CD19 Specific Immunotherapy for Follicular Lymphoma

滤泡性淋巴瘤的 CD19 特异性免疫治疗

• 批准号: 6992455
• 负责人: Michael C Jensen
• 金额: $ 8.35万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-02 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6992455
• 关键词: CD19 molecule; NOD mouse; antibody; autologous transplantation; biotechnology; cell growth regulation; cell migration; cell proliferation; cell transplantation; clinical research; clinical trial phase I; combination cancer therapy; gene therapy; human genetic material tag; human subject; human therapy evaluation; immunoregulation; interleukin 2; leukapheresis; neoplasm /cancer immunotherapy; neoplasm /cancer relapse /recurrence; nonHodgkin' s lymphoma; nonhuman therapy evaluation; passive immunization; patient oriented research; therapy adverse effect; thymidine kinase

Currently available therapeutics for follicular lymphoma (FL) have limited curative potential and significant toxicities, particularly for the older FL patient population. Novel treatment modalities, such as immunotherapy, that can combine enhanced anti-tumor efficacy with diminished toxicities through targeting of malignant B-cells of FL are needed. The studies proposed here will build on the advances made in FL immunotherapy through antibody-based therapeutics by developing complimentary cellular immunotherapy-based approaches for this disease. We have made significant progress in developing the methodologies for isolating and expanding genetically-modified T-cells that express a CD19-specific chimeric immunoreceptor and display potent and specific anti-tumor effector functioning against CD19 + lymphomas. Moreover, the City of Hope has established platforms for manufacturing clinical-grade genetically-modified ex vivo-expanded T-cell products under FDA-authorized IND's. A pilot Phase I clinical trial is proposed to treat, for the first time, FL patients with refractory/progressive disease with autologous ex vivo-expanded CD19-specific T-cell lines (Aim 1). In addition to answering questions of feasibility, safety, and anti-tumor responses, this trial will study the in vivo persistence, lymph node homing, and immunogenicity of these cell products. The magnitude and duration of in vivo persistence of adoptivelytransferred CD19-specific T-cells will likely be important parameters for clinical efficacy. While we will study the impact of pre-adoptive therapy lymphodepletion and exogenous IL-2 administration on promoting persistence in the context of our pilot study, Aim 2 of this proposal will focus on pre-clinical development of strategies to selectively express the anti-CD19 immunoreceptor in T-cells having desired anti-viral specificity through their endogenous TCRs. Ultimately we hypothesize that such bi-specific T-cells will be amenable to in vivo expansion through vaccination with viral antigen. Aim 3 will focus on promoting the survival and recycling of CD19-specific T-cells in the lymphoma microenvironment by their co-expression of CD28 for coordinated delivery of activation and co-stimulation signals by tumor cells of FL. We anticipate that insights gained from the pilot clinical trial and proposed pre-clinical studies will facilitate the implementation of second-generation adoptive immunotherapy protocols for FL with applications to other B-lineage lymphomas

目前可用的滤泡性淋巴瘤 (FL) 治疗方法的治疗潜力有限且具有显着的毒性，特别是对于老年 FL 患者群体。需要新的治疗方式，例如免疫疗法，通过靶向 FL 的恶性 B 细胞，将增强的抗肿瘤功效与减少的毒性结合起来。这里提出的研究将建立在通过基于抗体的疗法在 FL 免疫疗法取得的进展的基础上，通过开发针对这种疾病的基于细胞免疫疗法的补充方法。我们在开发分离和扩增转基因 T 细胞的方法方面取得了重大进展，这些 T 细胞表达 CD19 特异性嵌合免疫受体，并显示出针对 CD19 + 淋巴瘤的有效且特异性的抗肿瘤效应器功能。此外，希望之城还建立了根据 FDA 授权的 IND 生产临床级转基因离体扩增 T 细胞产品的平台。拟开展一项试点 I 期临床试验，首次使用自体体外扩增的 CD19 特异性 T 细胞系治疗难治性/进行性疾病的 FL 患者（目标 1）。除了回答可行性、安全性和抗肿瘤反应等问题外，该试验还将研究这些细胞产品的体内持久性、淋巴结归巢和免疫原性。过继转移的 CD19 特异性 T 细胞在体内持续存在的程度和持续时间可能是临床疗效的重要参数。虽然我们将在我们的试点研究中研究过继治疗前淋巴清除和外源性 IL-2 给药对促进持久性的影响，但该提案的目标 2 将侧重于临床前开发选择性表达抗 CD19 的策略T细胞中具有所需抗病毒特异性的免疫受体 通过其内源性TCR。最终，我们假设这种双特异性 T 细胞将能够通过接种病毒抗原进行体内扩增。目标 3 将侧重于通过 CD28 的共表达来促进淋巴瘤微环境中 CD19 特异性 T 细胞的存活和回收，以协调 FL 肿瘤细胞传递激活和共刺激信号。我们预计，从试点临床试验和拟议的临床前研究中获得的见解将有助于实施第二代 FL 过继免疫治疗方案，并应用于其他 B 系淋巴瘤