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

描述（由申请方提供）：我们提出了一项I期研究，以评估疫苗接种方案[皮内（i.d.）]注射来自培养的脑肿瘤起始细胞的裂解物 在患有世界卫生组织（WHO）II级低级别神经胶质瘤（LGG）的成人中同时局部应用免疫佐剂（咪喹莫特）来治疗BTIC。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作为抗原来源，因为它们作为独特的群体在肿瘤中持续存在，并通过产生新的肿瘤而引起复发。LGG和高级别胶质瘤（HGG）组织似乎都含有表达BITC标记物CD 133+的肿瘤细胞。我们已经建立了胶质母细胞瘤（GBM）患者来源的BTIC系，GBM 6，在良好生产规范（GMP）条件下生长。流式细胞术数据表明，GBM 6表达许多重要的GAA，包括白细胞介素-13受体（IL-13 R）2，EphA 2和Her-2。此外，GBM 6还表达关键BTIC抗原，包括CD 133、巢蛋白和Sox-2。这些数据表明，用GBM 6裂解物接种疫苗可以提供免疫和免疫预防潜力，以降低LGG中肿瘤复发的风险。我们将联合收割机的身份证。在一个实施方案中，施用GBM 6裂解物和咪喹莫特（一种FDA批准的免疫佐剂，其增强疫苗的功效和抗神经胶质瘤免疫力）。我们推测，这种基于全肿瘤抗原的疫苗与咪喹莫特组合将安全地诱导有效的抗胶质瘤免疫应答。由于既往放射治疗（RT）可能会影响疫苗的免疫活性，我们将根据患者是否接受RT将新诊断的高危LGG患者分为两个队列。我们将治疗总共18例患者（9例患者/队列），以评估每个队列的以下特定目标： 目标1：GBM 6特异性T细胞应答的诱导：我们将使用干扰素（IFN）-g-酶联免疫斑点（ELISPOT）测定外周血单核细胞（PBMC）对GBM 6裂解物的应答率和免疫应答的程度。我们将比较2个队列（高危LGG伴和不伴术后RT）中GAA特异性免疫应答的发生率和程度。如果9例受试者中至少有4例缓解，我们将认为队列值得进一步研究。 目标二：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导。如果这 为了证实疫苗策略是安全的并且证明如上文定义的免疫活性（目标1），我们将设计更大的多地点II期临床试验，其中将评估无进展存活作为主要终点。

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.