Soluble-Antigen-Based PET/MR for the Specific Detection of BCMA CAR+ T-Cell Lymphoma

Chimeric antigen receptor (CAR) T-cell therapy carries a rare but critical risk of secondary CAR+ T-Cell Lymphoma (CAR-TCL), highlighting the urgent need for precise diagnostic tools. Current noninvasive imaging methods struggle to differentiate CAR-TCL from inflammatory sequelae, while biopsy presents several clinical challenges. In this study, we developed a novel positron emission tomography (PET) imaging probe, [⁶⁸Ga]Ga-BCMA-NOTA, by repurposing the extracellular domain of B-cell maturation antigen (BCMA-ECD) as a specific molecular recognizer for the BCMA-CAR single-chain variable fragment (scFv). Leveraging the high-affinity antigen-antibody interaction, the recombinant BCMA probe was produced with high purity (>98%) and demonstrated nanomolar affinity for the BCMA CAR scFv (K_D = 5.17 nM). The probe was synthesized with excellent radiochemical purity (>95%) and a good radiochemical yield (>50%). In preclinical xenograft models, [⁶⁸Ga]Ga-BCMA-NOTA PET/MR imaging demonstrated high and specific uptake in BCMA CAR-positive tumors (2.56 ± 0.61%ID/g), compared to negligible uptake in BCMA CAR-negative tumors (0.21 ± 0.05%ID/g), with a tumor-to-muscle (T/M) ratio of 16.0 ± 3.8. The uptake was blockable, confirming the probe's target specificity in vivo. Importantly, in a head-to-head comparison, [⁶⁸Ga]Ga-BCMA-NOTA provided significantly superior imaging contrast and a stronger correlation with tumor burden (R² = 0.93) compared to [¹⁸F]FDG (R² = 0.76). This BCMA CAR scFv-specific probe offers a powerful new tool for the precise noninvasive visualization of BCMA CAR-positive malignancies, with significant clinical translational potential for ensuring the long-term safety and monitoring of CAR-T therapies.