Study Maps Body’s Response to Checkpoint Inhibitors

An international team of researchers has used whole-body PET scans and radioactively labeled antibody tracer to map response to immune checkpoint inhibitors, an immunotherapy for cancer that has shown remarkable success in most cases, but also unpredictable patient response. The findings could be relevant to future treatment decisions.

The immune system evolved to clear away intruders like microorganisms, but also cells that have mutated beyond recognition. Tumor cells, however, have ways to silence immune T-cells that infiltrate tumors. Immune checkpoint inhibitors, which work by removing this immune-suppression mechanism,  have been an important breakthrough in cancer treatment, releasing the “full power” of T-cells on tumors, according to Liesbeth de Vries, professor of Medical Oncology at the University Medical Centre Groningen.

Unfortunately, patient response to immune checkpoint inhibitors is variable. “We would like to know early on which patients do not respond and maybe need some additional activation of their immune system,” says De Vries. 

To this end, De Vries and a team of scientists from the Departments of Medical Oncology, Clinical Pharmacy and Pharmacology, Pathology and Medical Biology, and Medical Imaging Center of the University Medical Center Groningen; the Department of Epidemiology, Julius Center for Health Sciences, University Medical Center Utrecht; and Genentech (San Francisco) used whole body PET scans with a hemi-antibody (half of an antibody structure) directed against CD8+, a marker of activated T-cells.  and labeled with zirconium-89. Scans were made before and thirty days after the start of treatment. “Activated T-cells are everywhere in the entire body, but so far, our knowledge about their distribution was largely based on biopsies,” says first author Laura Kist de Ruijter. “We wanted to study the full picture.”

The team collected tumor biopsies from their patients to confirm the accuracy of the PET scan results. “We compared the amount of radioactivity in the biopsies measured by autoradiography with staining for CD8+ cells,” de Ruijter says. “And we found higher tracer uptake in lesions with high CD8+ infiltration.”

These observations show that tracer uptake is a good measure of immune activation and gave the team confidence in proceeding to whole body scans. They found that the upfront presence of CD8+ cells predicted the outcome for the patient, and findings during treatment were striking. “We were stunned by the heterogeneity in response we saw, both within individual patients and between patients,” de Vries says.

This study is the first to investigate this response in the entire body of patients treated with immune checkpoint inhibitors, but the outcome is complicated. “It was generally assumed that around 30 days of treatment there would be a clear-cut difference between responders and non-responders in CD8+ T-cell presence, but that was not the case,” de Vries says. The response is much more dynamic, with a large spatial and temporal variation in the presence in tumor lesions of activated T cells.

This insight is important, as it becomes clear that immune checkpoint inhibitors can be effective in an increasing number of cancer types. “The field is rather overwhelming. These drugs are now being used not just as a last resort, but also evaluated to prevent metastasis or to reduce tumor size before an operation,” de Vries adds.

 Moreover, adding other medicines to improve effects can be considered. Since this comes at the price of more side effects, more information about which patients will respond to immune checkpoint inhibitors is warranted.

 The findings were published recently in Nature Medicine.