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: 10665550
• 负责人: Gang Han
• 金额: $ 40.79万
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665550
• 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; Coculture Techniques; Coupling; Cross Reactions; 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; 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; Proliferating; Property; Protocols documentation; 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; biomaterial compatibility; cancer cell; cancer immunotherapy; cancer therapy; chimeric antigen receptor; chimeric antigen receptor T cells; cytokine; cytokine release syndrome; design; efficacy evaluation; 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; optical fiber; 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.

项目概要/摘要： 嵌合抗原受体（汽车）是由以下组成的工程化重组受体： 来自T细胞受体（TCR）和共刺激受体的关键信号模块 以获得有效的抗肿瘤免疫力。将工程化的CAR-T细胞重新输注到 患者识别和攻击癌细胞。CAR-T细胞疗法已经显示出非常 在临床试验中取得了可喜的成果。然而，由于缺乏对剂量的精确控制， 位置和T细胞活性的时间，这种方法涉及一些显着的安全性 需要克服的挑战。例如，细胞因子释放综合征（CRS）， 由于响应CAR-T而大量且不受控制地释放细胞因子，可能导致 症状从发烧到可能致命的器官破坏。此外，本发明还提供了一种方法， 传统的CAR T细胞也与正常的靶向破坏有关。 组织，这被称为“靶向，脱肿瘤”效应，因为肿瘤抗原也 在几种正常组织中以一定水平表达。因此，不受控制的 积极扩增的CAR-T细胞与心脏、肺或肝脏中的细胞交叉反应， 对病人造成毁灭性的后果。为了解决这个具有挑战性的问题，我们 建议开发允许时空控制的非侵入性方法 嵌合抗原受体（CAR）T细胞用于通过使用B细胞的癌症治疗 淋巴瘤作为测试案例。这一建议是基于两个关键的发现， 团队成员。首先，我们已经创造了一种光遗传学调节 通过赋予基质相互作用可见光敏感性来实现钙信号传导的功能 分子1（STIM 1），激活T细胞中的ORAI 1钙通道， 免疫反应。第二个是我们开发的上转换纳米粒子 （UCNPs），更具体地说，它们用作体内中继节点以捕获和转换低浓度的 功率、深层组织渗透和近红外辐射（NIR）转换为可见光， 体内光遗传应用。在我们的初步结果中，我们已经证明， 使用离体UCNP和光遗传双重工程方法确实可以 光遗传学指导免疫细胞（即，树突细胞）攻击小鼠中的黑素瘤， 并且NIR光疗法有效地抑制黑色素瘤生长和转移， 肺我们提出三个具体目标。对于目标1，我们将开发光可调谐的汽车 基因改造的治疗性T细胞在目标2中，我们将设计新一代的UCNP 提高了与OptoCAR的兼容性。在目标3中，我们将确定 纳米光遗传学CAR-T平台在体外和体内。这一新战略将克服 目前基于CAR-T的方法的许多局限性，并将使新的 应用于基础科学和人类健康。

项目成果

Nano-optogenetic immunotherapy.

• DOI: 10.1002/ctm2.1020
• 发表时间: 2022-09
• 期刊: CLINICAL AND TRANSLATIONAL MEDICINE
• 影响因子: 10.6
• 作者: Huang, Kai;Liu, Xiaoxuan;Han, Gang;Zhou, Yubin
• 通讯作者: Zhou, Yubin

Harnessing natural killer cells to develop next-generation cellular immunotherapy.

• DOI: 10.1002/cdt3.40
• 发表时间: 2022-12
• 期刊: Chronic diseases and translational medicine
• 作者: Liu, Siyao;Nguyen, Kaycee;Park, Dongyong;Wong, Nelson;Wang, Anson;Zhou, Yubin
• 通讯作者: Zhou, Yubin