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，对治疗的反应各不相同，预测治疗的反应仍然是一个主要障碍。活检分析与CD8+T细胞在肿瘤中的渗透有关，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细胞可以准确地预测小鼠对免疫治疗的反应。此外，VHH的聚乙二醇化显著提高了这一PET成像的灵敏度。这项研究的目标是(1)创建一种针对人CD8的VHH，(2)开发一种非酶的、位置特定的化学物质，以允许VHH与聚乙二醇分子和放射性同位素的GMP可缩放双重结合，以及(3)在人源化的小鼠模型中验证该试剂用于基于PET的人CD8+T细胞运输的成像。这些目标的成功完成将为将这项创新技术转化为临床环境提供基础，这是第一次非侵入性跟踪人类免疫系统的CD8扫描。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，并以最大的治疗效益量身定做治疗。

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.