Biomarker Identification to Increase Adjunctive Cryoablation and Checkpoint-Inhibitor Immunotherapy Response

生物标志物鉴定可提高辅助冷冻消融和检查点抑制剂免疫治疗的反应

基本信息

批准号：
10222626
负责人：
Eric Wehrenberg-Klee
金额：
$ 26.97万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10222626
关键词：
Ablation Active Sites Adaptive Immune System Affect Antigens Applications Grants Biological Markers Biopsy Specimen Blood Blood specimen CD8-Positive T-Lymphocytes CD8B1 gene Cancer Patient Carcinoma Cell Death Cell membrane Cell physiology Cells Clinical Clinical Protocols Clinical Research Clinical Trials Cryosurgery Data Dendritic Cells Dendritic cell activation Development Disease Ensure Environment Flow Cytometry Freezing Future Genomics Granzyme Image Immune Immune checkpoint inhibitor Immune response Immunity Immunologic Factors Immunologic Techniques Immunology Immunooncology Immunotherapy Implant In complete remission Inflammation Inflammatory Interventional radiology Mediating Mentors Modeling Mus Mutation Necrosis Neoplasm Metastasis Patients Positron-Emission Tomography Protocols documentation Reaction Regimen Research Resistance Route Rupture Site T-Lymphocyte Techniques Testing Therapeutic Time Transitional Cell Carcinoma Tumor Antigens Tumor Markers Urothelium Variant Work anti-tumor immune response biomarker identification career checkpoint inhibition checkpoint therapy clinical development cytokine effector T cell imaging agent immunogenic improved improved outcome insight mouse model neoplastic cell non-genomic pembrolizumab pre-clinical pre-clinical research preclinical study predicting response predictive marker programmed cell death protein 1 prospective research clinical testing resistance mechanism responders and non-responders response response biomarker single-cell RNA sequencing skills success tool tumor tumor-immune system interactions

项目摘要

1 Checkpoint inhibitors (CPI) have significantly improved outcomes in many tumor types, but there is still 2 immense room for improvement. A tremendous amount of preclinical and clinical research thus is aimed at 3 evaluating combination therapeutic regimens that may increase CPI response rate as well as identifying 4 biomarkers that indicate whether a patient will benefit from or be resistant to immunotherapy. 5 Cryoablation is a promising adjunctive strategy that may be able to significantly increase the CPI response 6 rate. Cryoablation of a single metastatic focus causes necrotic cell death, rupturing cell membranes through 7 alternating freeze and thaw cycles. Tumoral antigens are released along with inflammatory intracellular 8 contents. This markedly inflammatory reaction activates dendritic cells to take up the released tumor antigen 9 which, in turn, activates the adaptive immune system to attack tumor sites elsewhere in the body. 10 I have developed a dual-implanted tumor model to investigate the systemic benefit of adjunctive cryoablation 11 and have found that when added to CPI therapy cryoablation significantly increases the complete response 12 rate of the non-ablated tumor relative to CPI alone. As adding cryoablation to CPI is minimally studied, there 13 remains significant work to identify biomarkers to determine which tumors will benefit most by cryoablation 14 addition. To identify response biomarkers I am helped by a unique investigative tool that I co-invented, 15 granzyme B PET imaging. Localizing to the site of active immune-mediated tumor killing, granzyme B PET 16 allows us to distinguish CPI responders from non-responders prior to changes in tumor size. We can then 17 interrogate the immune-response while it is still active, facilitating unique insights. 18 In this proposal, in a murine tumor model I will develop an optimized preclinical cryoablation and CPI regimen 19 across multiple tumor lines reflective of the range of CPI responsiveness. In these models I will then use 20 granzyme B PET imaging to help identify genomic and non-genomic biomarkers of response and identify 21 mechanisms of resistance to the combination of cryoablation and CPI. I will also simultaneously be leading a 22 clinical trial evaluating the ability of cryoablation to increase pembrolizumab response in metastatic urothelial 23 carcinoma. From patient blood and biopsy specimens obtained at the time of cryoablation I propose to analyze 24 the tumoral and systemic immune microenvironment for response biomarkers in these patients. These data will 25 be essential to guide the development of future optimized clinical protocols evaluating the ability of cryoablation 26 to increase systemic immunity across multiple tumor types. I will conduct this research in the excellent 27 research environment of MGH, guided by mentors expert in the fields of immunology, immuno-oncology, and 28 interventional radiology. Their guidance will help ensure the success of this project and my successful 29 transition to an independent research career.

1 检查点抑制剂 (CPI) 显着改善了许多肿瘤类型的预后，但仍存在一些不足 2 巨大的改进空间。因此，大量的临床前和临床研究旨在 3 评估可能提高 CPI 反应率的联合治疗方案并确定 4 种生物标志物表明患者是否会受益于免疫疗法或对免疫疗法产生耐药性。 5 冷冻消融是一种很有前途的辅助策略，可能能够显着提高 CPI 反应 6 率。单个转移灶的冷冻消融会导致坏死性细胞死亡，通过破裂细胞膜 7 次交替冷冻和解冻循环。肿瘤抗原与细胞内炎症一起释放 8个内容。这种明显的炎症反应激活树突状细胞吸收释放的肿瘤抗原 9，进而激活适应性免疫系统来攻击身体其他部位的肿瘤部位。 10 我开发了一种双移植肿瘤模型来研究辅助冷冻消融的全身益处 11 并发现，当冷冻消融添加到 CPI 疗法中时，显着提高了完全缓解 12 未消融肿瘤相对于单独 CPI 的比率。由于在 CPI 中加入冷冻消融的研究很少，因此 13 识别生物标志物以确定哪些肿瘤将通过冷冻消融获益最多仍然是一项重要的工作 14 补充。为了识别反应生物标志物，我得到了我共同发明的独特研究工具的帮助， 15 颗粒酶 B PET 成像。定位到主动免疫介导的肿瘤杀伤位点，颗粒酶 B PET 图 16 使我们能够在肿瘤大小变化之前区分 CPI 反应者和非反应者。那么我们就可以 17 在免疫反应仍然活跃时对其进行询问，从而促进独特的见解。 18 在本提案中，我将在小鼠肿瘤模型中开发一种优化的临床前冷冻消融和 CPI 方案 19 跨多个肿瘤系反映了 CPI 反应范围。在这些模型中我将使用 20 颗粒酶 B PET 成像，帮助识别基因组和非基因组反应生物标志物并识别冷冻消融和 CPI 联合治疗的 21 种耐药机制。我还将同时领导 22 项临床试验评估冷冻消融提高转移性尿路上皮细胞帕博利珠单抗反应的能力 23 癌。我建议从冷冻消融时获得的患者血液和活检标本中进行分析 24 这些患者中反应生物标志物的肿瘤和全身免疫微环境。这些数据将 25 对于指导评估冷冻消融能力的未来优化临床方案的开发至关重要 26 提高多种肿瘤类型的全身免疫力。我将在优秀的情况下进行这项研究 MGH 27个研究环境，由免疫学、免疫肿瘤学和免疫学领域专家导师指导 28 介入放射学。他们的指导将有助于确保该项目的成功以及我的成功 29 过渡到独立研究生涯。