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In Sequencing Study, Better Outcomes for Patients on Yervoy with Stable T-Cell Clonotypes

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NEW YORK (GenomeWeb) — A study using next-generation sequencing to measure changes in T-cell receptor genes of patients treated with anti-CTLA-4 drugs like Bristol-Myers Squibb's Yervoy (ipilimumab) has found that patients whose T-cell landscape changed little from a pre-treatment baseline had improved survival compared to those who showed a drop in the T-cell clones that were most frequent prior to treatment.

According to the authors, the study, published today in Science Translational Medicine, suggests that patients who maintain the presence of baseline high-frequency clones during treatment may represent a molecular or clonal subset more likely to respond to treatment.

If the results are confirmed and replicated, patients could potentially have their immune repertoire sequenced prior to and early in treatment to determine if they show high-frequency clonotype maintenance and are therefore more likely to derive benefit from Yervoy and other anti-CTLA-4 drugs.

"Because only a proportion of patients obtain long-term benefit, identification of these preferential clonotypes could improve patient selection for [those] receiving single-agent CTLA-4 blocking antibodies," the authors wrote.

An assay based on the group's discovery could also aid in identifying patients demonstrating "pseudoprogression," where patients appear to have disease progression but later respond. Testing for maintenance of baseline clonotypes could pick out those patients that may benefit from continued treatment and should not be taken off a drug when they show early radiologic progression.

Lawrence Fong, the study's corresponding author, told PGx Reporter this week that he and his colleagues did not approach the study expecting their sequencing effort to yield a mechanism for distinguishing responders from non-responders.

Researchers have long wondered why some patients respond to Yervoy and similar drugs, while others do not. In conducting the latest study, Fong and his colleagues were trying to gain a better understanding of the mechanism of action of these therapies.

"We didn’t dive into this thinking that was what we would necessarily find … [but] a correlation with clinical outcomes just sort of fell out once we started looking at the data," he said.

Clinical studies have shown that around 30 percent of people treated with Yervoy have improved survival and only around 10 percent are likely to have long-term benefits.

When the UK's National Institute for Health and Clinical Excellence initially recommended against use of Yervoy by the National Health Service in 2011, chief executive Andrew Dillon noted that one reason among many for the negative recommendation was that "no patient characteristics or biomarkers [had] yet been identified to help identify [the] small group of people most likely to gain long-term benefit."

NICE subsequently recommended the drug for previously treated advanced melanoma after negotiating a discounted price that brings Yervoy within the institute's cost-effectiveness measures.

In the mean time, exactly how Yervoy and other anti-CTLA-4 drugs work in the body, benefiting some but not others, remains a mystery. In their sequencing study, Fong and his colleagues turned to immune repertoire sequencing to try to understand the biological effect Yervoy has on the genomic landscape of patients' T cells.

The group sequenced the T-cell receptors in 25 metastatic prostate cancer patients treated with Yervoy and the drug GM-CSF in a clinical trial, 21 metastatic melanoma patients treated with tremelimumab, an investigational Pfizer CTLA-4 drug, as well as nine untreated healthy controls.

Overall, the researchers found that anti-CTLA-4 treatment increased T-cell receptor diversity. Compared to the spectrum of rearrangements in TCR genes prior to treatment, after treatment patients had more unique clonotypes, and the repertoire of these distinct clones continued to evolve over subsequent months on the drug, the authors wrote.

While this increasing clonal diversity was not associated with clinical outcome, the researchers were intrigued to find that after dividing patients into short survival and long survival groups using the median survival as a cutoff, those with better survival seemed to maintain a population of the clones present at high frequency before they started treatment. In contrast, patients in the short overall survival group saw the presence of their highest-frequency baseline clonotypes fall with treatment.

Among the T cells stably maintained in patients with better outcomes were high-avidity cells, such as virus-reactive T cells, which "may be relevant in the antitumor response," the authors wrote in their paper. Fong added that the results indicate that tracking patients' T-cell clonotype maintenance before and during early treatment may provide insights for guiding the use of anti-CTLA-4 drugs.

"Unfortunately if we have just a single time point, a baseline, we can't necessarily identify who might have clinical benefit,” he said. “But looking at how they sustain those clones after the start treatment … that would be the potential application of this," he said.

Most likely, a clinical translation of the groups' finding would have to involve sequencing each patient's immune repertoire, similarly to what the group did in the study, Fong said, because while maintenance of high-frequency clones signified better outcomes across the board, the actual identity of those clones differed from patient to patient.

According to the group, larger, prospective validation will be necessary to determine whether maintenance of baseline high-frequency clonotypes after the start of treatment can serve as prognostic or predictive biomarkers.

Fong said the team is planning such a study now.

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