Granzyme B PET imaging predicts immunotherapy response early, outperforming conventional methods

The clinical success of cancer immunotherapy necessitates dynamic and functional biomarkers to predict treatment outcomes. Current methods, like tissue biopsy and conventional imaging, often have spatial and temporal limitations, delaying critical insights into anti-tumor immune activity. Granzyme B (GzmB), a serine protease released by activated cytotoxic CD8⁺ T lymphocytes and natural killer cells during target-cell killing, serves as a direct, mechanistically linked marker of immune effector function, offering a promising solution to this diagnostic gap.

This review synthesizes findings from preclinical investigations using ⁶⁸Ga- and 18F-labeled peptide-based tracers, specifically [⁶⁸Ga]Ga-NOTA-GZP and **[18F]AlF-mNOTA-GZP, across various cancer models. It also incorporates emerging first-in-human studies, evaluating the feasibility, safety, and predictive potential of GzmB PETin diverse tumor types. The studies assessedGzmBas a marker of **cytotoxic T-cell** and **NK cell** activity, comparing its predictive power against conventional imaging like[18F]FDG PET` and tissue biopsies to identify early responders to immune checkpoint blockade and combination therapies.

Preclinical investigations consistently demonstrated that GzmB PET tracers, including [⁶⁸Ga]Ga-NOTA-GZP and [18F]AlF-mNOTA-GZP, enabled early discrimination between responders and non-responders to immune checkpoint blockade and combination therapies. This predictive capability often preceded measurable tumor shrinkage or metabolic changes detected by [18F]FDG PET. Emerging first-in-human studies further supported the feasibility, safety, and predictive potential of GzmB PET across multiple tumor types. These studies highlighted GzmB as a proximal and mechanistically linked marker of immune effector function, directly reflecting the activity of cytotoxic CD8⁺ T lymphocytes and natural killer cells. The ability of GzmB PET to provide non-invasive, whole-body assessment of cytotoxic activity in vivo addresses significant spatial and temporal limitations of traditional diagnostic approaches.

GzmB PET consistently demonstrated early discrimination between responders and non-responders to immune checkpoint blockade, often preceding measurable tumor shrinkage or metabolic changes on [18F]FDG PET.