PET Imaging of System A Amino Acid Transport Detects Early Response to Immune Checkpoint Inhibitor Therapy in a Syngeneic Mouse Model.

Immune checkpoint inhibitor (ICI) therapy is effective and in routine clinical use for various cancers, but accurately identifying which patients will respond remains a significant challenge. The PET agent ¹⁸F-FDG has uptake by cancer cells as well as inflammation induced by ICI therapy, complicating and often limiting the utility of ¹⁸F-FDG for early response assessment during ICI therapy. An imaging agent that accurately distinguishes responders from nonresponders early in the course of ICI therapy could enable intensification or change of therapy for nonresponders. In this study, the ¹⁸F-labeled amino acid ¹⁸F-MeFAMP, a fluorinated analog selectively targeting system A amino acid transport, was compared with ¹⁸F-FDG in the MC38 syngeneic mouse model of ICI therapy. ¹⁸F-MeFAMP was chosen because of the relatively low uptake of system A substrates in inflammatory tissues combined with growing evidence suggesting system A transporters are involved in immunotherapy. Methods: PET/CT imaging was used to compare tumor uptake of ¹⁸F-MeFAMP with tumor uptake of ¹⁸F-FDG before and 6 d after starting dual ICIs in MC38 tumor-bearing female C57BL/6 mice. SUVs, biologic tumor volumes, and total lesion activity were measured along with selected tumor-to-organ ratios. Histogram analysis of tracer uptake was performed to assess differences in tumor activity distribution between responders and nonresponders. Results: ¹⁸F-FDG showed no significant differences at baseline or after ICI regardless of response. In contrast, ¹⁸F-MeFAMP SUVs defined using a 40% of SUVmax threshold (SUV40%) decreased significantly in responders (-60.0% ± 15.6%, P < 0.0001), whereas nonresponders showed no significant change (+45.5% ± 51.2%, P = 0.09). Similar patterns were observed with SUVmax, biologic tumor volume, and total lesion activity measures with ¹⁸F-MeFAMP. Histogram analysis revealed significant ¹⁸F-MeFAMP uptake differences between groups before and after imaging (P < 0.05). ¹⁸F-MeFAMP demonstrated low uptake in common metastatic sites, including liver, lungs, and brain. Conclusion: ¹⁸F-MeFAMP better detected early ICI response than ¹⁸F-FDG with favorable whole-body imaging properties. These findings support further investigation of ¹⁸F-MeFAMP for early evaluation of response to ICI and the role of system A substrates in cancer and immune cells before and during ICI.