Editorial: Enhancing CAR T-cell therapy with imaging

EDITORIAL Chimeric Antigen Receptor T-cell (CAR-T) therapy has revolutionized cancer treatment, particularly for hematological malignancies, by genetically engineering patient-derived T cells to specifically recognize and attack cancer cells [1-3]. Despite its success in blood cancers, the extension of CAR-T therapy to solid tumors has been hindered by various biological barriers, including poor infiltration of CAR-T cells into tumor sites and the immunosuppressive tumor microenvironment that reduces CAR-T cell persistence and activity [3-7]. Understanding the dynamic behavior of CAR-T cells in solid tumors, such as their trafficking patterns, localization, and functional status, remains crucial for improving therapeutic outcomes. Advanced molecular and cellular imaging techniques provide essential tools for real-time, non-invasive monitoring of CAR-T cells within living organisms. These technologies, including bioluminescence imaging (BLI), fluorescence imaging, magnetic resonance imaging (MRI), positron emission tomography (PET), and photoacoustic imaging, allow researchers to track CAR-T cell distribution, expansion, and tumor infiltration over time [8]. Each imaging modality offers unique advantages—with PET providing high sensitivity and whole-body tracking, MRI delivering detailed anatomical resolution, and optical methods enabling multiparametric assessments—collectively offering comprehensive insights into the in vivo kinetics and therapeutic effects of CAR-T cells [3-8]. The research topic recently edited for Frontiers in Immunology was intended to decipher the role of imaging techniques in the context of CAR-T therapy, by enhancing the assessment of CAR-T cell biodistribution, trafficking kinetics, targeting, and monitoring within solid tumors. The research papers received and published have highlighted some of the aspects that most importantly relate to chimeric antigen technology. Gehrke at al. Firstly illustrated the utility of direct CAR-T cells visualization by means of dSTORM super-resolution microscopy, which allowed to detect the surface expression of CARs targeting SLAMF7, BCMA and CD19 with minimal background. The authors could also determine T cell subtype, donor material, and CAR construct as contributing factors shaping CAR surface expression and identified putative influence of CAR surface expression on CAR-T cell activation state. Further concluding that they could potentially build the basis for more intricate and combinatorial studies to further improve the efficacy of CAR-T cell immunotherapy, predict therapeutic outcome and ensure optimal care for patients. The clinical impact of metabolic imaging was instead argument of the paper provided by Ladbury at al. who used F18-fluorodeoxyglucose positron emission tomography (PET) after bridging radiation therapy (bRT) to predict prognosis in B-cell lymphoma patients undergoing CAR-T cells therapy. The parameters analyzed included metabolic tumor volume (MTV), maximum standardized uptake value (SUVmax), SUVmean, and total lesion glycolysis (TLG). As expected, bRT led to substantial reductions in all these parameters, with the extent of the delta variation significantly correlating to progression-free survival (PFS), freedom from distant progression (FFDP), and local control (LC). The authors conclude the need for prospective cohorts to validate the value of interim PET following bRT for quantifying changes in disease burden and associated prognosis. Another interesting aspect related to immunotherapy in general is the occurrence of atypical responses, and particularly of pseudoprogression [3,9]. For this purpose, Zhao et al. have described for the first time a case of pseudoprogression after CAR-T cell therapy in solid tumors. The example brought to the attention of the reader is an elderly patient with advanced gastric cancer and hepatic metastases showing an enlargement 1 month after CAR-T cell infusion. The lesions were reported to shrink the next month as seen through computed tomography scanning, confirming the typical behaviour of pseudoprogression. Integration of imaging modalities into CAR-T therapy research not only aids in optimizing treatment strategies but also accelerates clinical translation. Imaging facilitates the evaluation of CAR-T cell biodistribution, helps identify barriers like off-target accumulation or insufficient tumor penetration, and can monitor treatment-related toxicities. Furthermore, engineering CAR-T cells with imaging reporter genes enhances the capability for longitudinal tracking, enabling the assessment of therapeutic efficacy and safety in preclinical models and clinical trials [10]. Thus, imaging-driven approaches promise to overcome existing challenges in solid tumor CAR-T therapy by offering precise, personalized guidance for cell therapy optimization [6,7].