Determining treatment sensitivity in B cell lymphoma by novel microfluidics-based NK cell immunogenicity platform

通过基于微流体的新型 NK 细胞免疫原性平台确定 B 细胞淋巴瘤的治疗敏感性

基本信息

  • 批准号:
    9919540
  • 负责人:
  • 金额:
    $ 37.93万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-05-01 至 2022-10-31
  • 项目状态:
    已结题

项目摘要

Abstract B cell non-Hodgkin lymphomas (bNHL) are the most common lymphoma subtype representing >85% of all NHLs. bNHL are typically treated the anti-CD20 antibody (e.g., rituximab) alone or in combination with chemotherapy. There are currently, however, no biological methods or markers to predict the sensitivity or resistance to rituximab (or any other) antibody therapy. A key feature of antibody activity occurs through natural killer (NK) cell-mediated killing of antibody-coated target tumor cells, however, antitumor activity and subsequent resistance, is poorly understood. In this application, we propose to develop and validate a high throughput droplet based microfluidic platform to investigate the key features of NK cells associated with rapid, slow or inactive tumor killing kinetics in NHL. We will first adapt a novel approach and integrate the biocompatible acoustofluidic droplet sorter during the droplet microarray formation to determine the phenotypes of immune-target cell interaction in microfluidic droplets. We will validate a droplet-based microfluidic device to interrogate single-cell dynamic responses and cell-cell interactions within intact droplets. Next, we will demonstrate a high-purity (>95%), high-throughput (>10,000 events/s), four-channel acoustofluidic droplet sorter to integrate with droplet analysis array. The downstream 4-channel sorting will allow, after establishing the kinetic profiles of interactions, to identify and sort droplets containing active lymphocytes into a distinctive pool; separate basal lymphocytes into another pool based on fluorescence. A unique function of selecting sorting criteria based on imaging analysis can be provided by the combination of droplet imaging array and acoustofluidic droplet sorters, which is unachievable for conventional fluorescence activated droplet sorters (FADS) since imaging tracking is inherently tricky in high-speed flow. Thus, our approach serves as a “bottom-up” method of classification, by first identifying distinct functional categories and then probing the content of the individual cell category to determine the key factors for the molecular classification of heterogeneous immune functions of NK cells related to target cell kill. In addition, we will identify NK cell heterogeneity and bio-functional characteristics to discover novel drug combinations for NK cell dependent immunotherapy via an integrated acoustofluidic droplet sorting platform. We will demonstrate that the accuracy of phenotype identification of our device and its suitability for clinical applications by monitoring and classifying NK/NHL single cell interactions in the presence of monoclonal antibodies and performing biochemical secretome assay from ‘hyperactive’, ‘basal’ and non-responsive pools. By combing these findings with drug screening and identification of phenotype altering drugs, we will demonstrate the applicability of this technology for personalized medicine and rational clinical immunotherapeutic applications. We envision our platform may be leveraged in a variety of single-cell analysis applications in immunotherapy and it will provide high value to the bioengineering, biomedical, and therapeutic research communities.
摘要 B细胞非霍奇金淋巴瘤(bNHL)是最常见的淋巴瘤亚型,占美国 所有NHL bNHL通常用抗CD 20抗体(例如,利妥昔单抗)单独或与 化疗然而,目前没有生物学方法或标记来预测敏感性或 对利妥昔单抗(或任何其他)抗体治疗的抗性。抗体活性的一个关键特征是通过天然的 杀伤(NK)细胞介导的抗体包被的靶肿瘤细胞的杀伤,然而, 阻力,知之甚少。在这个应用中,我们建议开发和验证高通量液滴 基于微流控平台,研究NK细胞与快速、缓慢或失活相关的关键特征, NHL中的肿瘤杀伤动力学。我们将首先采用一种新的方法, 在微滴微阵列形成过程中使用微滴分选器以确定免疫靶细胞的表型 微流体液滴中的相互作用。我们将验证基于液滴的微流控装置来询问单细胞 完整液滴内的动态响应和细胞-细胞相互作用。接下来,我们将展示一种高纯度的 (>95%)、高通量(> 10,000个事件/秒)、四通道声流液滴分选仪,可与液滴分选仪集成 分析数组下游4通道分选将允许在建立相互作用的动力学曲线后, 将含有活性淋巴细胞的液滴识别并分类到一个独特的池中;分离基底淋巴细胞 根据荧光的不同将其放入另一个水池。基于成像分析选择分类标准的独特功能 可以通过液滴成像阵列和声流液滴分选器的组合来提供, 这对于常规的荧光激活液滴分选器(FADS)是不可实现的,因为成像跟踪固有地 在高速水流中很棘手因此,我们的方法是一种“自下而上”的分类方法,首先确定 不同的功能类别,然后探测各个单元格类别的内容以确定键 与靶细胞杀伤相关的NK细胞的异质性免疫功能的分子分类的因素。 此外,我们将鉴定NK细胞的异质性和生物功能特征以发现新药 通过集成的声流液滴分选平台进行NK细胞依赖性免疫治疗的组合。我们 将证明我们的设备表型鉴定的准确性及其临床适用性 通过在单克隆抗体存在下监测和分类NK/NHL单细胞相互作用, 抗体,并从“高活性”、“基础”和无应答池进行生物化学分泌组测定。 通过将这些发现与药物筛选和表型改变药物的鉴定相结合,我们将 证明了该技术在个性化医疗和合理临床应用中的适用性, 免疫学应用。我们设想我们的平台可以用于各种单细胞分析 它将为生物工程,生物医学和治疗提供高价值 研究社区。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Andrew M Evens其他文献

Enhancing the treatment landscape: PET-guided BrECADD for advanced-stage, classical Hodgkin lymphoma
改善治疗格局:用于晚期经典型霍奇金淋巴瘤的正电子发射断层扫描(PET)引导下的硼中子俘获增敏放疗(BrECADD)
  • DOI:
    10.1016/s0140-6736(24)01404-1
  • 发表时间:
    2024-07-27
  • 期刊:
  • 影响因子:
    88.500
  • 作者:
    Andrew M Evens
  • 通讯作者:
    Andrew M Evens
The genetic landscape of immune-competent and HIV lymphoma
  • DOI:
    10.1186/1750-9378-7-s1-o1
  • 发表时间:
    2012-04-19
  • 期刊:
  • 影响因子:
    2.800
  • 作者:
    Jenny Zhang;Vladimir Grubor;Cassandra L Love;Anjishnu Banerjee;Kristy L Richards;Piotr Miezcowski;Cherie H Dunphy;William WL Choi;Wing-Yan Auv;Gopesh Srivastava;Patricia L Lugar;David A Rizzieri;Anand S Lagoo;Leon Bernal-Mizrachi;Karen P Mann;Christopher R Flowers;Kikkeri N Naresh;Andrew M Evens;Leo I Gordon;Magdalena B Czader;Javed I Gill;Eric D Hsi;Qingquan Liu;Alice Fan;Katherine Walsh;Dereje D Jima;Micah Luftig;Ting Ni;Jun Zhu;Amy Chadburn;Shawn Levy;David B Dunson;Sandeep S Dave
  • 通讯作者:
    Sandeep S Dave
No Place like Home: Home-Based Intravenous Arsenic Trioxide for the Treatment of Acute Promyelocytic Leukemia (APL)
  • DOI:
    10.1182/blood-2023-190597
  • 发表时间:
    2023-11-02
  • 期刊:
  • 影响因子:
  • 作者:
    Brooke Kania;David Awad;Michael Kane;Andrew M Evens;Neil Palmisiano
  • 通讯作者:
    Neil Palmisiano
A Phase I/II Study of Tazemetostat Combined with Abbreviated Rituximab/Bendamustine Therapy for High Tumor Burden Follicular Lymphoma in Frontline Treatment: A Big Ten Cancer Research Consortium Study
  • DOI:
    10.1182/blood-2024-202639
  • 发表时间:
    2024-11-05
  • 期刊:
  • 影响因子:
  • 作者:
    Vaishalee P Kenkre;Yong Lin;Narendranath Epperla;Saurabh A Rajguru;Julie E Chang;Priyanka A. Pophali;Elyse I Harris;Christopher D Fletcher;Matthew Matasar;Hussam Eltoukhy;David A. Bond;Yazeed Sawalha;Beth Christian;Timothy Voorhees;Mariah Endres;Mitch Howard;Damayanti Bhavsar;Misty Fleming;Jordan S. Carter;Andrew M Evens
  • 通讯作者:
    Andrew M Evens
Nivolumab-AVD Is Better Tolerated and Improves Progression-Free Survival Compared to Bv-AVD in Older Patients (Aged ≥60 Years) with Advanced Stage Hodgkin Lymphoma Enrolled on SWOG S1826
  • DOI:
    10.1182/blood-2023-180114
  • 发表时间:
    2023-11-02
  • 期刊:
  • 影响因子:
  • 作者:
    Sarah C. Rutherford;Hongli Li;Alex F. Herrera;Michael Leblanc;Sairah Ahmed;Kelly L. Davison;Carla Casulo;Nancy L. Bartlett;Joseph M Tuscano;Brian Hess;Pallawi Torka;Pankaj Kumar;Ryan W Jacobs;Joo Y Song;Sharon M. Castellino;Brad S. Kahl;John P. Leonard;Sonali M. Smith;Jonathan W. Friedberg;Andrew M Evens
  • 通讯作者:
    Andrew M Evens

Andrew M Evens的其他文献

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{{ truncateString('Andrew M Evens', 18)}}的其他基金

Modeling Multi-Source Data in Hodgkin Lymphoma
霍奇金淋巴瘤的多源数据建模
  • 批准号:
    10579326
  • 财政年份:
    2022
  • 资助金额:
    $ 37.93万
  • 项目类别:
Modeling Multi-Source Data in Hodgkin Lymphoma
霍奇金淋巴瘤的多源数据建模
  • 批准号:
    10441776
  • 财政年份:
    2022
  • 资助金额:
    $ 37.93万
  • 项目类别:
MAP Kinase Signaling in Lymphoma: A Novel Therapeutic Paradigm
淋巴瘤中的 MAP 激酶信号转导:一种新的治疗范式
  • 批准号:
    8373276
  • 财政年份:
    2012
  • 资助金额:
    $ 37.93万
  • 项目类别:
MAP Kinase Signaling in Lymphoma: A Novel Therapeutic Paradigm
淋巴瘤中的 MAP 激酶信号转导:一种新的治疗范式
  • 批准号:
    8814762
  • 财政年份:
    2012
  • 资助金额:
    $ 37.93万
  • 项目类别:
MAP Kinase Signaling in Lymphoma: A Novel Therapeutic Paradigm
淋巴瘤中的 MAP 激酶信号转导:一种新的治疗范式
  • 批准号:
    8528522
  • 财政年份:
    2012
  • 资助金额:
    $ 37.93万
  • 项目类别:
MAP Kinase Signaling in Lymphoma: A Novel Therapeutic Paradigm
淋巴瘤中的 MAP 激酶信号转导:一种新的治疗范式
  • 批准号:
    8680184
  • 财政年份:
    2012
  • 资助金额:
    $ 37.93万
  • 项目类别:
NU 02H8: A PHASE I TRIAL OF REDOX REGULATION IN PATIENTS WITH RELAPSED NHL
NU 02H8:复发 NHL 患者氧化还原调节的 I 期试验
  • 批准号:
    7604257
  • 财政年份:
    2006
  • 资助金额:
    $ 37.93万
  • 项目类别:
NU 02H8: A PHASE I TRIAL OF REDOX REGULATION IN PATIENTS WITH RELAPSED NHL
NU 02H8:复发 NHL 患者氧化还原调节的 I 期试验
  • 批准号:
    7376849
  • 财政年份:
    2005
  • 资助金额:
    $ 37.93万
  • 项目类别:
Targeting the Mitochondria to Treat Lymphoma and Myeloma
靶向线粒体治疗淋巴瘤和骨髓瘤
  • 批准号:
    7075323
  • 财政年份:
    2005
  • 资助金额:
    $ 37.93万
  • 项目类别:
Targeting the Mitochondria to Treat Lymphoma and Myeloma
靶向线粒体治疗淋巴瘤和骨髓瘤
  • 批准号:
    7455834
  • 财政年份:
    2005
  • 资助金额:
    $ 37.93万
  • 项目类别:

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