NanoOptogenetic immunotherapy for B cell lymphoma

B细胞淋巴瘤的纳米光遗传学免疫疗法

• 批准号: 10400658
• 负责人: Gang Han
• 金额: $ 41.86万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10400658
• 关键词: Abdomen; Acute Lymphocytic Leukemia; Address; Area; Axilla; B-Cell Lymphomas; Biological; CAR T cell therapy; CD19 gene; Calcium; Calcium Channel; Calcium Signaling; Cancer Patient; Cells; Characteristics; Clinical Trials; Coupling; Cultured Tumor Cells; Dendritic Cells; Development; Dose; Engineering; Fever; Fiber Optics; Generations; Goals; Growth; Health; Heart; Hematologic Neoplasms; Human; Immune; Immune response; Immunotherapy; In Vitro; Infrared Rays; Intervention; Lead; Light; Lighting; Liver; Location; Lung; Malignant Neoplasms; Metastatic Neoplasm to the Lung; Methodology; Methods; Microscopic; Modality; Monoclonal Antibodies; Mus; Nanotechnology; Neck; Nodal; Non-Hodgkin' s Lymphoma; Normal tissue morphology; Optics; Organ; Patients; Penetration; Performance; Photophobia; Phototherapy; Production; Property; Protocols documentation; Receptor Cell; Receptor Signaling; Recombinants; Research; Resolution; STIM1 gene; Safety; Scheme; Science; Side; Signal Transduction; Site; Skin; Surface; Symptoms; Syndrome; System; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Toxic effect; Triplet Multiple Birth; Tumor Antigens; Tumor Immunity; Visible Radiation; anti-tumor immune response; base; biomaterial compatibility; cancer cell; cancer immunotherapy; cancer therapy; chimeric antigen receptor; chimeric antigen receptor T cells; cytokine; cytokine release syndrome; design; engineered T cells; immunoengineering; immunoregulation; improved; in vivo; innovation; interest; leukemia treatment; leukemia/lymphoma; melanoma; member; mouse model; nano; nanoparticle; neoplastic cell; next generation; novel; optogenetics; receptor; response; side effect; spatiotemporal; therapy outcome; tool; tumor; wireless

Project Summary/Abstract: Chimeric antigen receptors (CARs) are engineered recombinant receptors composed of key signaling modules from both the T cell receptor (TCR) and co-stimulatory receptors to mount effective anti-tumor immunity. Engineered CAR-T cells be reinfused into the patient to recognize and attack cancer cells. CAR-T cell therapy has shown very promising results in clinical trials. However, owing to a lack of precise control of the dose, location, and timing of T cell activity, this method involves some significant safety challenges to be overcome. For example, cytokine release syndrome (CRS), occurred due to a large and uncontrolled release of cytokines in response to CAR-T, may cause symptoms ranging from fever to potentially fatal organ destructions. In addition, conventional CAR T cells are also associated with the targeted destruction of normal tissue, which is known as “on-target, off-tumor” effects since tumor antigens are also expressed at a certain level in several normal tissues. Therefore, the uncontrolled aggressively amplified CAR-T cells cross-react with cells in the heart, lung or liver and cause devastating consequences in patients. To address this challenging issue, we propose to develop non-invasive methodologies that allow for the spatiotemporal control of chimeric antigen receptor (CAR) T cells for cancer treatment by using B cell lymphoma as a test case. This proposal is based on two key discoveries made by the members of the team. First, we have created a way to optogenetically modulate the function of calcium signaling by conferring visible light sensitivity to stromal interaction molecule 1 (STIM1), activating the ORAI1 calcium channel in T cells to mount effector immune responses. The second is our development of upconversion nanoparticles (UCNPs), more specifically their use as in vivo relay nodes to capture and convert low power, deep tissue-penetrant, and near infrared radiation (NIR) into visible light for in vivo optogentic applications. In our preliminary results, we have demonstrated that the use of ex vivo UCNPs and optogentic dual engineering approach can indeed optogenetically instruct immune cells (i.e,, dentritic cells) to attack melanoma in mice, and that NIR light therapy effectively suppresses melanoma growth and metastasis to lungs. We propose three specific aims. For Aim 1, we will develop photo-tunable CARs in engineered therapeutic T cells. In Aim 2, we will devise new generations of UCNPs with improved compatibility with OptoCARs. In Aim 3, we will determine the efficacy of nano-optogenetic CAR-T platforms in vitro and in vivo. This new strategy will overcome many of the limitations of current CAR-T based approaches, and will enable new applications in both fundamental science and human health.

项目摘要/摘要： 嵌合抗原受体（CARS）是由组成的重组受体 来自T细胞受体（TCR）和共刺激受体的关键信号模块 安装有效的抗肿瘤免疫。工程化的CAR-T细胞被重新融入 患者识别和攻击癌细胞。 CAR-T细胞疗法表现出非常 在临床试验中有希望的结果。但是，由于缺乏对剂量的精确控制， 位置和T细胞活动的时间，此方法涉及一些明显的安全性 要克服的挑战。例如，发生细胞因子释放综合征（CRS） 由于对CAR-T的响应较大且不受控制的细胞因子释放，可能会导致 症状从发烧到潜在的致命器官破坏。此外， 常规的汽车T细胞也与正常的目标破坏有关 组织，被称为“靶向，肿瘤的效果”，因为肿瘤抗原也是 在几个正常组织中以一定水平表达。因此，不受控制 积极扩增的CAR-T细胞与心脏，肺或肝脏中的细胞交叉反应，并 导致患者造成破坏性后果。为了解决这个挑战问题，我们 提出开发非侵入性方法的提议，以实现时空控制 通过使用B细胞的嵌合抗原受体（CAR）T细胞进行癌症治疗 淋巴瘤作为验证案例。该提议基于两个关键发现 团队成员。首先，我们创建了一种方法来调制 钙信号传导的功能，通过对基质相互作用的可见光灵敏度来传导的功能 分子1（STIM1），激活T细胞中的Orai1钙通道以安装效应器 免疫反应。第二个是我们的上转换纳米颗粒的发展 （UCNPS），更具体地说，它们用作体内继电器节点以捕获和转换低 功率，深层组织探测器和近红外辐射（NIR），可见光 体内副本应用。在我们的初步结果中，我们证明了 实际上可以使用过体内UCNP和精选双重工程方法 在光源教导免疫细胞（即脆性细胞）中攻击小鼠黑色素瘤， NIR光疗法有效地抑制了黑色素瘤的生长和转移 肺。我们提出了三个具体目标。对于AIM 1，我们将开发可调的汽车 在工程疗法T细胞中。在AIM 2中，我们将设计新一代的UCNP 具有改善与光学的兼容性。在AIM 3中，我们将确定 体外和体内的纳米异源性CAR-T平台。这个新策略将克服 当前基于CAR-T的方法的许多局限性，并将启用新的 在基本科学和人类健康中的应用。