Development and characterisation of [F]TTDP, a novel T cell immunoglobulin and ITIM domain tracer, in humanised mice and non-human primates.

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 F-labeled TIGIT-targeted D-peptide, [F]TTDP, and investigated the specificity of [F]TTDP both to murine TIGIT and human TIGIT by a series of in vitro and in vivo assays. [F]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 [F] TTDP PET to explore the tracer's in vivo distribution and translational potential in non-human primates.

RESULTS

[F]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 [F]TTDP PET imaging, and tumour uptake of [F]TTDP was significantly correlated with the TIGIT expression of TILs in the TIME. [F]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, [F]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 [F]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 [F]TTDP PET imaging in rhesus macaque, indicating its excellent translational potential in the clinic.