Nanoparticles for In Vivo Labeling of T Cells During Cancer Immunotherapy

用于癌症免疫治疗期间 T 细胞体内标记的纳米颗粒

• 批准号: 10634620
• 负责人: Carlos M Rinaldi-Ramos
• 金额: $ 16.61万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-03 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10634620
• 关键词: Acceleration; Adoptive Cell Transfers; Anatomy; Atypical lymphocyte; Award; Binding; Biodistribution; Biomedical Engineering; Blocking Antibodies; Blood Circulation; Blood Circulation Time; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Vaccines; Cell Communication; Cell Survival; Cell membrane; Cell surface; Cells; Clinical; Clinical Trials; Confusion; Cytotoxic T-Lymphocytes; Desmoplastic Melanoma; Detection; Development; Dissociation; Doctor of Philosophy; Environment; Excision; Ferritin; Flow Cytometry; Foundations; Glioblastoma; Head and Neck Squamous Cell Carcinoma; Hemoglobin; Hodgkin Disease; Image; Immune checkpoint inhibitor; Immune response; Immune system; ImmunoPET; Immunocompetent; Immunoglobulin Fragments; Immunotherapy; In Situ; Ionizing radiation; Iron; Label; Life; Magnetic Resonance Imaging; Magnetism; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Medicine; Melanoma Cell; Merkel cell carcinoma; Microscopy; Modeling; Mus; Neoadjuvant Therapy; Nobel Prize; Non-Small-Cell Lung Carcinoma; Oncolytic viruses; Organ; Outcome; Pathway interactions; Patients; Penetration; Phenotype; Physics; Physiology; Prior Therapy; Qualifying; Recurrence; Recurrent Malignant Neoplasm; Refractory; Renal Cell Carcinoma; Research; Research Project Grants; Resolution; Role; Science; Scientist; Signal Transduction; Site; Solid; Solid Neoplasm; Squamous cell carcinoma; T-Lymphocyte; Tail; Technology; Tissues; Tracer; Tumor Antigens; Veins; Work; biomaterial compatibility; biomedical imaging; cancer immunotherapy; cancer recurrence; cancer therapy; clinical translation; cytotoxic; density; imaging modality; imaging study; immune checkpoint blockade; immune imaging; improved; in vivo; insight; iron oxide; iron oxide nanoparticle; melanoma; molecular imaging; mouse model; nanoparticle; neoplastic cell; non-invasive imaging; novel; optical imaging; particle; patient prognosis; preclinical evaluation; prognostic; programmed cell death protein 1; public health relevance; quantitative imaging; recruit; research and development; response; success; superparamagnetism; tool; trafficking; treatment planning; treatment response; treatment strategy; treatment stratification; tumor; tumor microenvironment; uptake

Project Summary Despite decades of research, the prognosis for patients with malignant brain tumors remains poor and novel treatment strategies are urgently needed. Malignant gliomas are particularly refractory to treatment, uniformly fatal, and have not seen improvement in outcomes for over three decades. Immunotherapy has tremendous promise for eradicating cancers with exquisite precision by leveraging the cytotoxic capabilities of tumor antigen- reactive lymphocytes. Immune checkpoint blockade therapy blocking the programmed death 1 (PD-1) pathway is used clinically against melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, renal cell carcinoma, and Hodgkin's lymphoma. Although anti-PD-1 therapy alone is ineffective against malignant gliomas, recent clinical trials with recurrent glioblastoma multiforme (GBM) suggest benefit of neoadjuvant anti- PD-1 therapy prior to tumor resection. Preliminary results with an immunocompetent mouse model of recurrent GBM suggests a role for CD8+ T cell recruitment during neoadjuvant anti-PD-1 therapy prior to tumor resection. This Exploratory/Developmental Bioengineering Research Grant will develop technology to enable non-invasive quantitative imaging of CD8+ tracer recruitment to the site of tumor resection using magnetic particle imaging (MPI), a new imaging modality with potential advantages over immunoPET imaging. MPI tracers will be formulated consisting of superparamagnetic iron oxide nanoparticles (SPION) with targeting motifs to selectively label CD8+ T cells, enabling non-invasive, unambiguous, and quantitative imaging of their biodistribution. Preliminary results show the PI has already developed MPI tracers with high sensitivity and long blood circulation time. Selective in vivo labeling of T cells will be achieved by functionalizing these optimized MPI tracers with antibody fragments that bind to T cell surface markers, resulting in internalization or persistent binding to the T cell membrane. An important consideration in labeling T cells in vivo and in situ in solid tumors is penetration of the imaging label. Preliminary results demonstrate accelerated and enhanced tumor accumulation of systemically administered SPIONs through magnetic targeting. The PI hypothesizes that magnetic targeting of T cell targeting SPIONs at the site of tumor resection will lead to increased SPION/T cell interactions and increased sensitivity to the presence of T cells at the tumor resection site. In Aim 1 T cell labeling with the MPI tracers will be optimized ex vivo and the effect of labeling on T cell viability and cytotoxic phenotype will be evaluated. Then, in Aim 2 in vivo T cell labeling using systemically administered tracers will be evaluated in the context of neoadjuvant anti-PD-1 therapy prior to tumor resection in a mouse model of recurrent GBM. The proposed work will capitalize on magneto responsiveness of the SPION tracers to accelerate and enhance tumor penetration using magnetic targeting. Success in the proposed research will add MPI as a tool in the growing immunoimaging toolbox, helping accelerate development and mechanistic understanding of cancer immunotherapies through in situ and in vivo labeling of CD8+ T cell biodistribution and recruitment to tumors.

项目摘要 尽管经过几十年的研究，恶性脑瘤患者的预后仍然很差，而且是新奇的。 迫切需要治疗策略。恶性胶质瘤尤其难以治疗，一致认为 致命的，并且三十多年来没有看到结果的改善。免疫疗法具有巨大的影响力 通过利用肿瘤抗原的细胞毒性能力，有望精准地根除癌症- 反应性淋巴细胞。免疫检查点阻断治疗阻断程序死亡1(PD-1)通路 临床上用于治疗黑色素瘤、非小细胞肺癌、头颈部鳞状细胞癌、肾脏 细胞癌和霍奇金淋巴瘤。尽管单用抗PD-1治疗对恶性肿瘤无效 最近对复发性多形性胶质母细胞瘤(GBM)的临床试验表明，新辅助抗肿瘤药物有好处。 肿瘤切除前PD-1治疗。免疫活性复发性小鼠模型的初步结果 GBM提示CD8+T细胞在肿瘤切除前新辅助抗PD-1治疗中的作用。 这项探索性/开发性生物工程研究补助金将开发技术，使非侵入性 磁粒子成像定量检测肿瘤切除部位CD8+示踪剂的研究 (MPI)，一种新的成像方式，具有免疫PET成像的潜在优势。MPI追踪器将是 由具有选择性靶向基序的超顺磁性氧化铁纳米颗粒(SPION)组成的配方 标记CD8+T细胞，实现对其生物分布的非侵入性、明确和定量成像。 初步结果表明，PI已经开发出具有高灵敏度和长血液循环的MPI示踪剂 时间到了。通过将这些优化的MPI示踪剂功能化，将实现对T细胞的选择性体内标记 与T细胞表面标志物结合的抗体片段，导致T细胞内化或持久结合 细胞膜。在体内和实体瘤中原位标记T细胞的一个重要考虑因素是穿透 成像标签。初步结果显示加速和增强了肿瘤的聚集 通过磁靶向系统管理SPION。PI假设磁靶向 肿瘤切除部位靶向SPION的T细胞将导致Spion/T细胞相互作用增加 对肿瘤切除部位T细胞存在的敏感性增加。用MPI标记AIM-1 T细胞 示踪剂将在体外进行优化，标记对T细胞活性和细胞毒表型的影响将是 已评估。然后，在AIM 2中，使用系统给药示踪剂的体内T细胞标记将在 复发性基底膜小鼠模型肿瘤切除前新辅助抗PD-1治疗的背景。这个 拟议的工作将利用Spion示踪剂的磁响应性来加速和增强肿瘤 使用磁靶向穿透。拟议研究的成功将使MPI成为日益增长的 免疫成像工具箱，帮助加速癌症的发展和机制理解 通过原位和体内标记CD8+T细胞在肿瘤中的生物分布和募集进行免疫治疗。