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.

抽象的最近在了解免疫检查点在下降中所起的作用方面取得了重大进展调节对癌症的免疫反应。这些发现反过来又促进了免疫学的发展检查点抑制剂可激活细胞毒性 T 细胞，并已表现出惊人的积极临床结果跨越多种肿瘤类型。然而，尽管许多患者获得了持久缓解，但总体缓解率仍然很低。免疫检查点抑制剂也与高比例的潜在致命性相关免疫相关的不良事件。此外，评估治疗反应具有挑战性，因为肿瘤可能由于免疫细胞的涌入，最终的反应在解剖成像上可能会显得更大。这相同的免疫浸润掩盖了 FDG-PET 分析，因为免疫细胞对 FDG 具有高度的渴求。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。患者是治疗时间经常超过必要的时间，因为无法确定他们是否有反应。为了解决响应评估的困难，人们付出了巨大的努力来调查预测生物标志物，包括新颖的成像方法。迄今为止分析的成像生物标志物专注于识别肿瘤免疫浸润的存在，尚未证明可以强烈预测回复。它们缺乏实用性可能是因为它们无法区分主动免疫和非主动免疫渗透，后者被认为是免疫治疗失败的常见原因。监控细胞毒性 T 淋巴细胞 (CTL) 活性，我们开发了一流的基于肽的 PET 显像剂与颗粒酶 B 结合，颗粒酶 B 是 CTL 在主动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。我们还询问了接受检查点抑制剂治疗的人类用于颗粒酶 B 表达的黑色素瘤样品。这些结果证实了我们的高临床前发现颗粒酶 B 的表达与免疫治疗的反应相关。最后，我们设计了一个人类类似物我们的肽，它与人类样本中的颗粒酶 B 特异性结合。该提案旨在最终确定优化人体探针并告知患者群体和近期临床评估的时间。到为了实现这一目标，我们将首先开发第二代肽，其可以提供增强的亲和力或改进了颗粒酶 B 测量的药代动力学，并在人源化小鼠中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，我们将继续我们的评估人类检查点抑制剂处理的黑色素瘤活检标本中颗粒酶 B 的表达。以给药间隔为重点的靶标表达量化将有助于通过以下方式最大限度地提高临床影响：在进行后续治疗之前确定反应。我们共同希望这些目标能够迅速实现将颗粒酶 B 成像技术推进临床，以提供急需的反应生物标志物。