Dr Subudhi is, however, skeptical that PD-1 or PD-L1 expression evaluated in isolation within the tumor tissue will translate to a clinically meaningful predictive biomarker.

“A lot of people and companies are looking at PD-1 and PD-L1 right now but my opinion is, I don’t think it’s a reliable biomarker, for a number of reasons,” he said.

“Number one, people are using different techniques to detect PD-L1. Some use tumor epithelial cells, some sample microenvironments. They’re using different cutoffs — 1%, 5%, wherever they see statistical significance.”

What’s more, PD-L1 expression is “dynamic,” Dr Subudhi said. “It can disappear or it can go up; it’s not steady and constant.”

Tumor responses to treatment might also affect PD-L1’s utility as a biomarker, Dr Subudhi pointed out. “Prostate cancer doesn’t usually express much PD-L1 but we’re getting ready to publish that after 2 doses of ipilimumab, prostate cancer starts expressing high levels of PD-L1. It’s a really dynamic biomarker — and so in my opinion not a reliable biomarker. But a lot of people disagree.

“Over the next few years, as we better understand how tumor immunity works and tumor microenvironments, we’ll have to look not just at the easily-accessible primary tumors for biomarkers,” he said.

Mutational load — the number of acquired tumor genome mutations rather than the presence or absence of particular mutations — is linked to immune checkpoint inhibitor therapy outcomes in melanoma and lung cancer.

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“Our preliminary results suggest the same is true in prostate cancer — but it’s not an all-or-nothing thing,” he said. “We think it’s going to be mutational load plus other factors that make a more predictable biomarker.”

References

  1. Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer. 2016;54:139-148. doi: 10.1016/j.ejca.2015.11.016
  2. Subudhi SK, Aparicio A, Gao J, et al. Clonal expansion of CD8 T cells in the systemic circulation precedes development of ipilimumab-induced toxicities. Proc Natl Acad Sci U S A. 2016;113(42):11919-24. doi: 10.1073/pnas.1611421113