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.鲁尼和L.王）是为了提高扩展性和持久性， 使用两种新方法过继转移肿瘤特异性T细胞。(1)成立第三方公司- 产生含有细胞内信号传导结构域的GD 2嵌合抗原受体（CAR）， 假设CD 28和OX 40增强和维持肿瘤内的T细胞应答，而 提供对肿瘤微环境中产生的抑制性配体的抗性。(ii)一个 应通过将GD2.CAR移植到T细胞特异性受体上来实现肿瘤外增殖性增强。 水痘-带状疱疹病毒（VZV），存在一种有效的减毒活加强疫苗 其通过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移植的VZV特异性T细胞用于治疗患有VZV的患者的临床试验中进行探索。 晚期GD 2阳性肉瘤（A i s 1和2）。因为这将是一项“首次人体”研究， 转导的T细胞还将结合基于胱天蛋白酶-9二聚化的可诱导安全开关 分子，这是在最近的一项临床试验中验证，对移植物与。宿主疾病可惜 最年轻的儿童肉瘤患者将是VZV阴性的，这使得很难产生VZV特异性抗体。 自体T细胞，并证明这些血清阴性患者接种减毒活病毒。 因此，目标3将在临床前模型中评估针对GD 2的细胞疫苗，其应提供 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，该细胞系具有 作为NB的细胞疫苗进行了广泛的测试。GD 2由JF细胞强烈表达，并且可以通过免疫细胞化学方法来检测。 直接通过JFNB细胞和间接通过局部抗原- 递呈细胞。对JFNB细胞进行遗传修饰以表达细胞因子，如IL 15和GM-CSF， 增强T细胞增殖以及募集和激活树突状细胞应促进肿瘤外增殖 CAR阳性T细胞以类似于VZV刺激天然T细胞受体的方式。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（iC 9安全基因）以及项目4（TGF β的DNR）的安全性和有效性。 相关性（参见说明）： 晚期肉瘤和其他高危实体瘤的T细胞治疗的进展 由于可靶向肿瘤抗原的弱表达或缺乏以及免疫抑制剂的性能差， 注入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 新的疫苗接种策略，以确保足够的T细胞刺激，无论是内部和外部的能力 肿瘤部位。