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: 10632441
• 负责人: Hideho Okada
• 金额: $ 14.54万
• 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/10632441
• 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

ABSTRACT 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.

抽象的 免疫疗法对大脑恶性肿瘤的最终成功（例如恶性神经胶质瘤）将需要 对免疫学的深入了解与解决方案有关以下长期挑战的解决方案： 1）胶质瘤特异性抗原的稀少和异质表达； 2）不良的归人和持久性 效应细胞毒性T淋巴细胞（CTL）； 3）神经胶质瘤诱导的免疫抑制。我的实验室已经 在每个领域中有助于发现关键发现，并将我们的发现纳入新的免疫疗法 神经胶质瘤患者的临床试验。在当前的建议中，我们将通过 结合我们在临床前的胶质瘤抗原和尖端细胞工程技术方面的专业知识 研究。我们假设新型细胞工程和抗原靶向方法的整合 通过克服 抗原的异质表达和脑免疫学中的独特挑战。我们将评估 以下策略：1。新型神经胶质瘤新抗原，可用于安全有效的免疫疗法。我们将利用 我们目前的NINDS奖项（R01NS096954和R21NS093654），并表征T-Cell接收器（TCRS） 特定于儿科和成人神经胶质瘤的新抗原。 2。顺序嵌合抗原 用于靶向多种抗原的接收器（CAR）/TCR系统。作为安全靶向神经胶质瘤相关的一种方式 肿瘤微环境中的抗原（GAA），而不会损害大脑外的正常细胞，我们将 评估新型的顺序合成缺口（Synnotch）CAR/TCR系统，其中抗原信号传导 通过第一辆车或针对肿瘤特异性抗原的TCR诱导第二辆抗GAA/TCR诱导 在肿瘤部位触发CTL活性。 3。通过创建第三级来靶向神经胶质瘤免疫环境 淋巴器官（TLOS）。缺乏淋巴机器人和专业抗原呈递细胞是 被认为是大脑免疫复杂不足的主要原因。我们将评估是否归纳 脑肿瘤部位的TLO将促进有效且持久的神经胶质瘤抗原特异性免疫 脑肿瘤部位的反应。这三种策略将在逻辑上集成到组合方法中。 新型抗原和TCR将被采用到同步汽车/TCR系统中，TLO方法将 与Synnotch CAR/TCR系统结合使用时也是最有益的。正如预期的 Ninds R35机制，这些策略可能涉及高风险。但是，根据我们的原理证明 初步数据，我们将在R35机制的长期支持下持续追求我们的目标，并且 灵活，迅速适应新技术。这些研究还将与其他持续的领域集成 在我们实验室的研究。例如，溶瘤病毒介导的靶抗原和吸引CTL的表达 趋化因子（“有效载荷”方法）将帮助我们克服缺乏和异质表达 抗原以及CTL的肿瘤归巢为神经胶质瘤组织。 R35将允许这些集成。