Slow cycling cell RNA based T cell therapy to prevent recurrence in GBM

项目总结和摘要 传统的癌症治疗针对快速循环的细胞，然而缓慢分裂的群体往往不会受到影响 通过它们的自我更新能力重现肿瘤。我们报道了慢循环细胞（SCC）的存在 对治疗具有极强的抗性，并在胶质母细胞瘤（GBM）的复发中起关键作用。临床 能够靶向这种特定表型的策略具有改善预后的巨大希望。 重要的是，这些致病性驱动因子证明了预测的免疫原性抗原的表达， 我们建议在免疫治疗背景下利用的治疗机会。我们建立了 采用全肿瘤RNA脉冲树突状细胞的过继细胞治疗（ACT）的新平台 (DCs)来扩增肿瘤反应性T淋巴细胞。我们目前正在进行多项临床试验， 在脑肿瘤患者中的治疗模式（ACTION-IND#17298、REMATCH-IND#14058、BRAVO-IND#17298）。 该项目的目标是利用这个治疗平台的力量，实现强大的目标， 使用复发性GBM的新模型的治疗抗性克隆。我们假设， 肿瘤特异性T细胞可被SCC RNA脉冲的树突细胞导向促进复发的克隆， 从而阻止疾病复发。 为了检验我们的假设，本提案的具体目标是： 目标1.在临床前试验中确定基于慢循环细胞RNA的T细胞治疗的免疫原性和功效 复发性GBM模型 目标2.在人类自体环境中评估基于慢循环细胞RNA的T细胞平台。 成功完成后，该提案极有可能对治疗方案产生有利影响， 恶性胶质瘤患者。

PROJECT SUMMARY AND ABSTRACT Conventional cancer treatments target fast-cycling cells, however slowly dividing populations tend to be spared recapitulating the tumor via their self-renewing abilities. We reported the existence of slow-cycling cells (SCCs) that are extremely resistant to therapies and play a critical role in recurrence of glioblastoma (GBM). Clinical strategies able to target this specific phenotype hold great promises for improving prognosis. Importantly, these pathogenic drivers demonstrated expression of predicted immunogenic antigens providing therapeutic opportunities that we propose to exploit in the context of immunotherapy. We have established a new platform for adoptive cellular therapy (ACT) employing the use of total tumor RNA-pulsed dendritic cells (DCs) to expand tumor reactive T lymphocytes. We are currently testing in multiple clinical trials this treatment modality in patients with brain tumors (ACTION-IND#17298, REMATCH-IND#14058, BRAVO-IND#17298). The goal of this project is to leverage the power of this therapeutic platform to achieve robust targeting of treatment-resistant clones using a novel model of recurrent GBM. We hypothesize that the cytotoxic activity of tumor-specific T cells can be directed toward clones promoting recurrence by SCC RNA-pulsed dendritic cells, thus impeding disease relapse. To test our hypothesis, the specific aims of this proposal are to: Aim 1. Determine the immunogenicity and efficacy of slow-cycling cell RNA-based T cell treatment in a preclinical model of recurrent GBM Aim 2. Evaluate the slow-cycling cell RNA-based T cell platform in a human autologous setting. Successfully completed, this proposal has a strong likelihood to impact favorably on treatment options for patients with malignant gliomas.