Preclinical development of breakthrough immunotherapy for brain tumors

脑肿瘤突破性免疫疗法的临床前开发

基本信息

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
项目类别：
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

项目摘要

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（例如恶性神经胶质瘤）免疫疗法的最终成功需要将对免疫学的深入了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）归巢不良；和效应细胞毒性 T 淋巴细胞 (CTL) 的持续性；3) 神经胶质瘤诱导的免疫抑制。我的实验室一直在这些领域做出重要发现，并整合了我们的发现。在当前的提案中，我们将通过结合我们在神经胶质瘤抗原方面的专业知识和临床前研究中的尖端细胞工程技术来利用我们当前的研究方向。抗原靶向方法将使我们能够通过克服抗原的异质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. 安全、有效的新型神经胶质瘤新抗原。我们将利用我们当前的 NINDS 奖项（R01NS096954 和 R21NS093654）并表征针对儿童和成人神经胶质瘤的新抗原的 T 细胞受体（TCR）。 2. 用于靶向多种的序列嵌合抗原受体（CAR）/TCR 系统。作为一种安全靶向肿瘤微环境中的神经胶质瘤相关抗原（GAA）而不损害肿瘤外正常细胞的方法。在大脑中，我们将评估新型顺序合成Notch (synNotch) CAR/TCR系统，其中通过针对肿瘤特异性抗原的第一个CAR或TCR的抗原信号传导诱导第二个抗GAA CAR/TCR以触发CTL活性3. 通过创建三级淋巴器官（TLO）来靶向神经胶质瘤免疫环境淋巴器官和专业抗原呈递细胞的缺乏被认为是免疫反应不足的主要原因。我们将评估在脑肿瘤部位诱导 TLO 是否会促进脑肿瘤部位有效且持久的神经胶质瘤抗原特异性免疫反应，这 3 种策略将被逻辑地整合到新的抗原和 TCR 的组合方法中。被纳入 synNotch CAR/TCR 系统中，并且 TLO 方法在与 synNotch CAR/TCR 系统结合时也将是最有益的，正如根据 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不懈地追求我们的目标，并灵活、迅速地采用新技术，这些研究也将与正在进行的其他领域相结合。例如，溶瘤病毒介导的靶抗原和CTL吸引趋化因子的表达（“有效负载”方法）将帮助我们克服抗原表达的缺乏和异质性以及肿瘤归巢的问题。 R35 将允许这些整合。