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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结精确癌症医学目前专注于癌症突变谱系的知识和针对个别患者的基因或途径改变的药物的量身定做的应用，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在黑色素瘤和其他癌症中显示出戏剧性和持久的临床反应，但强健缺乏可预测的生物标志物，天生的抵抗力很常见。因此，迫切需要更多复杂的体外功能测试模式，概括了人类肿瘤生物学，以预测对针对性和基于免疫的疗法，以制定实时的个性化治疗计划。我们最近开发了一种评估ICB体外反应的新方法，该方法使用小鼠和患者的来源器官型肿瘤球体(MDOTS/PDOTS)在三维微流控系统中培养(Jenkins等，自然，正在审查中)。我们证明了从新鲜的小鼠和人类肿瘤样本中分离出的球体保留自体淋巴和髓系细胞群，包括抗原敏感的肿瘤浸润性CD4 和CD8T淋巴细胞，并在短期体外培养中对ICB产生反应。更好地理解在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阻断的预测性生物标志物/模型努力筛选可增强对免疫检查点阻断反应的治疗组合，以及可能最终会为免疫治疗的“个性化”提供一个平台。我目前是达纳-法伯/哈佛癌症中心血液学的临床研究员- 肿瘤学奖学金计划。在导师的指导下，我80%以上的时间都投入到我正在进行的研究中大卫·A·芭比博士(DFCI，布罗德研究所)。我剩下的时间都花在了临床实践和临床上培训，主要在黑色素瘤中心的MGH癌症中心工作。我的目标是成功地从高级研究员过渡到研究指导员，最终成为终身教职的独立研究员位置。我正在申请K08临床科学家导师研究职业发展奖，以提供为实现这一目标提供必要的培训和资金支持。在芭比娃娃博士和 Flaherty，并在我的顾问委员会(Wong博士、Janne和Fisher)的指导下，我将访问必要的资源和培训，以制定一个成功的，独立的研究计划超过资金奖励的期限。