Preclinical development of breakthrough immunotherapy for brain tumors

脑肿瘤突破性免疫疗法的临床前开发

• 批准号: 10551829
• 负责人: Hideho Okada
• 金额: $ 72.53万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-15 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551829
• 关键词: Address; Adopted; Adult Glioma; Antigen Targeting; Antigen-Presenting Cells; Antigens; Area; Award; Brain; Brain Neoplasms; Cells; Childhood Glioma; Collaborations; Cytotoxic T-Lymphocytes; Data; Engineering; Environment; Glioma; Goals; Homing; Immune; Immune response; Immunology; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Laboratories; Malignant Glioma; Malignant Neoplasms; Mediating; National Institute of Neurological Disorders and Stroke; Normal Cell; Oncolytic viruses; Patients; Research; Signal Transduction; Site; System; T-Cell Receptor; Technology; Tissues; Tumor Antigens; chemokine; chimeric antigen receptor; chimeric antigen receptor T cells; flexibility; high risk; immunotherapy clinical trials; lymphoid organ; neoantigens; new technology; notch protein; novel; preclinical development; preclinical study; success; tertiary lymphoid organ; tumor; tumor microenvironment

The ultimate success of immunotherapy for brain malignancies, such as malignant glioma, will require integration of in-depth understanding of immunology with solutions for the following long-standing challenges: 1) paucity and heterogeneous expression of glioma-specific antigens; 2) poor homing and persistence of effector cytotoxic T lymphocytes (CTLs); and 3) glioma-induced immunosuppression. My laboratory has been contributing to critical discoveries in each of these areas, and integrated our findings into novel immunotherapy clinical trials for glioma patients. In the current proposal, we will leverage our current research directions by combining our expertise on glioma antigens and cutting-edge cell-engineering technologies in preclinical studies. We hypothesize that integration of novel cell-engineering and antigen-targeting approaches will allow us to develop safer and more effective immunotherapy strategies by overcoming heterogeneous expression of antigens and unique challenges in brain immunology. We will evaluate the following strategies: 1. Novel glioma neoantigens for safe and effective immunotherapy. We will leverage our current NINDS awards (R01NS096954 and R21NS093654) and characterize T-cell receptors (TCRs) specific to neoantigens derived from both pediatric and adult gliomas. 2. Sequential chimeric antigen receptor (CAR)/TCR system for targeting multiple antigens. As a way to safely target glioma-associated antigens (GAAs) in the tumor microenvironment without damaging normal cells outside of the brain, we will evaluate the novel sequential Synthetic Notch (synNotch) CAR/TCR system, in which antigen signaling through the first CAR or TCR against a tumor-specific antigen induces the second, anti-GAA CAR/TCR to trigger the CTL activity at the tumor site. 3. Targeting the glioma immune environment by creating tertiary lymphoid organs (TLOs). The absence of lymphatic organs and professional antigen presenting cells are thought to be major reasons for insufficient immune responses in the brain. We will evaluate whether induction of TLOs in the brain tumor site will facilitate efficient and long-lasting glioma antigen-specific immune responses in the brain tumor site. These 3 strategies will be logically integrated into combination approaches. Novel antigens and TCRs will be adopted into the synNotch CAR/TCR system, and the TLO approach would also be most beneficial when combined with the synNotch CAR/TCR system. As expected per the purpose of the NINDS R35 mechanism, these strategies may involve high risks. However, based on our proof-of-principle preliminary data, we will persistently pursue our goals with the long-term support by the R35 mechanism, and flexibly and swiftly adopt new technologies. These studies will also integrate with other areas of ongoing studies in our lab. For example, oncolytic virus-mediated expression of target antigen and CTL-attracting chemokine (“payload” approaches) would help us to overcome the paucity and heterogeneous expression of antigens as well as tumor homing of CTLs to the glioma tissue. The R35 would allow these integrations.

脑恶性肿瘤（如恶性神经胶质瘤）免疫治疗的最终成功将需要将对免疫学的深入理解与以下长期挑战的解决方案相结合：1）神经胶质瘤特异性抗原的缺乏和异质表达; 2）效应细胞毒性T淋巴细胞（CTL）的归巢和持久性差;以及3）神经胶质瘤诱导的免疫抑制。我的实验室一直在为这些领域的关键发现做出贡献，并将我们的发现整合到针对胶质瘤患者的新型免疫治疗临床试验中。在目前的提案中，我们将利用我们目前的研究方向，结合我们在神经胶质瘤抗原和临床前研究中的尖端细胞工程技术的专业知识。我们假设，新的细胞工程和抗原靶向方法的整合将使我们能够通过克服抗原的异质性表达和脑免疫学中的独特挑战来开发更安全，更有效的免疫治疗策略。我们将评估以下策略：1。用于安全有效免疫治疗的新型胶质瘤新抗原。我们将利用我们目前的NINDS奖项（R 01 NS 096954和R21 NS 093654），并表征对来自儿童和成人胶质瘤的新抗原特异性的T细胞受体（TCR）。2.用于靶向多种抗原的顺序嵌合抗原受体（CAR）/TCR系统。作为一种在肿瘤微环境中安全靶向神经胶质瘤相关抗原（GAA）而不损伤脑外正常细胞的方法，我们将评估新型连续合成Notch（synNotch）CAR/TCR系统，其中通过第一CAR或TCR针对肿瘤特异性抗原的抗原信号传导诱导第二抗GAA CAR/TCR以触发肿瘤部位的CTL活性。3.通过创建三级淋巴器官（TLO）靶向胶质瘤免疫环境。淋巴器官和专职抗原呈递细胞的缺乏被认为是大脑中免疫应答不足的主要原因。我们将评估在脑肿瘤部位诱导TLO是否会促进脑肿瘤部位的有效和持久的胶质瘤抗原特异性免疫应答。这三种策略将在逻辑上整合为组合方法。新的抗原和TCR将被采用到synNotch CAR/TCR系统中，并且当与synNotch CAR/TCR系统组合时，TLO方法也将是最有益的。正如NINDS R35机制的目的所预期的那样，这些策略可能涉及高风险。然而，基于我们的原理验证初步数据，我们将在R35机制的长期支持下坚持追求我们的目标，并灵活快速地采用新技术。这些研究还将与我们实验室正在进行的其他研究领域相结合。例如，溶瘤病毒介导的靶抗原和CTL吸引趋化因子的表达（“有效载荷”方法）将帮助我们克服抗原的缺乏和异质表达以及CTL向胶质瘤组织的肿瘤归巢。R35将允许这些集成。