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: 10059272
• 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/10059272
• 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; Receptor Cell; Research; Signal Transduction; Site; System; T-Cell Receptor; Technology; Tissues; Tumor Antigens; base; 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.

免疫疗法对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的深度理解，以应对以下长期存在的挑战：1）胶质瘤特异性抗原的稀疏和异质表达； 2）效应子细胞毒性T淋巴细胞（CTLS）的归因和持久性； 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每个领域中的关键发现做出贡献，并将我们的发现纳入了新型免疫疗法临床试验中，用于神经胶质瘤患者。在当前的建议中，我们将通过结合临床前研究中的胶质瘤抗原和尖端细胞工程技术的专业知识来利用当前的研究方向。我们假设新型细胞工程和抗原靶向方法的整合将使我们通过克服抗原的异质表达和脑免疫学中的独特挑战来制定更安全，更有效的免疫疗法策略。我们将评估以下策略：1。新型神经胶质瘤新抗原，以进行安全有效的免疫疗法。我们将利用当前的NINDS奖项（R01NS096954和R21NS093654），并表征针对来自儿科和成人神经胶质瘤的新抗原特异性的T细胞受体（TCRS）。 2。用于靶向多种抗原的顺序嵌合抗原受体（CAR）/TCR系统。 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 地点。 3。通过创建三级淋巴机器人（TLOS）来靶向神经胶质瘤免疫环境。人们认为缺乏淋巴器官和专业抗原呈递细胞是大脑免疫复杂不足的主要原因。我们将评估脑肿瘤部位中TLO的诱导是否会促进脑肿瘤部位中有效且持久的胶质瘤抗原特异性免疫反应。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，与Synnotch CAR/TCR系统结合使用，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。但是，根据我们的原则初步数据证明，我们将通过R35机制的长期支持来持续实现目标，并灵活而迅速采用新技术。这些研究还将与我们实验室中正在进行的研究的其他领域集成。例如，溶瘤病毒介导的靶抗原和CTL趋化因子（“有效载荷”方法）的表达将有助于我们克服抗原的稀疏和异质表达，以及CTL的肿瘤归位为胶质瘤组织。 R35将允许这些集成。