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 免疫学与违反长期挑战的解决方案的整合： 1）胶质瘤特异性抗原的稀疏和异质表达； 2） 效应细胞毒性T淋巴细胞（CTL）和3）胶质瘤诱导的免疫选择。 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 胶质瘤患者的临床试验。 结合我们在临床前的胶质瘤抗原和切割边缘工程技术方面的专业知识 我们假设新型细胞工程和抗原靶向方法 通过克服 在大脑免疫学中，我们将评估您的抗抗病性和独特的挑战。 以下策略：1。新型神经瘤新抗原可用于安全有效的免疫疗法 我们目前的NINDS奖项（R01NS096954和R21NS093654），表征了T细胞受体（TCRS） 特定于儿科和成人神经胶质瘤的新抗原。 靶向多种抗原的受体（CAR）/TCR系统。 肿瘤微观诊断中的抗原（GAA），大脑外部有破坏的正常细胞，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诱导第二个抗GA/TCR诱导 在肿瘤部位触发CTL活性。 淋巴器官（TLOS）。 被认为是对大脑免疫反应不足的主要原因。 脑肿瘤部位的TLO将促进有效而持久的胶质瘤抗原Imunee 脑肿瘤部位的反应将在逻辑上整合到组合方法中。 新型抗原和TCR将被采用到同步汽车/TCR系统中，而TLO接近walld 与同步汽车/TCR系统结合使用时也是最有益的。 Ninds R35机制，这些策略可能涉及高风险。 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 灵活和划线采用新技术。 例如，我们的实验室研究。 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的肿瘤组织胶质瘤组织将允许这些整合。