Quantitative control of CAR T cells via image-guided delivery and monitoring

通过图像引导递送和监测对 CAR T 细胞进行定量控制

• 批准号: 10261575
• 负责人: Michael David Farwell
• 金额: $ 63.88万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10261575
• 关键词: Acute; Advanced Malignant Neoplasm; Affinity; Antibodies; Antigen Targeting; Antigens; Antitumor Response; Architecture; Binding; Biodistribution; Biological; CAR T cell therapy; CD19 gene; Cell Therapy; Cells; Cessation of life; Chemistry; Clinical; Coupling; Development; Diagnostic Imaging; Docking; Drug Delivery Systems; ERBB2 gene; Effectiveness; Engineered Gene; Functional Imaging; Generations; Goals; Health; Health Benefit; Human; Image; Imaging Device; Immunologic Receptors; Immunomodulators; In Vitro; Infusion procedures; Label; Ligands; Link; Lymphoblastic lymphoma; Measures; Mediating; Methods; Monitor; Mus; Normal tissue morphology; Oncology; Organ; Outcome; PET/CT scan; Peripheral; Positron-Emission Tomography; Process; Public Health; Radioimmunoconjugate; Radiolabeled; Reagent; Reporter; Research; Safety; Solid Neoplasm; Specificity; System; T cell therapy; T-Lymphocyte; Testing; Therapeutic; Tissues; Toxic effect; Trastuzumab; Treatment Protocols; Tumor Antigens; Tumor-infiltrating immune cells; Variant; X-Ray Computed Tomography; antibody diagnostic; antigen-specific T cells; base; cancer therapy; cancer type; cell killing; cellular targeting; chimeric antigen receptor; chimeric antigen receptor T cells; companion diagnostics; cost; covalent bond; cytokine release syndrome; design; engineered T cells; gene therapy; genetically modified cells; image guided; imaging approach; imaging probe; immunopathology; improved; in vivo; innovation; large cell Diffuse non-Hodgkin' s lymphoma; medication safety; molecular imaging; multidisciplinary; mutant; neoplastic cell; non-invasive imaging; novel; predicting response; radiotracer; reagent testing; receptor; response; small molecule; synthetic biology; targeted cancer therapy; targeted delivery; theranostics; trafficking; tumor; tumor specificity; uptake

Abstract- CONFIDENTIAL To provide a means for quantitative control of CAR T cell activity, our team first created universal immune receptors (UnivIRs), a versatile platform for the de novo generation and quantitative control of tumor antigen- specific T cells where human T cells are genetically engineered with novel docking immune receptors and can be conferred with highly personalized tumor specificity through the subsequent loading/re-targeting with “tagged” antigen-specific antibodies, scFvs or other receptor ligands. Building upon these principles, we have created an orthogonal image-guided T cell delivery (IGTD) method where localization of the targeting ligand and delivery of CAR T cells with tailored payloads are guided and monitored through noninvasive imaging in order to facilitate safe and effective targeted therapy for cancer. Our theranostic IGTD platform utilizes novel targeting biologics with covalent binding tags that can be imaged, or engaged by CAR T cells to activate their antigen-specific anti-tumor response. These targeting biologics can be used for diagnostic imaging prior to CAR T cell delivery, to assess localization of the agent to the tumor, predict response to therapy, and evaluate for potential on-target off-tumor toxicity. In addition, our IGTD method will permit in vivo cell tracking via direct radiolabeling of CAR T cells prior to infusion, or via a small molecule PET imaging probe that binds the CAR construct on the T cells. Our multidisciplinary team's goal is to optimize this IGTD method to allow local, image- guided delivery of the therapeutic T cell product to the target tissue, to allow localized and controlled delivery of immunomodulatory agents for maximal activity and safety, and to provide functional imaging readouts on the therapeutic process(es) that occur during treatment. We build upon strong preliminary results to test the central hypothesis that CAR therapy can be improved by targeting multiple and diverse antigens either simultaneously or sequentially and safely applied through integrated pre-therapeutic diagnostic imaging and innovative CAR platform re-development. By uniting diverse scientific expertise in advanced T cell gene-engineering with molecular imaging and chemistry, we propose to 1) develop, test and optimize novel universal immune receptors that uniquely and covalently bind tagged and image-labeled TAA-specific antibodies to recapitulate CAR architecture and activity in vivo; 2) evaluate their potential to simultaneously attack multiple TAAs on tumor cells as well as suppressive cells in the microenvironment to maximize outcome, 3) develop radiolabeled antibody-based diagnostic PET/CT imaging to measure antibody localization to tumor and TAA biodistribution prior to universal CAR T cell administration and test for its ability to predict safety and response; and 4) serially monitor and understand universal CAR T cell distribution in tumor and healthy organs using PET-based “live” in vivo tracking of antibody-armed CAR T cells following infusion. Successful development of this platform is designed to revolutionize CAR gene therapy by allowing for the therapeutic coupling of adaptable antigen- targeted T cells with PET guided monitoring for therapeutic activity, drug delivery and safety in vivo.

抽象机密 为了提供对CAR T细胞活动的定量控制手段，我们的团队首先创建了普遍的免疫 受体（Univirs），这是一个多功能平台，用于从头产生和定量控制肿瘤抗原 特定的T细胞，其中人T细胞是通过新型对接免疫受体进行基因设计的，并且可以 通过随后的加载/重新定位，以高度个性化的肿瘤特异性授予 “标记”抗原特异性抗体，SCFV或其他受体配体。在这些原则的基础上，我们有 创建了一种正交图像引导的T细胞输送（IGTD）方法，其中定位靶向配体 并通过无创成像进行指导和监测带有量身定制有效载荷的汽车T单元 为了促进癌症的安全有效靶向治疗。我们的热IGTD平台利用新颖 用可以成像的共价结合标签靶向生物制剂，或者由CAR T细胞参与以激活其 抗原特异性抗肿瘤反应。这些靶向生物制剂可用于诊断成像 CAR T细胞输送，评估药物对肿瘤的定位，预测对治疗的反应并评估 为潜在的靶向上的肿瘤毒性。此外，我们的IGTD方法将允许通过直接进行体内细胞跟踪 在输注之前或通过结合CAR的小分子PET成像探针的辐射标记 在T细胞上构建。我们的多学科团队的目标是优化这种IGTD方法，以允许本地图像 - 将治疗性T细胞产物传递到目标组织，以允许局部和控制的递送 免疫调节剂，以实现最大的活动和安全性，并在 治疗过程中发生的治疗过程。我们以强大的初步结果为基础来测试中央 假设可以通过靶向多种和潜水抗原来改善汽车治疗 或通过集成的治疗前诊断成像和创新的汽车依次安全地应用 平台重新开发。通过将高级T细胞基因工程领域的潜水员科学专业知识结合在一起 分子成像和化学，我们建议1）开发，测试和优化新型的通用免疫 独特而共价结合标记和图像标记的TAA特异性抗体的受体以概括 体内汽车建筑和活动； 2）评估他们简单地攻击多个TAA的潜力 肿瘤细胞以及微环境中的抑制细胞以最大化结果，3）发展得标记。 基于抗体的诊断PET/CT成像，以测量抗肿瘤和TAA生物分布的抗体定位 在通用汽车的给药之前，并测试了其预测安全性和响应的能力； 4）串行 使用基于宠物的“ Live”来监测和了解肿瘤和健康器官中的通用汽车T细胞分布 输注后，体内跟踪抗体臂T细胞。这个平台的成功开发是 旨在通过允许适应性抗原的治疗耦合来彻底改变汽车基因治疗 用宠物指导监测的靶向T细胞在体内进行治疗活性，药物递送和安全性。