High-flow microfluidics of leukapheresis blood products for functional analysis of breast circulating tumor cells

白细胞分离血液制品的高流量微流体用于乳腺循环肿瘤细胞的功能分析

• 批准号: 10544808
• 负责人: Daniel A. Haber
• 金额: $ 63.47万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-08 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10544808
• 关键词: Active Sites; Antibodies; Antibody-drug conjugates; Biological; Biomedical Engineering; Biopsy; Blood; Blood Cells; Blood Platelets; Blood Screening; Blood Volume; Breast; Breast Cancer Patient; Breast Cancer therapy; Cancer Patient; Cell Count; Cell Separation; Cell surface; Cells; Circulation; Clinical; Complex; Cultured Tumor Cells; DNA; DNA Sequence Alteration; Epitopes; Excision; Generations; Genetic; Goals; Hematopoietic stem cells; Hour; Hypoxia; Immunologics; Immunotoxins; Lesion; Leukapheresis; Leukocytes; Magnetism; Malignant Neoplasms; Measures; Metastatic breast cancer; Microfluidic Microchips; Microfluidics; Molecular; Monitor; Mus; Mutation; Mutation Analysis; Needles; Neoplasm Circulating Cells; Neoplasm Metastasis; PD-1/PD-L1; Patient Selection; Patients; Performance; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Plasma; Population; Population Heterogeneity; Primary Neoplasm; Procedures; Process; Prognosis; Property; Reporting; Resistance; Sampling; Sampling Biases; Selection for Treatments; Solid Neoplasm; Sorting; Stream; TACSTD1 gene; Technology; Therapeutic; Therapeutic Intervention; Time; Tumor Antigens; Tumor Burden; Tumor Markers; Tumor-Derived; Whole Blood; Woman; acquired drug resistance; antibody conjugate; blood product; cancer care; cancer cell; cancer invasiveness; cancer therapy; checkpoint therapy; clinical application; design; drug development; drug sensitivity; drug testing; high throughput technology; immunosuppressed; individual patient; individualized medicine; insight; liquid biopsy; magnetic beads; microfluidic technology; molecular subtypes; multidisciplinary; neoplastic cell; novel; novel therapeutics; patient subsets; personalized cancer care; pre-clinical; precision oncology; predictive marker; response; small molecule inhibitor; stem-like cell; success; targeted treatment; therapeutic target; tool; triple-negative invasive breast carcinoma; tumor; tumorigenic

Liquid biopsies are poised to revolutionize cancer therapies, by enabling frequent blood-based monitoring of tumor-derived materials, as cancers evolve in response to therapeutic interventions. Nowhere is this more evident than in triple negative metastatic breast cancer, where women may undergo multiple serial courses of therapy over many years, each associated with an initial response, followed by the acquisition of drug resistance. Plasma DNA (ctDNA) mutation analyses provide a measure of tumor burden and may identify targetable mutations for small molecule inhibitors, but they do not allow ex vivo culture of intact circulating tumor cells (CTCs) for individualized preclinical drug sensitivity (“precision oncology”). Isolation of CTCs has been achieved using small blood volumes (5-10 mL), but these cells are so rare that it has not been feasible to establish clinically robust ex vivo CTC cultures. Our hypothesis is that we can massively increase the amount of blood screened through standard clinical leukapheresis (1-2 L), and in return, achieve 100+-fold increase in the number of isolated CTCs to establish routine ex vivo culture of CTCs. It is also important to note that ex vivo CTC cultures obtained by sampling 1-2 L blood will reflect the “real time” molecular subtype, genetic composition, and evolving drug sensitivity profile of an individual patient's metastatic breast cancer, including multiple lesions that together contribute to the blood-borne CTC population and the patient's overall tumor burden. We will develop a high-throughput microfluidic technology that achieves highly efficient depletion of tagged blood cells away from unmanipulated single and clustered CTCs and provides “tumor independent enrichment” performance, which is applicable to cells disseminated from any solid tumor type without making any a priori assumption on the physical and/or biological properties of tumor cells. We will also establish the microenvironmental conditions conducive to high efficiency ex vivo CTC cultures from women with metastatic triple negative breast cancer. Success would be transformative both for new drug development and for individualized patient selection among existing therapies for breast cancer patients, and others.

液体活检被毒死以彻底改变癌症疗法，通过经常基于血液的监测 肿瘤衍生的材料，癌症响应治疗干预而发展。没有更多的地方 证据要比三重阴性转移性乳腺癌，女性可以参加多个串行课程 多年的治疗，每种都与初始反应有关，然后获得药物 反抗。血浆DNA（CTDNA）突变分析提供了肿瘤灼伤的测量 小分子抑制剂的靶向突变，但不允许在完整循环的离体培养 肿瘤细胞（CTC），用于个性化的临床前药物敏感性（“精度肿瘤学”）。 CTC的隔离有 使用小血量（5-10 mL）实现了，但是这些细胞非常罕见，以至于它不可行 建立临床上强大的离体CTC培养物。我们的假设是我们可以大大增加 通过标准的临床白细胞术（1-2 L）筛选的血液，作为回报，实现100+倍的增加 分离的CTC数量以建立CTC的常规离体培养。同样重要的是要注意到体内 通过抽样1-2升血液获得的CTC培养物将反映“实时”分子亚型，遗传 组成和不断发展的药物敏感性概况的转移性乳腺癌，包括 多种病变共同导致血液传播的CTC种群和患者的整体肿瘤 负担。我们将开发一种高通量微流体技术，可实现高效的部署 标记的血细胞远离无操纵的单一和聚类的CTC，并提供“独立于肿瘤 富集”的性能，适用于从任何实体瘤类型中传播的细胞而无需进行的细胞 任何关于肿瘤细胞物理和/或生物学特性的先验假设。我们还将建立 微环境条件导电到具有转移性女性的高效率过时的CTC培养物 三重阴性乳腺癌。对于新药物开发和对 在现有的乳腺癌患者和其他人的现有疗法中选择个性化患者。