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

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。活检分析表明，良好的预后与CD8+ T细胞浸润到肿瘤中有关，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聚乙二醇化显著提高了这种PET成像的灵敏度。本研究的目标是：(1)创建人类CD8特异性的VHH，(2)开发一种非酶、位点特异性的化学物质，允许VHH与PEG分子和放射性同位素进行gmp可扩展的双偶联，以及(3)验证该试剂在人源化小鼠模型中用于基于pet的人类CD8+ T细胞运输成像。这些目标的成功完成将为这项创新技术转化为临床环境中的“CD8扫描”提供基础，这是首个非侵入性跟踪人体免疫系统的技术。这项技术将成为下一个护理标准，与免疫疗法结合使用，以快速评估治疗反应并定制治疗方案，从而获得最大的治疗效益。

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.