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.

抽象的最近在理解免疫检查中的作用方面取得了重大进展调节对癌症的免疫反应。这些发现又导致了免疫的发展激活细胞毒性T细胞的检查点抑制剂，并表现出呈阳性的临床结果跨多种肿瘤类型。但是，尽管许多患者持续恢复，但总体反应率保持低。免疫检查点抑制剂也与高百分比的潜在致命有关免疫相关的不良事件。此外，评估治疗反应是具有挑战性的，因为肿瘤可能最终，由于免疫细胞的涌入，在解剖成像上的大小可能增加。这由于免疫细胞是高度FDG狂热的，相同的免疫浸润会掩盖FDG-PET分析。缺乏有用的反应评估具有显着复杂的患者护理和临床发育。患者是经常在疗法上保留的时间比必要的时间更长，因为无法确定它们是否在做出反应。为了解决响应评估的困难，已经进行了巨大的努力调查预测生物标志物，包括新型成像方法。迄今为止分析的成像生物标志物具有专注于确定肿瘤免疫浸润的存在，并未证明有力地预测回复。他们缺乏效用之可能是因为他们无法区分主动和无效免疫浸润，后者被认为是免疫疗法衰竭的常见原因。监视细胞毒性T淋巴细胞（CTL）活性，我们已经开发了基于一流的肽的宠物成像剂与颗粒酶B结合，Granzyme B是CTL积极攻击肿瘤细胞时释放的丝氨酸蛋白酶。我们已经在两个不同的免疫疗法模型中证明了我们的成像剂，并证明它能够预测对检查点抑制剂的反应。我们还询问了受检查点抑制剂治疗的人黑色素瘤样品用于颗粒酶B表达。这些结果证实了我们的临床前发现颗粒酶B表达与免疫疗法的反应相关。最后，我们设计了一个人类的类似物我们的肽，该肽在人类样品中特别与颗粒B结合。该建议旨在确定优化了人类探测，并告知患者人群，并定时进行近期临床评估。到实现这一目标，我们将首先开发可能提供增强亲和力或改进了用于颗粒酶B测量的药代动力学，并在人源性小鼠中进行评估免疫疗法模型。为了更好地构建临床试验成像时间点，我们将继续我们的评估人类检查点抑制剂治疗的黑色素瘤活检标本中颗粒酶B表达。量化专注于给药间隔的目标表达将有助于通过在进行后续治疗之前鉴定反应。在一起，我们希望这些目标可以迅速将颗粒酶B成像进入诊所，以提供迫切需要的反应生物标志物。