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September 5, 2025Open Access

Granzyme B PET Imaging Enables Early Assessment of Immunotherapy Response in a Humanized Melanoma Mouse Model

Key Points

PET imaging indicated significantly higher tracer uptake in mice receiving combination therapy, correlating with tumor size reduction.
The estimated inhibition constant (Ki) for the novel tracer was recorded at 4.2 nM, highlighting its promising binding affinity.
Humanized NSG mice utilized PET imaging during ICI therapy to assess tracer biodistribution and treatment responses over time.
Findings suggest that increased tracer uptake may indicate immune-related adverse events in melanoma models undergoing combination therapy.

Abstract

Background/Objectives: This study evaluated a novel PET tracer, 68Ga-NOTA-CYT-200, which targets human granzyme B (GZB) as a biomarker for cytotoxic T-cell activation in a clinically relevant model of melanoma-bearing mice with a humanized immune system treated with immune checkpoint inhibitor (ICI) therapy. Methods: The binding affinity of the tracer was determined using an enzymatic colorimetric assay. Tumor-bearing humanized NSG mice underwent PET imaging before and during ICI monotherapy or combination therapy to assess 68Ga-NOTA-CYT-200 uptake within tumors and other organs. The tumor growth was carefully monitored. The treatment response was evaluated based on the percentage change in tumor size at days 5 and 15 after the treatment started. A tracer biodistribution study and immunohistochemical staining of the tumors and organs were also performed. Results: The inhibition constant (Ki) of 68Ga-NOTA-CYT-200 was estimated at 4.2 nM. PET imaging showed a significantly higher 68Ga-NOTA-CYT-200 uptake in mice receiving the combination therapy compared to those receiving monotherapy or a vehicle (p < 0.0001 or p = 0.0005, respectively), which correlated with the greatest reduction in tumor size in the combination ICI group. Regardless of treatment, the responders presented with a significantly higher 68Ga-NOTA-CYT-200 uptake at days 4 or 7 after the treatment began (p = 0.0002 and p = 0.0109, respectively). An increased uptake of 68Ga-NOTA-CYT-200, especially in the intestines and liver within the combination ICI group, suggested immune-related adverse events (IrAEs). Conclusions: Our study demonstrates that 68Ga-NOTA-CYT-200 PET imaging can predict the early treatment response in melanoma models treated with ICI and may also help in detecting IrAEs.

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