Phase I Vaccine Study using Brain Tumor Initiating Cells in WHO Grade II Gliomas

使用 WHO II 级神经胶质瘤中的脑肿瘤起始细胞进行 I 期疫苗研究

• 批准号: 8754952
• 负责人: Hideho Okada
• 金额: $ 18.3万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-25 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8754952
• 关键词: Adult; Adverse event; Antigens; Autoimmune encephalitis; Autologous; Biological Assay; Brain Neoplasms; Cancer Vaccines; Cell Line; Cells; Characteristics; Clinical; Clinical Research; Combined Vaccines; Cytotoxic T-Lymphocytes; Data; Development; Disease; Dose-Limiting; Drug Formulations; ERBB2 gene; Enzymes; Epitopes; Exhibits; FDA approved; Flow Cytometry; Frequencies; General Population; Glioblastoma; Glioma; Growth; HLA Antigens; Imiquimod; Immune response; Immunity; Immunization; Immunocompromised Host; Immunologic Adjuvants; Immunotherapeutic agent; Incidence; Infiltrative Growth; Interferons; Investigation; Link; Malignant - descriptor; Meta-Analysis; Monitor; Newly Diagnosed; Operative Surgical Procedures; Patients; Peptides; Peripheral Blood Mononuclear Cell; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Population; Postoperative Period; Prevention; Primary Brain Neoplasms; Progression-Free Survivals; Radiation therapy; Recurrence; Regimen; Relapse; Risk; Safety; Severities; Site; Source; Spottings; Stem cells; System; T cell response; T-Lymphocyte Epitopes; Testing; Therapeutic; Time; Tissues; Topical application; Toxic effect; Translating; Tumor Antigens; University of Pittsburgh Cancer Institute; Vaccinated; Vaccination; Vaccines; World Health Organization; base; clinical efficacy; cohort; cross reactivity; design; high risk; interleukin-13 receptor; intradermal injection; neoplastic; neoplastic cell; nestin protein; novel; phase 1 study; prevent; prophylactic; public health relevance; response; synthetic peptide; tumor; vaccine development; vaccine efficacy

DESCRIPTION (provided by applicant): We propose a phase I study to assess a vaccination regime [intradermal (i.d.)] injections of lysate derived from cultured brain tumor-initiating cells (BTICs) with concurrent topical application of an immunoadjuvant (imiquimod) in adults with World Health Organization (WHO) grade II low-grade gliomas (LGGs). Our objective is to collect immunological and safety data to determine whether a larger study of clinical efficacy is warranted. We selected the well-characterized BTICs as the antigen source since they persist in tumors as a distinct population and cause relapse by giving rise to new tumors. Both LGG and high-grade glioma (HGG) tissues appear to contain tumor cells expressing CD133+, a marker of BITCs. We have established a glioblastoma (GBM) patient-derived BTIC line, GBM6, grown under Good Manufacturing Practice (GMP) conditions. Flow cytometry data demonstrate that GBM6 expresses many important GAAs, including interleukin-13 receptor (IL- 13R)¿2, EphA2, and Her-2. Moreover, GBM6 also expresses key BTIC antigens, including CD133, nestin, and Sox-2. These data suggest vaccinating with GBM6 lysate could offer both immunotherapeutic and immunoprophylactic potential to reduce the risk of tumor recurrence in LGG. We will combine i.d. administration of GBM6 lysate and Imiquimod, an FDA-approved immunoadjuvant that enhances the efficacy of vaccines and anti-glioma immunity. We hypothesize that this whole tumor antigen-based vaccine combined with Imiquimod will safely induce potent anti-glioma immune response. Because prior radiation therapy (RT) may influence the immunological activity of vaccines, we will stratify newly diagnosed high-risk LGG patients into two cohorts, depending on whether patients received RT. We will treat a total of 18 patients (9 patients/cohort) to evaluate the following specific aims in each cohort: Aim 1: Induction of GBM6-specific T-cell response: We will determine the response rate and magnitude of immune response in peripheral blood mononuclear cells (PBMC) against the GBM6-lysate, using interferon (IFN)-g-enzyme-linked immuno-spot (ELISPOT). We will compare the rate and magnitude of GAA-specific immune responses in the 2 cohorts (high-risk LGG with and without post-operative RT). We will consider a cohort worthy of further investigation if there are at least 4 responses in the 9 subjects. Aim 2: Safety: The incidence and severity of adverse events (AEs) associated with the vaccine regime will be assessed, with an early stopping rule based on the frequency of dose-limiting toxicity (DLT). We will closely monitor the potential induction of autoimmune encephalitis. If this pilot phase I trial confirms the vaccine strategy is safe and demonstrates immunological activity as defined above (Aim 1), we will design a larger multi-site phase II clinical trial in which progression-free survival will be evaluated as the primary endpoint.

描述（由应用提供）：我们提出了一项I期研究，以评估疫苗接种状态[皮内（I.D.）]对源自培养的脑肿瘤发射细胞的裂解物的注射 （BTICS）随着世界卫生组织（WHO）II级低级神经胶质瘤（LGGS）的成人（LGGS）的成年人（LGGS）的同时局部应用。我们的目标是收集免疫学和安全数据，以确定是否有必要对临床效率进行更大的研究。我们选择了良好的BTIC作为抗原来源，因为它们持续存在于肿瘤中，并通过引起新的肿瘤来减轻。 LGG和高级神经胶质瘤（HGG）组织似乎都包含表达CD133+的肿瘤细胞，这是BITC的标记。我们已经建立了在良好的制造实践（GMP）条件下生长的胶质母细胞瘤（GBM）患者衍生的BTID系列GBM6。流式细胞仪数据表明，GBM6表达了许多重要的GAA，包括白介素13受体（IL-13R）»2，EPHA2和HER-2。此外，GBM6还表达关键的BTIC抗原，包括CD133，Nestin和Sox-2。这些数据表明，用GBM6裂解物接种疫苗可以提供免疫治疗和免疫原性潜力，以降低LGG肿瘤复发的风险。我们将结合I.D. GBM6裂解物和咪喹莫德（FDA批准的免疫辅助剂）的给药，可提高疫苗和抗神经瘤免疫学的效率。我们假设整个基于肿瘤的抗原疫苗与咪喹莫德的疫苗将安全诱导潜在的抗脱脂瘤免疫反应。由于先前的放射疗法（RT）可能会影响疫苗的免疫学活性，因此我们将根据患者是否接受RT的方式将新诊断的高危LGG患者分为两名同类。我们将总共治疗18名患者（9例患者/队列），以评估每个队列中的以下特定目标： 目标1：诱导GBM6特异性T细胞响应：我们将使用Interferon（IFN）-G-酶 - 酶 - 酶联免疫斑点（ELISPOT）来确定外周血单核细胞（PBMC）对GBM6-溶酶的免疫激素的反应率和大小。我们将比较两个队列中GAA特异性免疫反应的速率和幅度（具有术后RT的高风险LGG）。如果9受试者中至少有4个回应，我们将考虑值得进一步调查的队列。 目标2：安全性：将评估与疫苗制度相关的不良事件（AE）的事件和严重性，并根据剂量限制毒性（DLT）的频率进行早期停止规则。我们将密切监测自身免疫性脑炎的潜在诱导。如果这个 试点I期试验证实了疫苗策略是安全的，并证明了上述定义的免疫学活动（AIM 1），我们将设计一个较大的多站点II期临床试验，其中无进展生存率将作为主要端点评估。