权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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唐氏综合症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。激活细胞毒性T细胞的检查点抑制剂，并已显示出惊人的积极临床结果横跨多种肿瘤类型。然而，尽管许多患者持续缓解，但总体应答率仍然很低。免疫检查点抑制剂也与高比例的潜在致命性与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，解剖成像显示Response的大小会增加。这同样的免疫渗透使FDG-PET分析变得模糊，因为免疫细胞高度依赖FDG。缺乏一种有用的反应评估使患者护理和临床发展变得非常复杂。病人是经常持续治疗的时间超过必要的时间，因为无法确定它们是否有效。为了解决反应评估的困难，已经进行了大量的调查工作预测性生物标志物，包括新的成像方法。到目前为止分析的成像生物标记物有专注于识别肿瘤免疫浸润物的存在，并未被证明对回应。它们缺乏实用性可能是因为它们不能区分主动免疫和非主动免疫后者被认为是免疫治疗失败的常见原因。要监视为了提高细胞毒性T淋巴细胞(CTL)活性，我们开发了一种一流的基于多肽的PET显像剂它与颗粒酶B结合，颗粒酶B是CTL在积极攻击肿瘤细胞时释放的一种丝氨酸蛋白酶。我们已经在两种不同的免疫治疗模型中展示了我们的显像剂，并表明它能够预测对检查点抑制剂的反应。我们还审问了使用检查点抑制剂治疗的人类黑色素瘤标本中颗粒酶B的表达。这些结果证实了我们的临床前发现的高颗粒酶B的表达与免疫治疗应答相关。最后，我们设计了一个人体模拟器我们的多肽与人体样本中的颗粒酶B特异性结合。这项提案旨在敲定一项优化人体探头，告知患者群体和近期临床评估的时机。至为了实现这一目标，我们将首先开发第二代多肽，这些多肽可能会增强亲和力或颗粒酶B测定的药代动力学改进及其在人源化小鼠中的评价免疫治疗模式。为了更好地构建临床试验成像时间点，我们将继续我们的人类检查点抑制因子治疗的黑色素瘤活检标本中颗粒酶B表达的评估以给药间隔为重点的目标表达的量化将有助于通过以下方式最大化临床影响在进行后续治疗之前确定反应。共同努力，我们希望这些目标能够迅速实现将颗粒酶B成像技术应用于临床，提供急需的反应生物标记物。