A Single-Cell Proteomic instrument for Predictive Product Quality Check in Autologous CAR-T Immunotherapies

用于自体 CAR-T 免疫疗法中预测产品质量检查的单细胞蛋白质组学仪器

• 批准号: 9764920
• 负责人: Timothy S McConnell
• 金额: $ 169.93万
• 依托单位: ISOPLEXIS, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-21 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9764920
• 关键词: Address; Adoptive Transfer; Adverse event; Antibodies; Antibody Specificity; Autologous; Automation; Award; Awareness; Back; Biological Markers; Biological Sciences; Blood; CAR T cell therapy; CD19 gene; Calibration; Cancer Patient; Cell Therapy; Cells; Cellular immunotherapy; Clinic; Clinical; Computer software; Data; Development; Devices; Drug Costs; Environment; Enzyme-Linked Immunosorbent Assay; Evaluation; Failure; Flow Cytometry; Goals; Gold; Hematologic Neoplasms; Hematopoietic Neoplasms; Image; Immunotherapy; Infusion procedures; Journals; Lasers; Life; Measures; Mechanics; Monitor; National Cancer Institute; Optics; Patients; Pharmacologic Substance; Phase; Predictive Value; Process; Production; Protein Structure Initiative; Proteins; Proteomics; Protocols documentation; Publishing; Quality Control; Reporting; Running; Safety; Sampling; Scientist; Security; Site; Small Business Innovation Research Grant; System; T cell therapy; T-Lymphocyte; Technology; Testing; Therapeutic; Time; Toxic effect; Treatment Efficacy; United States National Institutes of Health; Validation; Work; base; chimeric antigen receptor; chimeric antigen receptor T cells; cost; cytokine; cytokine release syndrome; design; engineered T cells; immunotoxicity; improved; in vivo; innovation; instrument; instrumentation; large cell Diffuse non-Hodgkin' s lymphoma; leukemia/lymphoma; neurotoxicity; patient response; predictive test; programs; prospective; responders and non-responders; response; side effect; success

While CAR-T therapies have advanced in the clinic, there are still two specific issues using these breakthrough therapies for blood cancers: Durable responses in patients are only at 30-50% and Cytokine Release Syndrome occurs in 60-90% of treated patients. These limitations, for a drug that costs as much as $500,000, may cost an additional $250,000+ for treating adverse events leading to caution for many clinical centers to administer these therapies. IsoPlexis is developing its technology to predict responders, non-responders, and toxicity in patients, directly from the CAR T cell therapy product prior to entry in the patients. This would allow clinical centers to provide improved product release criteria improving CAR T therapy production and potentially increasing patient response while reducing expensive side effects. IsoPlexis recently published in the journal Blood in July of 2018 showing that across a National Cancer Institute Trial of 20 NHL patients, only the IsoCode Single-Cell Chip predicted responders and non-responders (p = 0.0119), where existing product evaluation technologies like flow cytometry and bulk ELISA did not. The IsoCode’s ability to detect 40+ secreted proteins per cell identified unique polyfunctional cells in responding patients (in a metric termed PSI). This published work with Kite Pharma and the NCI also demonstrated the ability to predict certain types of toxicities in combination with in vivo metrics, including grade 3+ neurotoxicity (p = 0.0007) and cytokine release syndrome (p = 0.0085). In its NCI phase II CAR-T SBIR, IsoPlexis validated this CAR-T IsoCode Chip, and built and tested the fully automated workflow for the IsoCode Chip on the IsoLight instrument. The IsoLight is a sample-to-answer device on which users can process 8 samples simultaneously. Images are taken overnight through a 3 laser-based optics system, and back- end ELISA steps are run in an automated fashion. The CAR-T polyfunctional results are directly available in the IsoSpeak software suite. The instrument is now working and analyzing CAR-T samples. IsoPlexis’ IsoCode Chip, for use in CAR-T, was recognized as the #1 Innovation of 2017 by the Scientist Magazine, as well as Fierce Life Sciences. The IsoLight instrument was recognized for ease of use by the leading Global Red Dot Design Award, and IsoSpeak was recognized as Top 10 Innovation by Pharma Tech Outlook. The Phase IIB goal advances the IsoLight RUO system and clinically validates the IsoCode and IsoLight across centers delivering an IsoLight Dx to provide the autologous T cell therapy market predictive therapeutic product evaluation. Aim 1: Develop automation for manufacturing consumable chip to meet larger production needs. Aim 2: Development of enterprise software modules, including CFR Part 211 compliance to enable GMP pharmaceutical environment for CAR-T product release. Aim 3: Develop automated IsoLight production and calibration processes verifying with four instruments over 6 months to meet IsoLight scalability requirements in CAR-T release. Aim 4: Achieve IsoLight clinical validation according to best-in-class ROC, and statistical parameters: One CAR-T trial in NHL (Moffitt CC), a CAR-T trial in ALL (Memorial Sloan Kettering CC), and a CAR-T trial in DLBCL (Stanford CC).

虽然CAR-T疗法在临床上取得了进展，但使用这些突破仍然存在两个具体问题。 血癌治疗：患者的持久反应仅为30-50%，细胞因子释放综合征 发生在60-90%的治疗患者中。这些限制，对于一种价格高达50万美元的药物来说， 额外的250，000美元以上用于治疗不良事件，导致许多临床中心谨慎管理这些药物 治疗IsoPlexis正在开发其技术来预测患者的反应者，无反应者和毒性， 在进入患者体内之前直接从CAR T细胞治疗产品中获得。这将使临床中心能够 提供改进的产品发布标准，改善CAR T治疗生产，并可能增加患者 同时减少昂贵的副作用。IsoPlexis最近于2018年7月发表在《血液》杂志上 显示在国家癌症研究所对20名NHL患者的试验中，只有IsoCode单细胞芯片 预测的应答者和无应答者（p = 0.0119），其中现有的产品评价技术，如流量 流式细胞术和批量ELISA则没有。IsoCode检测每个细胞40多种分泌蛋白质的能力是独一无二的 多功能细胞在应答患者中的表达（以称为PSI的度量）。这篇与Kite Pharma合作的论文， NCI还证明了结合体内指标预测某些类型毒性的能力， 包括3+级神经毒性（p = 0.0007）和细胞因子释放综合征（p = 0.0085）。在NCI第二阶段， CAR-T SBIR，IsoPlexis验证了这款CAR-T IsoCode芯片，并构建和测试了全自动工作流程 用于IsoLight仪器上的IsoCode芯片。IsoLight是一种样本到答案的设备，用户可以 同时处理8个样品。图像是通过一个3激光为基础的光学系统过夜，并返回- 以自动化方式运行结束ELISA步骤。CAR-T多功能结果可直接在 IsoSpeak软件套件。该仪器目前正在工作并分析CAR-T样本。IsoPlexis的IsoCode芯片， 用于CAR-T，被《科学家》杂志和《FiancialLife》评为2017年第一创新 以理工科为重IsoLight仪器因其易用性而获得领先的全球红点设计奖， IsoSpeak被Pharma Tech Outlook评为十大创新。IIB阶段的目标推进了 IsoLight RUO系统，并在临床上验证IsoCode和IsoLight跨中心提供IsoLight Dx 提供自体T细胞治疗市场预测性治疗产品评价。目标1：发展 自动化生产消耗芯片，以满足更大的生产需求。目标2：发展 企业软件模块，包括CFR Part 211合规性，以实现GMP制药环境 用于CAR-T产品发布。目标3：开发自动化IsoLight生产和校准流程， 在6个月的时间内使用4台仪器，以满足CAR-T版本中的IsoLight可扩展性要求。目标4：实现 根据同类最佳ROC和统计参数进行的IsoLight临床验证：一项在NHL中进行的CAR-T试验 （Moffitt CC）、ALL中的CAR-T试验（Memorial Sloan Kettering CC）和DLBCL中的CAR-T试验（斯坦福大学CC）。