PET Imaging May Predict Early Immunotherapy Response

A noninvasive PET imaging method may serve as a useful predictive biomarker for responses to cancer immunotherapy, according to a new study.

Researchers provided a preclinical proof of concept for the use of granzyme B, a downstream effector of tumoral cytotoxic T cells, as an early biomarker for tumors responding to immunotherapy with checkpoint inhibitors.

“In our study, we found a marker that was highly predictive of response to immunotherapy at a very early time after starting treatment, and we were able to design an imaging probe to detect this marker and accurately predict response noninvasively,” said Umar Mahmood, MD, PhD, professor of radiology at Harvard Medical School and director of the division of precision medicine at Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital in Boston.

With more clinical testing, “the ability to differentiate early in the course of treatment patients who are likely to benefit from immunotherapy from those who will not can greatly improve individual patient care and help accelerate the development of new therapies,” he said.

The researchers published their results in Cancer Research.

Traditional imaging techniques that measure tumor size, such as CT and MRI scans, or those that measure tumor glucose uptake, such as FDG-PET, cannot distinguish a nonresponding tumor from a tumor that is responding to immunotherapy but appears to grow in size because it is filled with immune cells and accompanied by increased glucose uptake.

Tissue biopsies can be unreliable because of tumor heterogeneity and constant changes in the levels of the biomarker proteins measured.

Mahmood and colleagues designed a probe that binds to granzyme B, attached the probe to a radiolabeled element, and conducted PET scans to see where immune cells are actively releasing tumor-killing granzyme B in tumor-bearing mice, before and after treatment with immune checkpoint inhibitors.

They found that mice with a high PET signal responded to the therapy and their tumors subsequently regressed, but those with a low PET signal did not respond to the therapy and their tumors continued to grow.

“Because PET imaging is quantitative, we could measure the degree of effectiveness and put a number on it,” Mahmood noted.

The researchers also tested the probe on nine human melanoma biopsy samples, six from patients treated with nivolumab and three treated with pembrolizumab. They detected high levels of granzyme B in the samples from responders and much lower levels in the samples from nonresponders.

Combination immunotherapy led to a significant increase in the tumor granzyme B PET signal as compared with monotherapy.

“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,” Mahmood concluded. “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.”