Development of a patient-derived organotypic spheroids (PDOTS) platform for prediction of clinical responses to immuno-oncology drugs

开发患者来源的器官型球体（PDOTS）平台，用于预测免疫肿瘤药物的临床反应

• 批准号: 10324751
• 负责人: Amir Reza Aref
• 金额: $ 38.18万
• 依托单位: XSPHERA BIOSCIENCES INCORPORATED
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10324751
• 关键词: Address; Aftercare; Antibodies; Apoptosis; Biological Products; Biological Sciences; CAR T cell therapy; Caliber; Cell Death; Cell Therapy; Cells; Cetuximab; Clinic; Clinical; Collagen; Colorectal Cancer; Colorectal Neoplasms; Complement; Complex; Cytokine Gene; Dana-Farber Cancer Institute; Data; Development; Dose; Drug Combinations; Evaluation; Experimental Neoplasms; Fractionation; Future; Gene Expression; Heterogeneity; Human; IgG1; Immune; Immune checkpoint inhibitor; Immunooncology; Immunotherapeutic agent; Investigational Therapies; Kinetics; Legal patent; Measures; Mediating; Methods; Microfluidic Microchips; Microfluidics; Modality; Monitor; Monoclonal Antibodies; Mus; Natural Killer Cells; Oncologist; Oncology; Pancreas; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Reporting; Research; Risk; Role; Signal Transduction; Specimen; Standardization; Test Result; Testing; Therapeutic; Time; Tumor Antigens; Vendor; Work; cancer therapy; colon cancer patients; commercialization; cytotoxicity; experience; gene therapy; immune activation; immunoregulation; individual patient; mutant; neoplastic cell; neutralizing monoclonal antibodies; novel; precision medicine; preclinical development; preservation; prospective; response; treatment duration; tumor; tumor microenvironment

ABSTRACT As many new immuno-oncology (IO) therapies for cancer are developed, oncologists will be faced with the challenge of choosing from hundreds of drugs with thousands of potential combinations to treat their patients. Xsphera Biosciences Inc. (XB) believes one solution to this challenge lies in a novel combination of a tumor processing method that produces patient-derived organotypic tumor spheroids (PDOTS) and a microfluidic device that preserves the tumor microenvironment of a patient’s tumor. XB aims to develop the PDOTS platform to 1) provide oncologists with data-driven treatment options for their patients and 2) provide biopharmaceutical companies with data that will de-risk IND initiation by reliably predicting patient clinical responses to IO and chemotherapeutic drugs. One of the key actions needed is a systematic evaluation and optimization of the different classes of immunotherapeutic drugs in the platform. These classes include, but are not limited to, tumor cell-targeted IgG1 antibodies (tumor-targeted Abs), checkpoint inhibitors, gene therapy, and cell therapy including chimeric antigen receptor T-cell therapy (CAR-T). This project aims to establish the parameters to test tumor-targeted Ab therapeutics in the Xsphera platform and, using cetuximab in colorectal cancer (CRC), confirm that the efficacy of cetuximab aligns with the historical clinical experience. Specific Aim 1 will characterize the effects of cetuximab on CRC PDOTS in the Xsphera platform and determine if the ex vivo responses in RAS wild type (RASwt) and RAS mutant tumors (RASmut) are consistent with those reported in the clinic. Cetuximab is indicated for RASwt but has shown no efficacy in tumors with RASmut.The immune activation in the PDOTS induced by cetuximab will be characterized, and the cytokine and gene expression profiles for immune activation and apoptosis will be measured and correlated with cytotoxicity data. Specific Aim 2 will characterize the kinetics of Ab-mediated immune activation to establish the optimal time to monitor cytotoxicity and immune activation signals. Using the dose of cetuximab that induced the highest level of cytotoxicity, the kinetics of Ab mediated cytotoxicity and immune modulation will be characterized during the first 3 days after Ab treatment. The timepoint with the highest cytotoxicity and immune modulatory signals and the lowest variability between replicates and between patients will support standardization on the timepoint for cetuximab treatment. Specific Aim 2 will further characterize the immune involvement by mAb neutralization of known immune effector mechanisms, including NK cells, CTL cells and the complement cascade. Results of Phase I will confirm whether clinically approved cetuximab is effective in the platform by quantifying cytotoxicity and characterizing immune activation and whether it aligns with historical clinical response data and for being restricted to RASwt.

摘要 随着许多新的癌症免疫肿瘤学（IO）疗法的开发，肿瘤学家将面临 从数百种药物中选择数千种潜在的组合来治疗他们的患者。 Xsphera Biosciences Inc. (XB)相信解决这一挑战的一个办法在于一种新的肿瘤组合， 产生患者来源的器官型肿瘤球状体（PDOTS）的处理方法和微流体 保留患者肿瘤微环境的装置。XB旨在开发PDOTS平台 1）为肿瘤学家提供患者的数据驱动治疗方案，2）提供生物制药 具有通过可靠预测患者对IO的临床反应来降低IND启动风险的数据的公司， 化疗药物需要采取的关键行动之一是系统地评价和优化 不同种类的免疫抑制药物。这些类别包括但不限于肿瘤 细胞靶向IgG 1抗体（肿瘤靶向Ab）、检查点抑制剂、基因治疗和细胞治疗 包括嵌合抗原受体T细胞疗法（CAR-T）。 该项目旨在建立在Xsphera平台中测试肿瘤靶向Ab治疗的参数， 使用西妥昔单抗治疗结直肠癌（CRC），证实西妥昔单抗的疗效与历史 临床经验。 具体目标1将描述西妥昔单抗对Xsphera平台中CRC PDOTS的影响，并确定 如果RAS野生型（RASwt）和RAS突变型肿瘤（RASmut）的离体反应与那些 据报道，在诊所。西妥昔单抗适用于RASwt，但在患有RASmut的肿瘤中没有显示出疗效。 将表征西妥昔单抗诱导的PDOTS中的免疫活化，并将细胞因子和基因 将测量免疫活化和细胞凋亡的表达谱并与细胞毒性数据相关联。 特异性目标2将表征Ab介导的免疫活化的动力学，以确定最佳时间， 监测细胞毒性和免疫激活信号。使用诱导最高水平的西妥昔单抗剂量 在细胞毒性研究期间，将表征Ab介导的细胞毒性和免疫调节的动力学。 Ab治疗后的前3天。具有最高细胞毒性和免疫调节信号的时间点， 重复之间和患者之间的最低变异性将支持时间点的标准化， 西妥昔单抗治疗。特异性目标2将通过mAb中和 已知的免疫效应机制，包括NK细胞、CTL细胞和补体级联。 I期试验的结果将通过定量研究证实临床批准的西妥昔单抗在平台中是否有效。 细胞毒性和表征免疫激活，以及其是否与历史临床应答数据一致， 被限制在RASwt。