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Researchers Seeking Biomarkers for Immune-Related Adverse Events During Immunotherapy

CHICAGO (GenomeWeb) – Researchers are on the hunt for germline or somatic risk variants that might serve as markers for predicting immune-related adverse events (irAEs) in individuals treated with immune checkpoint blockade-based immunotherapy.

At the American Society of Clinical Oncology annual meeting here on Friday, Cleveland Clinic medical oncologist Vamsidhar Velcheti touched on the spectrum of toxicity events that are being reported as individuals with cancer are treated with drugs designed to tinker with the immune system.

There is ongoing interest in identifying biomarkers to predict response to immunotherapy treatments such as checkpoint inhibitors, either alone or in combination with chemotherapeutic agents, Velcheti explained. But there's also a need to find better ways of predicting which patients will experience immune-related toxicities, which can crop up across a wide range of tissues as the drugs interfere with mechanisms that normally dampen immune responses to an individual's own tissues.

In a New England Journal of Medicine study last year, for example, researchers from the Vanderbilt University Medical Center and elsewhere described two cases of fatal myocarditis that occurred in melanoma patients treated with the anti-CTLA4 drug ipilimumab (Bristol-Myers Squibb's Yervoy) and the PD-1-targeting monoclonal antibody nivolumab (Opdivo).

Using a combination of ImmunoSeq, transcriptome sequencing, and other tumor- and microenvironment-profiling approaches, the authors of that study tracked down autoreactive T cells that had worked their way into the heart muscle tissue. Other cases of myocarditis turned up when they sifted through Bristol-Myers Squibb safety databases describing nearly 20,600 other patients treated with nivolumab and/or ipilimumab.

"Pharmacovigilance studies show that myocarditis occurred in 0.27 percent of patients treated with a combination of ipilimumab and nivolumab, which suggests that our patients were having a rare, potentially fatal, T-cell-driven drug reaction," they wrote.

In a letter to the editor in NEJM early this year, two French investigators responded to the study, noting that "cardiac events remain exceptional in phase 3 clinical trials of immune checkpoint inhibitors," though the "wide spectrum of immune-related adverse events is making it difficult for clinicians to properly evaluate rare but sometimes fatal events."

The duo noted that a registry for prospectively collecting data on irAEs was established at Gustave Roussy and contained information on 388 patients with adverse events over its first 18 months (though just one involved an apparent cardiovascular component).

These and other studies continue documenting the rare potential irAEs associated with checkpoint blockade agents, ranging from dermatitis or colitis to pneumonitis and beyond.

In an abstract published to coincide with the ASCO annual meeting, researchers from Vidant Health and East Carolina University suggested that irAE incidence and type may vary depending on the tumor being treated with immunotherapy, based on a chart review study involving more than 100 patients with metastatic lung cancer, metastatic melanoma, or metastatic renal cancer who were treated with nivolumab and/or ipilimumab.

"With the expanding use of [immune checkpoint blockade] in advanced malignancies, increased awareness of these clinically significant and potentially serious irAEs is indispensable," the authors wrote, arguing that it may be beneficial to explore irAE incidence based on tumor types in future trials.

But there is still a long way to go in predicting when, where, and in which immunotherapy-treated patients these rare complications may arise. That has investigators like Velcheti searching for somatic or germline mutations associated with irAEs, not only to predict and prevent these toxicities, but to get a clearer portrait of the immune system-self interplay and the processes that go awry during overzealous immune responses.

Though there are still challenges in predicting this autoimmunity, Velcheti argued that there are more tools than ever available to profile this process and pinpoint potential markers — from flow cytometry to isolate immune cells with subtly different phenotypes, to cytokine assays, blood-based proteomics, T cell or B cell receptor sequencing, and even microbiome profiling.

So, while validated clinical approaches for consistently predicting irAEs remain out of reach, he said, there are promising approaches for untangling irAE associations in clinical trials.