抑制下，GAA 疫苗可以与 HSV 疗法有效结合 项目 3. 我们将实施 I/I I 期疫苗接种试验，试验期间确定了人类 GAA 肽。 与聚 ICLC 联合治疗患有复发性恶性神经胶质瘤的参与者的初始资助期。这些 拟议的研究将为不久的将来开发有效的联合治疗提供坚实的基础 使用信号转导调节疫苗接种和/或 HSV 治疗的策略。