Ex Vivo Profiling of Immunotherapy Combinations Using Organotypic Tumor Spheroids

使用器官型肿瘤球体对免疫治疗组合进行体外分析

• 批准号: 10227671
• 负责人: Russell William Jenkins
• 金额: $ 18.91万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-16 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227671
• 关键词: 3-Dimensional; Advisory Committees; Antigens; Autologous; Award; BRAF gene; Biological Markers; CD8-Positive T-Lymphocytes; CDK4 gene; CT26; Cancer Center; Cancer Model; Clinical; Clinical Trials; Combination immunotherapy; Combined Modality Therapy; Cytokine Signaling; Data; Development; Drug Combinations; Drug Targeting; Fellowship Program; Funding; Future; Genes; Goals; Hematology; Human; Immune; Immune Targeting; Immune checkpoint inhibitor; Immune signaling; Immunocompetent; Immunological Models; Immunologics; Immunotherapeutic agent; Immunotherapy; Individual; Infiltration; Institutes; K-Series Research Career Programs; Knowledge; Lymphoid Cell; MC38; Malignant Neoplasms; Medicine; Mentors; Mentorship; Microfluidics; Modality; Modeling; Molecular; Mus; Mutation; Myeloid Cells; Nature; Oncology; PD-1 blockade; PD-1/PD-L1; PDL1 pathway; Pathway interactions; Patients; Phosphotransferases; Population; Positioning Attribute; Research; Research Personnel; Resistance; Resistance development; Resources; Sampling; Scientist; System; T-Cell Activation; TBK1 gene; Testing; Therapeutic; Time; Training; Treatment Efficacy; Tumor Biology; Tumor-infiltrating immune cells; anti-PD-1; anti-PD-1/PD-L1; anti-PD1 therapy; autocrine; chemokine; clinical practice; combat; cytokine; experience; immune checkpoint blockade; improved; in vivo; individual patient; inhibitor/antagonist; instructor; melanoma; mouse model; mutant; next generation; novel; novel drug combination; novel strategies; paracrine; personalized immunotherapy; personalized medicine; pre-clinical; precision medicine; precision oncology; predicting response; predictive marker; preservation; programmed cell death protein 1; programs; resistance mechanism; response; screening; success; tenure track; therapeutic evaluation; tissue culture; treatment planning; tumor; tumor microenvironment; tumor-immune system interactions

PROJECT SUMMARY Precision cancer medicine currently focuses on knowledge of the cancer mutation repertoire and the tailored application of drugs that target altered genes or pathways in individual patients, such as use of BRAF inhibitors in patients with BRAF mutant melanoma. Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have shown dramatic and durable clinical responses in melanoma and others cancers, but robust predictive biomarkers are lacking and innate resistance is common. Thus, a critical need exists for more sophisticated ex vivo functional testing modalities that recapitulate human tumor biology to predict response to targeted and immune-based therapies to develop personalized treatment plans in real-time. We recently developed a novel approach for evaluating ex vivo response to ICB using murine- and patient-derived organotypic tumor spheroids (MDOTS/PDOTS) cultured in a 3-dimensional microfluidic system (Jenkins et al., Nature, under review). We demonstrated that spheroids isolated from fresh mouse and human tumor samples retain autologous lymphoid and myeloid cell populations, including antigen-experienced tumor infiltrating CD4 and CD8 T lymphocytes, and respond to ICB in short-term ex vivo culture. Improved understanding of the immune and tumor response to immune checkpoint inhibitors within the tumor microenvironment will facilitate efforts to identify predictive biomarkers/models for immune checkpoint blockade in real-time, as well as future efforts to screen for therapeutic combinations that enhance the response to immune checkpoint blockade, and may ultimately provide a platform for the `personalization' of immunotherapy. I am currently a Clinical Fellow in Medicine in the Dana-Farber/Harvard Cancer Center Hematology- Oncology Fellowship Program. Over 80% of my time is devoted to my ongoing research under the mentorship of Dr. David A. Barbie (DFCI, Broad Institute). The remainder of my time is devoted to clinical practice and clinical training, working primarily at the MGH Cancer Center in the Center for Melanoma. My goal is to successfully transition from senior fellow to research instructor, and ultimately to an independent investigator in a tenure-track position. I am applying for the K08 Mentored Clinical Scientist Research Career Development Award to provide the necessary training and funding support to achieve this goal. Under the mentorship of Drs. Barbie and Flaherty, and the guidance of my advisory committee (Drs. Wong, Janne, and Fisher), I will access to the necessary resources and training to develop a successful, independent research program over the funding period of the award.

项目摘要 精密癌症医学目前专注于癌症突变库的知识和 量身定制的针对单个患者基因或途径改变基因或途径的药物，例如使用BRAF BRAF突变黑色素瘤患者的抑制剂。靶向PD-1/PD-L1的免疫检查点抑制剂 途径在黑色素瘤和其他癌症中显示出戏剧性耐用的临床反应，但是强大 缺乏预测性生物标志物，与生俱来的抗性很常见。因此，存在更多的需求 复杂的离体功能测试方式，概括了人类肿瘤生物学以预测对 针对性且基于免疫的疗法实时制定个性化治疗计划。我们最近 开发了一种新的方法，可以使用鼠和患者来评估对ICB的离体反应 在三维微流体系统中培养的器官型肿瘤球体（MDOTS/PDOTS）（Jenkins等，， 大自然，正在审查）。我们证明了从新鲜小鼠和人类肿瘤样品中分离出的球体 保留自体淋巴样和髓样细胞群，包括抗原经验的肿瘤浸润CD4 和CD8 T淋巴细胞，并在短期离体培养中对ICB做出反应。提高了对 免疫和肿瘤对肿瘤微环境内免疫检查点抑制剂的反应将有助于 努力识别实时和未来的免疫检查点封锁的预测性生物标志物/模型 努力筛选治疗组合，以增强对免疫检查点封锁的反应，并 最终可能为免疫疗法的“个性化”提供平台。 我目前是Dana-Farber/Harvard Cancer Center血液学的医学临床研究员 - 肿瘤学奖学金计划。我超过80％的时间专门用于我正在进行的指导下的研究 David A. Barbie博士（Broad Institute DFCI）。我的其余时间专门用于临床实践和临床 培训，主要在黑色素瘤中心的MGH癌症中心工作。我的目标是成功 从高级研究员到研究教练，并最终转移到终身制的独立调查员 位置。我正在申请K08指导的临床科学家研究职业发展奖，以提供 实现这一目标的必要培训和资金支持。在博士的指导下。芭比和 弗莱厄蒂（Flaherty）以及我的咨询委员会（WongDrs。Wong，Janne和Fisher）的指导，我将访问 必要的资源和培训，以制定成功的独立研究计划 奖励期。