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（由申请人提供）：我们提出一项 I 期研究来评估疫苗接种方案 [皮内 (i.d.)] 注射来自培养的脑肿瘤起始细胞的裂解物 (BTIC) 与同时局部应用免疫佐剂 (咪喹莫特) 治疗世界卫生组织 (WHO) II 级低级别胶质瘤 (LGG) 成人。我们的目标是收集免疫学和安全性数据，以确定是否需要进行更大规模的临床疗效研究。 我们选择充分表征的 BTIC 作为抗原源，因为它们作为独特的群体持续存在于肿瘤中，并通过产生新肿瘤而导致复发。 LGG 和高级神经胶质瘤 (HGG) 组织似乎都含有表达 CD133+（BITC 标记物）的肿瘤细胞。我们已经建立了源自胶质母细胞瘤 (GBM) 患者的 BTIC 系 GBM6，在良好生产规范 (GMP) 条件下生长。流式细胞术数据表明 GBM6 表达许多重要的 GAA，包括白细胞介素 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、巢蛋白和 Sox-2。这些数据表明，用 GBM6 裂解物进行疫苗接种可以提供免疫治疗和免疫预防潜力，以降低 LGG 肿瘤复发的风险。我们将结合 i.d. GBM6 裂解物和咪喹莫特的给药，咪喹莫特是 FDA 批准的免疫佐剂，可增强疫苗和抗神经胶质瘤免疫力的功效。我们假设这种基于肿瘤抗原的疫苗与咪喹莫特联合将安全地诱导有效的抗神经胶质瘤免疫反应。由于既往放射治疗（RT）可能会影响疫苗的免疫活性，因此我们将根据患者是否接受放射治疗将新诊断的高危 LGG 患者分为两组。我们将治疗总共 18 名患者（9 名患者/队列），以评估每个队列的以下具体目标： 目标 1：诱导 GBM6 特异性 T 细胞反应：我们将使用干扰素 (IFN)-g-酶联免疫斑点 (ELISPOT) 确定外周血单核细胞 (PBMC) 对 GBM6 裂解物的免疫反应的反应率和强度。我们将比较 2 个队列（接受和不接受术后 RT 的高风险 LGG）中 GAA 特异性免疫反应的速率和强度。如果 9 名受试者中至少有 4 项答复，我们将认为该队列值得进一步研究。 目标 2：安全性：将评估与疫苗方案相关的不良事件 (AE) 的发生率和严重程度，并根据剂量限制性毒性 (DLT) 的频率制定提前停止规则。我们将密切监测自身免疫性脑炎的潜在诱发情况。如果这个 试点一期试验确认了疫苗策略是安全的，并证明了上述定义的免疫活性（目标 1），我们将设计一项更大规模的多中心二期临床试验，其中将评估无进展生存期作为主要终点。