TOPIC 396: NON-INVASIVE DETECTION OF HUMAN CD8+ T CELLS: A PET-BASED APPROACH TO ASSESS THE HUMAN IMMUNESYSTEM - MOONSHOT

主题 396：人类 CD8 T 细胞的非侵入性检测：基于 PET 的人类免疫系统评估方法 - Moonshot

• 批准号: 10044540
• 负责人: KIERA CLAYTON
• 金额: $ 29.87万
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-16 至 2020-06-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10044540
• 关键词: Biopsy; CD8-Positive T-Lymphocytes; CD8B1 gene; Chelating Agents; Chemistry; Clinical; Foundations; Human; Immune system; Immunotherapy; Infiltration; Malignant Neoplasms; Mus; Non-Invasive Cancer Detection; Positron-Emission Tomography; Proteins; Radioisotopes; Radiolabeled; Reagent; Research; Scanning; Site; Technology; Therapeutic; Translations; Validation; Work; base; human imaging; humanized mouse; in vivo; individualized medicine; innovative technologies; mouse model; nanobodies; outcome forecast; pre-clinical; predicting response; standard of care; success; trafficking; treatment response; tumor

Immunotherapy has shown impressive success in treating several cancers, however, responses to treatment are variable, and predicting the response to therapy remains a major obstacle. Biopsy analyses has correlated good prognosis with infiltration of CD8+ T cells into the tumor and recent preclinical work suggests that tracking of CD8+ T cells in tumors using single domain antibody (VHH)–based PET imaging can accurately predict response to immunotherapy in mice. Furthermore, VHH PEGylation dramatically enhances the sensitivity of this PET imaging. The objectives of this research are to (1) create a VHH specific for human CD8, (2) develop a non-enzymatic, site-specific chemistry to allow for a GMP-scalable dual conjugation of the VHH to a PEG molecule and radioisotope, and (3) validate this reagent for PET-based imaging of human CD8+ T cell trafficking in a humanized mouse model. The successful completion of these objectives will provide the foundation for translation of this innovative technology to a clinical setting as a “CD8 Scan”, the first of its kind to non-invasively track the human immune system. This technology will become the next standard of care, used in conjunction with immunotherapy to rapidly assess responses to treatment and tailor treatment with the greatest therapeutic benefit.

免疫疗法在治疗几种癌症方面取得了令人印象深刻的成功，然而，对治疗的反应是可变的，预测对治疗的反应仍然是一个主要障碍。活检分析显示，良好的预后与CD8+ T细胞浸润到肿瘤中相关，最近的临床前工作表明，使用基于单域抗体（VHH）的PET成像跟踪肿瘤中的CD8+ T细胞可以准确预测小鼠对免疫治疗的反应。此外，VHH PEG化显著增强了这种PET成像的灵敏度。本研究的目的是（1）创建对人CD8特异性的VHH，（2）开发非酶促、位点特异性化学，以允许VHH与PEG分子和放射性同位素的GMP可扩展的双重缀合，以及（3）验证该试剂用于人源化小鼠模型中人CD8+ T细胞运输的基于PET的成像。这些目标的成功完成将为将这项创新技术转化为“CD8扫描”的临床环境奠定基础，这是第一种非侵入性跟踪人类免疫系统的技术。这项技术将成为下一个护理标准，与免疫疗法结合使用，以快速评估对治疗的反应，并定制具有最大治疗益处的治疗。