Precision targeting of T cell cytotoxicity with PET

使用 PET 精确靶向 T 细胞的细胞毒性

基本信息

批准号：
10179211
负责人：
Rahul Aggarwal
金额：
$ 52.42万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10179211
关键词：
Address Adopted Apoptotic Aspartic Acid Bacterial Infections Biochemistry Biological Markers Biology Biopsy Blood CTLA4 gene Cancer Model Cancer Patient Cell membrane Cells Chemistry Clear cell renal cell carcinoma Cleaved cell Clinic Clinical Clinical Management Data Detection Disease Drug Kinetics Enzymatic Biochemistry Enzymes Exposure to Family member Female Goals Granzyme HIV Hour Human Image Imaging technology Immune Immune checkpoint inhibitor Immune response Immune system Immunologic Markers Infection Injections Label Length Malignant neoplasm of urinary bladder Measurement Measures Mediating Membrane Modeling Molecular Conformation Mus Mutation Natural Killer Cell toxicity Neoplasm Metastasis Normal tissue morphology PET/CT scan Patients Peptide Hydrolases Peptides Phase Phase 0 Study Phospholipids Positron-Emission Tomography Proteins Radiolabeled Rattus Renal carcinoma Resistance Risk Rodent SARS coronavirus Safety Serine Protease Site Specificity Spleen T cell response T-Cell Activation T-Lymphocyte Technology Time Toxic effect Tracer Tumor Tissue Urothelial Cell Urothelium Viral Virus Diseases Work anti-CTLA-4 therapy anti-PD-1 anti-PD-1/PD-L1 antimicrobial peptide base cancer imaging cancer therapy checkpoint inhibition cohort combat cytotoxicity dosimetry enzyme activity experience extracellular first-in-human human imaging human study imaging approach imaging biomarker immune checkpoint immune-related adverse events immunological synapse immunomodulatory therapies in vivo inhibitor/antagonist innovation interest male multidisciplinary neoplastic cell novel phase 1 study pre-clinical programmed cell death ligand 1 radiochemical radiotracer responders and non-responders response serial imaging spatiotemporal standard of care success translational study tumor uptake

项目摘要

The recent clinical success of inhibitors against immune checkpoint proteins (e.g. CTLA-4, PD-L1), which are thought to stimulate T cell responses against tumors, has revolutionized cancer therapy. Yet even among patients with high tumor mutational burden, only approximately 20-30% of patients achieve deep response, and discerning responders from non-responders is challenging with conventional imaging. On this basis, there is an urgent unmet need to develop biomarkers that distinguish responsive and treatment resistant patients, as well as identify patients at risk for undesired immune related adverse events. We hypothesized that an imaging biomarker capable of selectively measuring the biology that T cells use to impart cytotoxicity might address these unmet needs. Since antitumor T cell cytotoxicity is conferred primarily by the pro-apoptotic serine protease granzyme B, we have developed a peptide-based chemosensor we term “restricted interaction peptide” that enables spatiotemporal measurements of granzyme B proteolytic activity as the enzyme traverses the immunological synapse between T cell and target cell. Upon proteolytic cleavage of the full length, pro-form of the restricted interaction peptide (termed GB1) by granzyme B, a radiolabeled antimicrobial peptide is liberated and undergoes a spontaneous conformational shift that results in stable (and non-toxic) membrane association. We have shown that radiolabeled GB1 detects T cell activation in tumors and normal tissues elicited by systemic immune checkpoint inhibitors. Following on these encouraging preclinical data, we have now assembled a multidisciplinary team to conduct translational studies to evaluate the utility of granzyme B biochemistry as a biomarker. Over three specific aims, we will (1) perform IND enabling studies for 64Cu-GB1, (2) conduct a phase 0 first in human study to determine tracer safety, pharmacokinetics, and dosimetry, and (3) execute a phase I study to determine the accuracy for detection of urothelial and renal cancers undergoing a productive immune response due to treatment with standard of care immune checkpoint inhibitors. If successful, this project will establish a new paradigm for the measurement of T cell cytotoxicity in vivo that could have implications for the clinical management of other problematic human disorders like bacterial or viral (HIV, SARS-CoV) infections. Moreover, the imaging approach is entirely new, and favorable data emerging from this project could motivate further studies to develop restricted interaction peptides to measure the enzymology of other disease associated proteases in vivo with PET.

最近针对免疫检查点蛋白（例如 CTLA-4、PD-L1）的抑制剂在临床上取得了成功，这些抑制剂人们认为它可以刺激 T 细胞对肿瘤的反应，从而彻底改变了癌症治疗。肿瘤突变负荷高的患者，只有大约20-30%的患者达到深度缓解，并且使用传统成像技术区分有反应者和无反应者具有挑战性。开发区分反应性患者和治疗耐药患者的生物标志物的迫切需求尚未得到满足用于识别有发生不良免疫相关不良事件风险的患者。能够选择性测量 T 细胞用于赋予细胞毒性的生物学特性的生物标志物可能会解决这些未满足的需求是因为抗肿瘤 T 细胞的细胞毒性主要是由促凋亡丝氨酸蛋白酶赋予的。颗粒酶 B，我们开发了一种基于肽的化学传感器，我们称之为“限制性相互作用肽” 能够在酶穿过时对颗粒酶 B 蛋白水解活性进行时空测量 T 细胞和靶细胞之间的免疫突触。颗粒酶 B 释放限制性相互作用肽（称为 GB1），这是一种放射性标记的抗菌肽并经历自发构象转变，导致稳定（且无毒）的膜缔合。我们已经证明，放射性标记的 GB1 可以检测全身性刺激引起的肿瘤和正常组织中的 T 细胞活化。根据这些令人鼓舞的临床前数据，我们现在组装了一个免疫检查点抑制剂。多学科团队进行转化研究，以评估颗粒酶 B 生物化学作为通过三个具体目标，我们将 (1) 进行 64Cu-GB1 的 IND 启用研究，(2) 进行一个阶段 0 首先在人体研究中确定示踪剂安全性、药代动力学和剂量测定，以及 (3) 执行第一阶段确定免疫系统有效检测尿路上皮癌和肾癌的准确性的研究如果成功，该项目将通过标准护理免疫检查点抑制剂治疗得到缓解。建立了体内 T 细胞细胞毒性测量的新范式，这可能对其他有问题的人类疾病的临床管理，如细菌或病毒（HIV、SARS-CoV）感染。此外，成像方法是全新的，该项目中出现的有利数据可能会激励进一步研究开发限制性相互作用肽来测量其他相关疾病的酶学 PET 体内蛋白酶。