Generating rapid antitumor immunity with lymphocyte-reprogramming nanocarriers

利用淋巴细胞重编程纳米载体产生快速抗肿瘤免疫力

基本信息

批准号：
9307201
负责人：
Matthias Stephan
金额：
$ 37.19万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9307201
关键词：
Advanced Malignant Neoplasm Affinity Antigens Autologous Binding Biomedical Engineering Bypass CD3 Antigens CRISPR/Cas technology Cancer Model Cancer Patient Cell physiology Cells Climate Clustered Regularly Interspaced Short Palindromic Repeats Communicable Diseases Custom DNA Diagnosis Endocytosis Event Fingerprint Gene-Modified Genes Genetic Engineering Goals Heterogeneity Homeostasis Immune Immune checkpoint inhibitor Immune system Immunity Immunologist Immunotherapy Impairment In Situ In Vitro Infusion procedures Injectable Intervention Laboratories Ligands Lymphocyte Malignant Neoplasms Malignant neoplasm of ovary Measures Mediating Medicine Messenger RNA Methods Mus NR0B2 gene Oncologist Operative Surgical Procedures Patients Pharmaceutical Preparations Phenotype Plasmids Polymers Production Protein Kinase Protein Tyrosine Phosphatase RNA ROR1 gene Reagent Receptor Gene Recurrence Relapse Research Resistance Resort Scheme System T memory cell T-Cell Receptor T-Lymphocyte Testing Therapy trial Time Toxic effect Training Translating Tumor Antigens Tumor Escape Tumor Immunity United States Vaccines Variant Viral Antigens base cancer cell cancer type chemotherapy chimeric antigen receptor clinically relevant combat cost design dosage endonuclease genome editing genome sequencing immune checkpoint immunoregulation improved improved functioning in vivo leukemia mesothelin multidisciplinary nanocarrier nanoparticle nanovector neoplastic cell novel ovarian neoplasm particle patient population prevent programs receptor receptor expression response standard care standard of care tumor whole genome

项目摘要

So far, medicine lacks an intervention that can rapidly generate anti-tumor immunity. For example, vaccines can train the immune system to selectively destroy cancer cells, however they may require months to do so--by which time tumors may become lethal. Infusions of autologous T cells targeted against tumor antigens using in vitro approaches are expensive and labor-intensive, and must be personalized for each patient in specialized cell-production facilities. We propose an alternative: the research outlined here seeks to develop an off-the- shelf reagent that can quickly program tumor-recognizing capabilities into T cells without extracting them for laboratory manipulation. Specifically, we hypothesize that circulating T cells can be programmed by gene- carrying polymeric nanoparticles (NPs) to express chimeric antigen receptors (CARs) that recognize selected antigens, enabling them to mediate rapid and vigorous rejection of tumors. We also hypothesize that co- delivering a CRISPR genome editing system to silence immune checkpoints will improve the efficacy and persistence of NP-programmed T cells. Our multidisciplinary team of immunologists, bioengineers, and geneticists has already developed a novel NP configuration that can successfully introduce leukemia-specific CAR receptor genes into circulating lymphocytes. The reprogrammed cells continue to produce these receptors for weeks, allowing them to act as a `living drug' that accumulates at the target, increases in number, serially destroys tumor cells, and ultimately differentiates into long-lived memory T cells. Our eventual goal is to provide a practical, low-cost, broadly-applicable treatment that can generate anti-tumor immunity “on demand” for oncologists in a variety of settings. As essential steps toward achieving this goal, we propose these Specific Aims: (1) To measure how effectively NP-programmed CAR expression causes the regression of advanced cancer; (2) To determine if antigen loss and tumor escape events are reduced when NP combinations program T cells to target a spectrum of antigens; and (3) To determine if silencing negative regulators of T cell function improves their anti-tumor activity. We expect our results will provide a basis to design various gene modification systems that can generate immunity against any type of cancer. Especially, they will reduce the likelihood of antigen escape variants because patients can be treated with NP-delivered CAR genes tailored to their tumor's antigenic fingerprint. These particles could be easily adapted to program lymphocytes to express high-affinity T cell receptors specific for various viral antigens, so our results may also provide a strategy for treating infectious diseases.

到目前为止，药物缺乏可以迅速产生抗肿瘤免疫力的干预措施。例如，疫苗可以训练免疫系统以选择性破坏癌细胞，但是它们可能需要几个月的时间 - 哪个时候肿瘤可能会致命。使用IN靶向针对肿瘤抗原的自体T细胞的输注体外方法是昂贵且劳动力密集的，必须对每个患者进行个性化专业化细胞生产设施。我们提出了一种替代方案：此处概述的研究试图开发一个现行可以将肿瘤识别能力迅速编程为T细胞的架子试剂，而无需提取它们实验室操作。具体而言，我们假设可以通过基因编程循环的T细胞携带聚合物纳米颗粒（NP）表达嵌合抗原受体（CAR）识别选定的抗原，使它们能够介导肿瘤的快速而有力地排斥。我们还假设该共同提供CRISPR基因组编辑系统以使免疫检查点保持沉默将提高效率和 NP编程的T细胞的持久性。我们的免疫学家，生物工程师和仿制药已经开发了一种新型的NP配置，可以成功引入白血病特异性汽车受体基因成循环淋巴细胞。重编程的细胞继续产生这些受体数周，使它们充当积累目标的“活着药物”，数量增加，数量增加，序列破坏肿瘤细胞，并最终区分为长寿命的记忆T细胞。我们最终的目标是提供一种实用，低成本，广泛的可供处理方法，可以“按需”产生抗肿瘤免疫学用于各种环境中的肿瘤学家。作为实现这一目标的重要步骤，我们提出了这些特定的目的：（1）测量NP编程的CAR表达如何导致高级回归癌症; （2）确定NP组合程序时是否减少抗原损失和肿瘤逃生事件 T细胞靶向抗原谱；（3）确定是否沉默T细胞功能的负面调节剂改善其抗肿瘤活性。我们希望我们的结果将为设计各种基因提供基础可以针对任何类型的癌症产生免疫力的修饰系统。特别是，他们会减少抗原逃生变体的可能性是因为患者可以用量身定制的NP递送的汽车基因治疗他们的肿瘤的抗原指纹。这些颗粒很容易适应程序淋巴细胞以表达高亲和力T细胞受体特有的各种病毒抗原，因此我们的结果也可能为治疗传染病。