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: 9762882
• 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/9762882
• 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; Cells; 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; 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; PD-1 blockade; PD-1/PD-L1; Pathway interactions; Patients; Phosphotransferases; Population; Positioning Attribute; Research; Research Personnel; Resistance; Resistance development; Resources; SLEB2 gene; Sampling; Scientist; System; T-Cell Activation; TBK1 gene; Testing; Therapeutic; Time; Training; Treatment Efficacy; Tumor Biology; anti-PD-1; 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; oncology; paracrine; personalized immunotherapy; personalized medicine; pre-clinical; precision medicine; precision oncology; predicting response; predictive marker; preservation; programs; resistance mechanism; response; screening; success; tenure track; therapeutic evaluation; tissue culture; treatment planning; tumor; tumor microenvironment

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.

项目概要 精准癌症医学目前侧重于癌症突变库的知识和 针对个体患者改变的基因或途径的药物的定制应用，例如使用 BRAF BRAF突变黑色素瘤患者的抑制剂。针对 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显着且持久的临床反应，但稳健 缺乏预测性生物标志物，先天耐药性很常见。因此，迫切需要更多 复杂的离体功能测试模式，可概括人类肿瘤生物学，以预测对药物的反应 靶向和免疫疗法，实时制定个性化治疗计划。我们最近 开发了一种使用小鼠和患者来源的药物来评估对 ICB 的离体反应的新方法 在 3 维微流体系统中培养的器官型肿瘤球体 (MDOTS/PDOTS)（Jenkins 等人， 自然，正在审查中）。我们证明从新鲜小鼠和人类肿瘤样本中分离出的球体 保留自体淋巴和骨髓细胞群，包括经历过抗原的肿瘤浸润 CD4 和 CD8 T 淋巴细胞，并在短期离体培养中对 ICB 做出反应。增进了对 肿瘤微环境中对免疫检查点抑制剂的免疫和肿瘤反应将促进 努力识别实时和未来免疫检查点封锁的预测生物标志物/模型 努力筛选增强免疫检查点阻断反应的治疗组合，以及 最终可能为免疫疗法的“个性化”提供一个平台。 我目前是达纳法伯/哈佛大学癌症中心血液学的医学临床研究员 - 肿瘤学奖学金计划。我 80% 以上的时间都花在了导师的指导下正在进行的研究 David A. Barbie 博士（DFCI、博德研究所）。我的剩余时间致力于临床实践和临床 培训，主要在麻省总医院癌症中心黑色素瘤中心工作。我的目标是成功 从高级研究员到研究讲师的转变，并最终成为终身教授的独立研究员 位置。我正在申请 K08 指导临床科学家研究职业发展奖，以提供 实现这一目标所需的培训和资金支持。在博士的指导下。芭比和 在 Flaherty 和我的顾问委员会（Wong 博士、Janne 博士和 Fisher）的指导下，我将访问 必要的资源和培训来开发一个成功的、独立的研究项目 颁奖期间。