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Cytotoxic lymphocyte function PET imaging to predict cancer immunotherapy response

细胞毒性淋巴细胞功能 PET 成像预测癌症免疫治疗反应

基本信息

批准号：
10219982
负责人：
Umar Mahmood
金额：
$ 38.28万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10219982
关键词：
Address Affinity Anatomy Antibodies Avidity Binding Biological Markers Biopsy Biopsy Specimen CD8B1 gene CTLA4 gene Cell Death Cells Clinic Clinical Clinical Research Clinical Trials Cytotoxic T-Lymphocytes Development Disease remission Dose Drug Kinetics Evaluation Failure Generations Goals Granzyme Human Image Immune Immune Tolerance Immune checkpoint inhibitor Immune response Immune system Immunomodulators Immunotherapy Incidence Life Lymphocyte Lymphocyte Function Malignant Neoplasms Measurement Measures Mediating Metabolic Methods Modeling Modification Monitor Outcome PD-1 inhibitors Patient Care Patients Peptides Pharmaceutical Preparations Play Positron-Emission Tomography Progression-Free Survivals Regimen Research Role Sampling Savings Serine Protease Signal Transduction Structure Time Treatment Efficacy Tumor Burden Tumor-infiltrating immune cells Vaccines Work analog anatomic imaging anti-CTLA-4 therapy anti-PD-1 antibody inhibitor base biomarker development biomarker discovery cancer cell cancer immunotherapy checkpoint therapy clinical development clinical imaging clinical translation cytotoxic design effective therapy engineered T cells exhaustion fluorodeoxyglucose fluorodeoxyglucose positron emission tomography humanized mouse imaging agent imaging approach imaging biomarker imaging modality imaging probe immune checkpoint immune-related adverse events improved inhibitor/antagonist interest melanoma molecular imaging mouse model neoplasm immunotherapy neoplastic cell novel novel therapeutic intervention patient population patient response pre-clinical preclinical development predicting response predictive marker programmed cell death ligand 1 programmed cell death protein 1 protein aminoacid sequence research clinical testing response response biomarker small molecule success targeted treatment tool treatment response tumor tumor heterogeneity

项目摘要

Abstract There have been recent significant advances in understanding the role that immune-checkpoints play in down regulating the immune response to cancer. These discoveries have in turn led to the development of immune- checkpoint inhibitors that activate cytotoxic T-cells, and have demonstrated strikingly positive clinical outcomes across multiple tumor types. However, despite durable remissions in many patients, the overall response rate remains low. Immune checkpoint inhibitors are also associated with a high percentage of potentially lethal immune-related adverse events. Further, assessing therapeutic response is challenging, as tumors that may ultimately respond can appear to increase in size on anatomic imaging due to an influx of immune cells. This same immune infiltrate obscures FDG-PET analysis, as the immune cells are highly FDG avid. The lack of a useful response assessment has significantly complicated patient care and clinical development. Patients are frequently kept on therapies longer than necessary, as it cannot be ascertained whether they are responding. In order to address the difficulty with response assessment, there has been significant effort investigating predictive biomarkers, including novel imaging methods. The imaging biomarkers analyzed thus far have focused on identifying the presence of tumoral immune infiltrate and have not proven strongly predictive of response. Their lack of utility is likely because they cannot distinguish between active and inactive immune infiltrate, the latter of which is hypothesized to be a common cause of immunotherapy failure. To monitor cytotoxic T lymphocyte (CTL) activity, we have developed a first-in-class peptide-based PET imaging agent that binds to granzyme B, a serine protease released by CTLs when they are actively attacking tumor cells. We have demonstrated our imaging agent in two different immunotherapy models and shown that it is able to predict response to checkpoint inhibitors. We have also interrogated checkpoint-inhibitor treated human melanoma samples for granzyme B expression. These results corroborate our pre-clinical findings of high granzyme B expression correlating with response to immunotherapy. Finally, we designed a human analogue of our peptide, which specifically bound to granzyme B in human samples. This proposal aims to finalize an optimized human probe and inform the patient population and timing for near-term clinical evaluation. To achieve this goal, we will first develop second-generation peptides that may provide enhanced affinity or improved pharmacokinetics for granzyme B measurement, and assess them in humanized mouse immunotherapy models. In order to better structure clinical trial imaging time-points, we will continue our assessment of granzyme B expression in human checkpoint inhibitor treated melanoma biopsy specimens. Quantification of target expression focused on dosing intervals will help to maximize clinical impact by identifying response prior to administration of subsequent therapy. Together, we hope these aims can rapidly advance granzyme B imaging into the clinic to provide the response biomarker that is so desperately needed.

摘要最近在理解免疫检查点在降低免疫力中的作用方面取得了重大进展。调节对癌症的免疫反应。这些发现反过来又导致了免疫系统的发展- 检查点抑制剂，激活细胞毒性T细胞，并已显示出惊人的积极临床结果在多种肿瘤类型中。然而，尽管许多患者出现了持久缓解，仍然很低。免疫检查点抑制剂也与高比例的潜在致命性免疫相关不良事件。此外，评估治疗反应是具有挑战性的，因为肿瘤可能由于免疫细胞的流入，最终应答在解剖成像上可能出现尺寸增加。这相同的免疫浸润物使FDG-PET分析模糊，因为免疫细胞是高度FDG亲合的。缺乏一个有用的反应评估使患者护理和临床开发变得非常复杂。患者经常持续治疗超过必要的时间，因为无法确定他们是否有反应。为了解决反应评估的困难，预测性生物标志物，包括新的成像方法。迄今为止分析的成像生物标志物集中于识别肿瘤免疫浸润的存在，并且尚未证明对肿瘤免疫浸润的强预测性。反应它们缺乏实用性可能是因为它们无法区分活性和非活性免疫浸润，后者被假设为免疫治疗失败的常见原因。监测细胞毒性T淋巴细胞（CTL）活性，我们已经开发了一流的肽为基础的PET显像剂结合粒酶B，粒酶B是CTL主动攻击肿瘤细胞时释放的丝氨酸蛋白酶。我们已经在两种不同的免疫治疗模型中证明了我们的成像剂，并表明它能够预测对检查点抑制剂的反应。我们还询问了检查点抑制剂治疗的人类黑色素瘤样品的颗粒酶B表达。这些结果证实了我们的临床前发现，颗粒酶B表达与免疫治疗应答相关。最后，我们设计了一个模拟人类的机器人我们的肽，特异性结合到人类样本中的颗粒酶B。该提案旨在最后确定一项优化人体探针，并告知患者人群和近期临床评价的时间。到为了实现这一目标，我们将首先开发第二代肽，改善颗粒酶B测量的药代动力学，并在人源化小鼠中对其进行评估免疫治疗模型为了更好地构建临床试验成像时间点，我们将继续评估人检查点抑制剂处理的黑素瘤活检标本中的颗粒酶B表达。靶表达的定量侧重于给药间隔将有助于通过以下方式最大化临床影响：在给予后续治疗之前识别应答。我们共同希望这些目标能够迅速将颗粒酶B成像推进到临床，以提供迫切需要的反应生物标志物。