免疫疗法
医学
体内分布
肺癌
癌症
正电子发射断层摄影术
黑色素瘤
癌症研究
背景(考古学)
药效学
癌症免疫疗法
免疫检查点
PD-L1
肿瘤科
内科学
体内
核医学
药代动力学
生物
古生物学
生物技术
作者
Akhilesh C. Mishra,Kuldeep Gupta,Dhavendra Kumar,Gabriela Lofland,Ajay Sharma,Lilja B. Solnes,Steven P. Rowe,Patrick M. Forde,Martin G. Pomper,Edward Gabrielson,Sridhar Nimmagadda
标识
DOI:10.1136/jitc-2023-007535
摘要
Background Combination therapies that aim to improve the clinical efficacy to immune checkpoint inhibitors have led to the need for non-invasive and early pharmacodynamic biomarkers. Positron emission tomography (PET) is a promising non-invasive approach to monitoring target dynamics, and programmed death-ligand 1 (PD-L1) expression is a central component in cancer immunotherapy strategies. [ 18 F]DK222, a peptide-based PD-L1 imaging agent, was investigated in this study using humanized mouse models to explore the relationship between PD-L1 expression and therapy-induced changes in cancer. Methods Cell lines and xenografts derived from three non-small cell lung cancers (NSCLCs) and three urothelial carcinomas (UCs) were used to validate the specificity of [ 18 F]DK222 for PD-L1. PET was used to quantify anti-programmed cell death protein-1 (PD-1) therapy-induced changes in PD-L1 expression in tumors with and without microsatellite instability (MSI) in humanized mice. Furthermore, [ 18 F]DK222-PET was used to validate PD-L1 pharmacodynamics in the context of monotherapy and combination immunotherapy in humanized mice bearing A375 melanoma xenografts. PET measures of PD-L1 expression were used to establish a relationship between pathological and immunological changes. Lastly, spatial distribution analysis of [ 18 F]DK222-PET was developed to assess the effects of different immunotherapy regimens on tumor heterogeneity. Results [ 18 F]DK222-PET and biodistribution studies in mice with NSCLC and UC xenografts revealed high but variable tumor uptake at 60 min that correlated with PD-L1 expression. In MSI tumors treated with anti-PD-1, [ 18 F]DK222 uptake was higher than in control tumors. Moreover, [ 18 F]DK222 uptake was higher in A375 tumors treated with combination therapy compared with monotherapy, and negatively correlated with final tumor volumes. In addition, a higher number of PD-L1+ cells and higher CD8 + -to-CD4 + cell ratio was observed with combination therapy compared with monotherapy, and positively correlated with PET. Furthermore, spatial distribution analysis showed higher [ 18 F]DK222 uptake towards the core of the tumors in combination therapy, indicating a more robust and distinct pattern of immune cell infiltration. Conclusion [ 18 F]DK222-PET has potential as a non-invasive tool for monitoring the effects of immunotherapy on tumors. It was able to detect variable PD-L1 expression in tumors of different cancer types and quantify therapy-induced changes in tumors. Moreover, [ 18 F]DK222-PET was able to differentiate the impact of different therapies on tumors.
科研通智能强力驱动
Strongly Powered by AbleSci AI