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- Title
Development and characterisation of [<sup>18</sup>F]TTDP, a novel T cell immunoglobulin and ITIM domain tracer, in humanised mice and non-human primates.
- Authors
Wang, Jing; Hu, Xinxin; Wang, Yueqi; A, Rong; Li, Xiaoqian; Sun, Ying; Guan, Zhengqi; Li, Xiaona; Wu, Yongyi; Wang, Jiannan; Zhao, Fangyu; Liu, Yang; Wang, Hongbin; Yu, Hong; Wang, Tianyi; Zhu, Mengyuan; Li, Xinyu; Zhang, Duoyi; Chen, Wei; Han, Zhaoguo
- Abstract
Purpose: The T cell immunoglobulin and ITIM domain (TIGIT) blockade immunotherapy response is directly associated with individual differences of TIGIT expression on tumour-infiltrating lymphocytes (TILs) in tumour immune microenvironment (TIME) of non-small cell lung cancer (NSCLC). Here, we developed a TIGIT-targeted PET tracer to evaluate its feasibility in predicting immunotherapy efficacy, aiming to manage NSCLC patients accurately. Methods: We synthesised a 18F-labeled TIGIT-targeted D-peptide, [18F]TTDP, and investigated the specificity of [18F]TTDP both to murine TIGIT and human TIGIT by a series of in vitro and in vivo assays. [18F]TTDP PET imaging was performed in humanised immune system (HIS) mice models bearing NSCLC patient-derived xenografts (PDXs) to evaluate the predictive value of FDA-approved combination immunotherapy of atezolizumab plus tiragolumab. Lastly, rhesus macaque was applied for [18F] TTDP PET to explore the tracer's in vivo distribution and translational potential in non-human primates. Results: [18F]TTDP showed high specificity for both murine TIGIT and human TIGIT in vitro and in vivo. The HIS NSCLC PDX platform was successfully established for [18F]TTDP PET imaging, and tumour uptake of [18F]TTDP was significantly correlated with the TIGIT expression of TILs in the TIME. [18F]TTDP PET imaging, in predicting treatment response to the combination immunotherapy in NSCLC HIS-PDX models, showed a sensitivity of 83.33% and a specificity of 100%. In addition, [18F]TTDP PET also showed cross-species consistency of the tracer biodistribution between non-human primate and murine animals, and no adverse events were observed. Conclusion: The combined implementation of the [18F]TTDP and HIS-PDX model creates a state-of-the-art preclinical platform that will impact the identification and validation of TIGIT-targeted PET image-guided diagnosis, treatment response prediction, beneficial patient screening, novel immunotherapies, and ultimately the outcome of NSCLC patients. We first provided in vivo biodistribution of [18F]TTDP PET imaging in rhesus macaque, indicating its excellent translational potential in the clinic.
- Subjects
POSITRON emission tomography; NON-small-cell lung carcinoma; MEDICAL sciences; TREATMENT effectiveness; TUMOR-infiltrating immune cells; T cells
- Publication
European Journal of Nuclear Medicine & Molecular Imaging, 2025, Vol 52, Issue 2, p416
- ISSN
1619-7070
- Publication type
Academic Journal
- DOI
10.1007/s00259-024-06911-7