Granzyme B-targeted PET Imaging Monitoring Tumor Responses to Immunotherapy

Overview

Malignant solid tumors, characterized by their persistently high incidence and mortality rates, pose a significant threat to human health and life, imposing a substantial societal burden. Molecular imaging enables the non-invasive, in vivo visualization of tumorigenesis and progression at the molecular level. Compared to traditional morphology-based imaging techniques, molecular imaging provides more precise information for early tumor diagnosis, treatment efficacy assessment, and clinical disease management. 18F-FDG PET/CT imaging is currently the most widely used molecular imaging modality. However, under immunotherapy, FDG accumulates extensively in activated T cells, leading to increased false-positive evaluations. It fails to effectively distinguish metabolic hyperactivity between proliferative tumor cells (indicative of true progressive disease) and infiltrating immune cells (associated with pseudoprogression), thereby complicating the assessment of immunotherapy efficacy. Therefore, exploring novel molecular imaging probes with high specificity is of critical importance for patients undergoing tumor immunotherapy, as it can lead to more accurate evaluation of treatment efficacy. Granzyme B (GZMB), a serine protease released from cytoplasmic granules of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, induces apoptosis in target cells, particularly tumor cells-a central mechanism of tumor immunotherapy. This makes GZMB a promising molecular target for evaluating immunotherapy efficacy. This study aims to assess tumor immunotherapy outcomes using GZMB-targeted PET imaging and compare its performance with 18F-FDG PET/CT. The goal is to achieve timely and accurate efficacy evaluation and longitudinal monitoring, identify potential beneficiaries, optimize clinical decision-making, and ultimately deliver personalized precision treatment to improve overall treatment outcomes.

This investigator-initiated trial (IIT) aims to investigate the clinical utility of Granzyme B (GZMB)-targeted PET imaging for the early prediction of immunotherapy response in patients with malignant solid tumors. GZMB, a protease secreted by cytotoxic T lymphocytes, serves as a direct indicator of immune-mediated tumor killing activity. The GZMB-targeted tracer has demonstrated high target affinity and favorable pharmacokinetics in preclinical studies, showing potential to overcome the limitations of 18F-FDG PET in distinguishing between pseudoprogression and true progression. In this prospective, single-arm observational study, patients with histologically confirmed malignant solid tumors (e.g., NSCLC, HNSCC, CRC, etc.) scheduled to receive immune checkpoint inhibitors (e.g., anti-PD-1/PD-L1) will undergo baseline 18F-FDG PET/CT scans. Following 2\~3 cycles of immunotherapy, they will undergo both GZMB-targeted PET/CT and 18F-FDG PET/CT scans within one week. PET parameters (SUVmax, SUVmean, tumor-to-background ratio) will be measured, calculated, and then correlated with pathologic response or objective response rate (ORR). The sensitivity, specificity, and accuracy of these parameters in monitoring tumor responses to immunotherapy will be analyzed. The diagnostic performance of both PET modalities will be compared. Additionally, this study will explore the correlations between PET parameters on GZMB-targeted PET imaging and the expression levels of GZMB and CD8+ in tumor tissue. The study is funded by Zhongnan Hospital of Wuhan University. The results may establish GZMB-targeted PET imaging as a non-invasive tool for identifying patients likely to benefit from immunotherapy, thereby enabling the development of personalized treatment strategies.