Monitoring Therapeutic Response to Anti-Fibroblast Activation Protein (FAP) CAR T Cells using [18F]AlF-FAPI-74
Precision medicine and targeted therapies are an emerging theme in modern cancer therapy, an example of these targeted therapies is CAR-T cell therapy. Tools to predict and monitor therapeutic responses to these cell therapies are highly necessary, as despite the success of CAR-T cell therapy against hematological malignancies, successful targeting of solid tumors with CAR T cells has been limited by a lack of durable responses and reports of toxicities. In the study of Mark Sellmyer et al. at the University of Pennsylvania, non-invasive PET imaging of [18F]-AIF-FAPI-74, targeting FAP (fibroblast activation protein, a cell surface serine protease), was used to image and quantify FAP expression and thus evaluate the potential role of pre-clinical [18F]AlF-FAPI-74 PET in predicting and monitoring response to FAP CAR T cell therapy. FAP was chosen as target, as tis pan-tumor marker that is expressed in activated fibroblasts in the tumor microenvironment, in over 90% of epithelial cancers. FAP imaging biomarkers are thus very useful for diagnosis and staging of different solid tumors.
In this study, the FAP inhibitor (FAPI) [18F]AlF-FAPI-74 probe was used to complement ongoing efforts to develop and optimize FAP CAR T cells. The selectivity of the radiotracer for FAP was characterized in vitro and its ability to monitor changes in FAP expression was evaluated using rodent models of lung cancer. The tracer is evaluated for its potential role in monitoring therapeutic response following administration of a novel FAP (4G5) CAR T cell therapy. PET is thus used as a tool to identify patients who are most likely to respond to FAP-targeted CAR T cells based on the level of target expression in the tumor and to monitor their response.
[18F]AlF-FAPI-74 showed selective retention in FAP+ cells in vitro, with effective blocking of the uptake in presence of unlabeled FAPI. In vivo, [18F]AlF-FAPI-74 was able to detect FAP expression on both tumor cells as well as FAP+ stromal cells in the tumor microenvironment with a high target-to-background ratio. It was further demonstrated that the utility of the tracer to monitor changes in FAP expression following FAP CAR T cell therapy, and the PET imaging findings showed a robust correlation with ex vivo analyses.This study clearly demonstrates the value of [18F]-AIF-FAPI-74 as a predictive and pharmacodynamic biomarker for FAP-targeted therapies by assessing the biodistribution of the target and thus informing on which patients are most likely to respond to FAP-targeted CAR T cells, as well as monitoring therapy response by means of PET imaging.