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: 7408984
• 负责人: Hideho Okada
• 金额: $ 24.38万
• 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
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7408984
• 关键词: Address; Antigens; Apoptotic; Appendix; Astrocytes; Biological Response Modifiers; 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; End Point; 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; Poly ICLC; Production; Property; Proteins; Recurrence; Role; STAT3 gene; Safety; Shapes; Signal Transduction; Simplexvirus; Site; Stat3 protein; Surrogate Markers; T-Lymphocyte; T-Lymphocyte Epitopes; TLR3 gene; Therapeutic; Therapeutic Effect; Therapeutic immunosuppression; Toll-like receptors; Treatment Efficacy; Treatment Protocols; Tumor Escape; Tumor Immunity; Tumor-Derived; Vaccination; Vaccine Antigen; Vaccines; base; cell growth; chemokine; chemokine receptor; cytokine; cytotoxic; design; human TLR3 protein; improved; indoleamine; inhibitor/antagonist; multidisciplinary; neoplastic cell; 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的长期目标是为中枢神经系统肿瘤制定安全有效的免疫疗法策略 结合项目1和3中正在采用的多学科方法。尽管有可行性 当前证据表明，抗肿瘤的系统性诱导 外围疫苗的免疫反应应与增强归巢的方式结合起来 CNS肿瘤部位中疫苗诱导的效应细胞的功能。确实，我们从以前的资金进行的研究 周期表明，干扰素（IFN） - α到CNS肿瘤中的基因递送有助于 IFN诱导蛋白中1型细胞毒性T淋巴细胞（CTL）的肿瘤 - 肿瘤和治疗功效 （IP）-10依赖方式。在更多中，可以实现更相关的“ Prime-brover”方案 临床上可行的方式，通过在CNS-Encrironment中使用IFN-Alpha的“天然”诱导剂， 例如Toll样受体（TLR）3配体，多粒细胞聚糖酸（Poly-IC），用聚赖氨酸稳定 和羧甲基纤维素（Poly-ICLC）。我们对GL261神经胶质瘤模型的初步研究具有 证明肌肉内（I.M.）多子施用可改善 与GL261衍生的神经胶质瘤相关抗原（GAA）CTL表位的疫苗接种，通过增强归巢 向中枢神经系统肿瘤部位表达抗原特异性CTL的IFN-gamma。基于poly-iclc的特性 诱导IFN和IP-10，我们假设给药有效地诱导了1型。 肿瘤部位的GAA特异性效应细胞以及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，我们将确定是否促进1型 表型是辅助GAA疫苗功效的关键因素。这些发现 研究将使我们能够在SA3中提出的临床试验中确定关键的替代标记。 与项目1和3的合作，在我们的SA2中，我们将评估抑制统计的假设 信号可能会提高基于GAA的聚-ICLC疫苗的疗效。此外，增强了本地IFN 通过肿瘤浸润效应细胞的表达，可能诱导吲哚胺2,3二氧酶（IDO），它抑制 T细胞和疱疹 - 刺激病毒（HSV）的增殖。我们将确定是否辅助多聚-ICLC 在IDO的抑制下，GAA-VACCINE可以有效地与HSV-Therapy合作结合 项目3。我们将实施I/I期I/I I阶段试验，该试验与在此期间确定的人类GAA肽 在复发性恶性神经胶质瘤的参与者中，最初的资金期与poly-ICLC结合使用。这些 拟议的研究将为有效组合治疗的近期发展提供强大的基础 使用疫苗接种和信号转导调制和/或HSV治疗的策略。