Vaccination to Enhance T cell Immunotherapy

疫苗接种增强 T 细胞免疫治疗

• 批准号: 8435584
• 负责人: CLIONA M ROONEY
• 金额: $ 29.13万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8435584
• 关键词: Antibodies; Antigen Receptors; Attenuated; CD28 gene; Chronic Lymphocytic Leukemia; Clinical Trials; Generations; Goals; Herpesvirus Type 3; Immunotherapy; Infusion procedures; Life; Ligands; Malignant Neoplasms; Neuroblastoma; Patients; Process; Resistance; Signal Transduction; T cell response; T cell therapy; T-Cell Receptor; T-Lymphocyte; Therapeutic; Transgenic Organisms; Tumor Antigens; Vaccination; Vaccine Antigen; antigen binding; booster vaccine; cytotoxic; improved; in vivo; novel strategies; receptor; sarcoma; success; tumor; tumor microenvironment

The long-term goal of Project 1 (C. Rooney and L. Wang) is to improve the expansion and persistence of adoptively transferred tumor-specific T cells using two novel approaches. (1) Incorporation of a third- generation chimeric antigen receptor (CAR) for GD2 containing intracellular signaling domains for CD28 and OX40 is hypothesized to enhance and sustain T- cell responses intratumorally, while providing resistance to inhibitory ligands elaborated within the tumor microenvironment. (ii) An extratumoral proliferative boost should be attained by engrafting the GD2.CAR onto T cells specific for the varicella-zoster virus (VZV), for which there exists a potent live-attenuated booster vaccine that increases the in vivo proliferation of VZV-specific T cells via their TCRs. These broad concepts will be explored in a clinical trial of GD2.CAR-engrafted VZV-specific T cells for the treatment of patients with advanced GD2-positive sarcomas ( A i m s 1 and 2). Because this will be a "first-in-man" study, the transduced T cells will also incorporate an inducible safety switch based on dimerization of the caspase-9 molecule, which was validated in a recent clinical trial against graft-vs.-host disease. Unfortunately, the youngest pediatric sarcoma patients will be VZV-negative, making it difficult to generate VZV-specific autologous T cells and to justify vaccination of these seronegative patients with a live-attenuated virus. Hence, Aim 3 will evaluate in a preclinical model a cellular vaccine against GD2 that should provide extratumoral stimulation via the CAR. This effort will rely on the JF neuroblastoma (NB) cell line, which has been extensively tested as a cellular vaccine for NB. GD2 is strongly expressed by JF cells and can be presented to GD2,CAR-positive T cells both directly by the JFNB cells and indirectly by local antigen- presenting cells. Genetic modification of JFNB cells to express cytokines, such as ILI 5 and GM-CSF, that enhance T-cell proliferation and recruit and activate dendritic cells should promote extratumoral proliferation of the CAR-positive T cells in ananalogous way to stimulation of the native T cell receptor by VZV. In part therefore our project uses concepts developed in Project 3 and provides potential ways of increasing the safety and efficacy of projects 2 and 3 (the iC9 safety gene) and Project 4 (the DNR for TGFbeta). RELEVANCE (See instructions): Progress in the development of T-cell therapy for advanced sarcomas and other high-risk solid tumors has been slowed by the weak expression or absence of targetable tumor antigens and poor performance of infused T cells . Project 1 seeks to address this problem by combining improved antigen receptor capabilities with a novel vaccination strategy to ensure adequate T-cell stimulation, both within and outside the tumor site.

项目 1（C. Rooney 和 L. Wang）的长期目标是提高 使用两种新方法过继转移肿瘤特异性 T 细胞。 (1) 成立第三个—— 生成含有细胞内信号结构域的 GD2 嵌合抗原受体 (CAR) 假设 CD28 和 OX40 可以增强和维持瘤内 T 细胞反应，而 提供对肿瘤微环境中精心设计的抑制性配体的抵抗力。 (二) 一个 应通过将 GD2.CAR 移植到 T 细胞特异性上来实现肿瘤外增殖促进 针对水痘带状疱疹病毒 (VZV)，有一种有效的减毒活加强疫苗 通过 TCR 增加 VZV 特异性 T 细胞的体内增殖。这些广泛的概念将 在 GD2.CAR 植入的 VZV 特异性 T 细胞治疗患有以下疾病的患者的临床试验中进行探索 晚期 GD2 阳性肉瘤（目标 1 和 2）。因为这将是一项“首次人体”研究 转导的 T 细胞还将包含基于 caspase-9 二聚化的诱导安全开关 分子，该分子在最近的一项针对移植物抗宿主病的临床试验中得到了验证。不幸的是， 最年轻的儿科肉瘤患者将呈 VZV 阴性，因此很难产生 VZV 特异性 自体 T 细胞，并证明为这些血清阴性患者接种减毒活病毒疫苗是合理的。 因此，Aim 3 将在临床前模型中评估针对 GD2 的细胞疫苗，该疫苗应提供 通过 CAR 进行肿瘤外刺激。这项工作将依赖于 JF 神经母细胞瘤 (NB) 细胞系，该细胞系已 作为 NB 细胞疫苗进行了广泛测试。 GD2 在 JF 细胞中强烈表达，并且可以 直接由 JFNB 细胞和间接由局部抗原呈递给 GD2、CAR 阳性 T 细胞 呈现细胞。对 JFNB 细胞进行基因改造以表达细胞因子，例如 ILI 5 和 GM-CSF， 增强 T 细胞增殖并招募和激活树突状细胞应促进瘤外增殖 以与 VZV 刺激天然 T 细胞受体类似的方式刺激 CAR 阳性 T 细胞。部分 因此，我们的项目使用项目 3 中开发的概念，并提供了增加 项目 2 和 3（iC9 安全基因）和项目 4（TGFbeta 的 DNR）的安全性和有效性。 相关性（参见说明）： 针对晚期肉瘤和其他高危实体瘤的 T 细胞疗法的开发取得了进展 由于可靶向肿瘤抗原的表达较弱或缺乏以及肿瘤细胞的性能不佳而减慢了 输注T细胞。项目1试图通过结合改进的抗原受体来解决这个问题 具有新颖的疫苗接种策略的能力，以确保内部和外部充分的 T 细胞刺激 肿瘤部位。