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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要尽管经过了数十年的研究，恶性脑肿瘤患者的预后仍然很差且新颖迫切需要治疗策略。恶性神经胶质瘤特别难以治疗，均匀致命的，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有望通过利用肿瘤抗原的细胞毒性能力以极高的精度根除癌症反应性淋巴细胞。免疫检查点阻断疗法阻断程序性死亡 1 (PD-1) 通路临床上用于治疗黑色素瘤、非小细胞肺癌、头颈鳞状细胞癌、肾癌细胞癌和霍奇金淋巴瘤。尽管单独使用抗PD-1疗法对恶性癌症无效胶质瘤，最近复发性多形性胶质母细胞瘤（GBM）的临床试验表明新辅助抗胶质瘤的益处肿瘤切除前的 PD-1 治疗。具有免疫功能的复发性小鼠模型的初步结果 GBM 提示在肿瘤切除前新辅助抗 PD-1 治疗期间 CD8+ T 细胞募集的作用。这项探索性/发展性生物工程研究补助金将开发技术以实现非侵入性使用磁粒子成像对肿瘤切除部位的 CD8+ 示踪剂募集进行定量成像（MPI），一种新的成像方式，与免疫PET成像相比具有潜在优势。 MPI 追踪器将由超顺磁性氧化铁纳米粒子 (SPION) 组成，具有靶向基序，可选择性标记 CD8+ T 细胞，实现其生物分布的非侵入性、明确且定量成像。初步结果显示PI已开发出高灵敏度、长血循环的MPI示踪剂时间。 T 细胞的选择性体内标记将通过使用这些优化的 MPI 示踪剂进行功能化来实现与 T 细胞表面标记物结合的抗体片段，导致内化或与 T 细胞持续结合细胞膜。在实体瘤中体内和原位标记 T 细胞的一个重要考虑因素是 T 细胞的渗透成像标签。初步结果表明肿瘤积累加速和增强通过磁性靶向系统地施用 SPION。 PI 假设磁性靶向 T 细胞在肿瘤切除部位靶向 SPION 将导致 SPION/T 细胞相互作用增加，增加对肿瘤切除部位 T 细胞存在的敏感性。 In Aim 1 使用 MPI 标记 T 细胞示踪剂将在体外进行优化，标记对 T 细胞活力和细胞毒性表型的影响将评价。然后，在目标 2 中，将使用全身施用的示踪剂进行体内 T 细胞标记的评估复发性 GBM 小鼠模型肿瘤切除前新辅助抗 PD-1 治疗的背景。这拟议的工作将利用 SPION 示踪剂的磁响应来加速和增强肿瘤使用磁性瞄准进行渗透。拟议研究的成功将使 MPI 成为不断增长的工具免疫成像工具箱，有助于加速癌症的发展和机制了解通过原位和体内标记 CD8+ T 细胞生物分布和招募到肿瘤的免疫疗法。