Although cancer immunotherapy can produce dramatic responses, only a minority of patients benefit from such therapy. Being able to differentiate treated responders from nonresponders early in the course of therapy would help to triage nonresponding patients away from ineffective therapies, reducing unnecessary side effects, and allow patients to try alternative therapeutic strategies.
Now, a preclinical study found that granzyme B positron-emission tomography (PET) imaging was able to distinguish mouse and human tumors that responded to immune checkpoint inhibitors from those that did not respond early in the course of treatment. The study’s findings suggest that granzyme B PET imaging may serve as a quantitative predictive imaging biomarker. The study by Larimer et al was published in Cancer Research.
The researchers designed novel PET imaging probes for the murine and human granzyme B isoforms that specifically and quantitatively bind granzyme B, a protein released by immune cells to kill cancer cells. Immunotherapy-treated mice were imaged prior to therapy-induced tumor volume reduction.
To assess the clinical value of a granzyme B imaging paradigm, the researchers then tested their PET imaging probe on nine biopsy specimens from patients with melanoma receiving checkpoint inhibitors. Six of the patients were treated with nivolumab (Opdivo), and three were treated with pembrolizumab (Keytruda).
When the researchers tested their probe in the mice before and after treatment with immune checkpoint inhibitors, they found that one group of mice had high PET signal strength, signifying high levels of granzyme B in the tumors, while the other group had low levels of PET signal in their tumors. When the two groups of mice were followed, the mice with a high PET signal responded to the therapy, and their tumors regressed. The mice with a low PET signal did not respond to the therapy, and their tumors continued to grow.
The researchers found the same was true in the human tumor samples. High levels of granzyme B were detected in the samples from responders, and much lower levels of granzyme B were detected in the samples from nonresponders.
“These findings could have a significant impact on drug development, as different combinations could be imaged at very early time points in patients and the levels of tumor granzyme B used to compare treatments and rank effectiveness,” said Umar Mahmood, MD, PhD, Professor of Radiology at Harvard Medical School and coauthor of this study, in a statement. “Further, therapeutics that achieve high levels of granzyme B release can be advanced faster and those leading to low granzyme B release can be altered or eliminated.”
Funding for this study was provided by the National Institutes of Health.
Dr. Mahmood is the cofounder of this imaging probe and a consultant for CytoSite BioPharma, a company that is further developing the granzyme B PET imaging probe for clinical translation. The other study authors disclosed no potential conflicts of interest.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.