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

基本信息

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
项目类别：
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&apos s lymphoma leukemia/lymphoma neurotoxicity patient response predictive test programs prospective responders and non-responders response side effect success

项目摘要

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疗法在诊所已进展，但使用这些突破仍然存在两个具体问题血液癌的疗法：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。这些限制对于一种费用高达500,000美元的药物可能会花费 $ 250,000+治疗不良事件，导致许多临床中心谨慎管理这些事件疗法。 Isoplexis正在开发其技术，以预测患者的反应者，无反应者和毒性，直接从患者进入CAR T细胞治疗产品。这将允许临床中心提供改进的产品释放标准，可改善CAR T疗法生产并可能增加患者响应同时减少昂贵的副作用。 Isoplexis最近发表在2018年7月的《血液》杂志上表明，在20名NHL患者的国家癌症研究所试验中，仅ISOCODE单细胞芯片预测的响应者和非反应者（p = 0.0119），现有的产品评估技术等流量细胞仪和散装ELISA没有。 Isocode能够检测每个单元格的40多个分泌蛋白的能力反应患者的多功能细胞（在称为PSI的公制中）。这项与风筝制药和 NCI还证明了能够与体内指标结合使用某些类型的毒性，包括3级以上的神经毒性（P = 0.0007）和细胞因子释放综合征（P = 0.0085）。在其NCI II期 CAR-T SBIR，Isoplexis验证了此CAR-T ISOCODE芯片，并构建并测试了全自动工作流程对于隔离仪器上的等级芯片。隔离是一种示例到答案设备，用户可以在其中过程8个样本。图像通过基于3激光的光学系统和背面拍摄过夜 END ELISA步骤以自动方式运行。 CAR-T多功能结果直接在 IsoSpeak软件套件。该仪器现在正在工作和分析CAR-T样品。等法芯片芯片，为了在Car-T中使用，被科学家杂志评为2017年第一的创新，以及凶猛的生活科学。领先的全球红点设计奖，以易于使用的方式认可， IsoSpeak被Pharma Tech Outlook认可为十大创新。 IIB阶段目标提高了隔离RUO系统，并在临床上验证了跨中心的等码和隔离提供自体T细胞治疗市场预测性治疗产品评估。目标1：发展制造可消耗品芯片的自动化以满足更大的生产需求。目标2：发展企业软件模块，包括CFR第211部分合规性，以启用GMP制药环境用于Car-T产品发布。 AIM 3：开发自动隔离生产和校准过程验证在6个月内使用四种乐器，以满足CAR-T版本中的相互伸缩性要求。目标4：实现根据一流的ROC和统计参数的隔离临床验证：NHL中的一次CAR-T试验（Moffitt CC），All（纪念Sloan Kettering CC）的CAR-T试验，DLBCL（Stanford CC）进行了CAR-T试验。