Immune-Suppressing Protein in Noncancerous Cells of Cancer Patients Offers Clue to Drug Response


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Roy Herbst, MD, PhD

A multicenter phase I study using an investigational immune therapy drug has found that the presence of the immune-suppressing protein PD-L1 in noncancerous immune cells can predict how patients with different types of advanced cancer will respond to treatment.  The study, led by a Yale Cancer Center investigator, was described recently in the journal Nature.1

The trial included patients with melanoma or cancers of the lung, kidney, colon, gastrointestinal tract, or head and neck whose tumors were evaluated for PD-L1 expression by a novel assay. PD-L1 is a protein expressed by many tumor types that can render the cancer invulnerable to immune system attack. Patients were treated with the MPDL3280A, an investigational anti-PDL1 antibody drug.
The trial differed from other immune therapy trials in that it incorporated serial biopsies of patients before and during treatment to identify a tumor profile that is predictive of response, said the paper’s first author, Roy Herbst, MD, PhD, Ensign Professor of Medicine and Pharmacology, and Chief of Medical Oncology in the Yale Cancer Center and Smilow Cancer Hospital at Yale New Haven.

“What we found surprised us,” Dr. Herbst said. “We knew that the expression of PD-L1 in tumor cells is critical in blocking the immune system, we were intrigued to find that the expression of PD-L1 in non-tumor cells (macrophages) was even more predictive of response to the drug. Furthermore through our serial biopsies we learned mechanistically the characteristics of both functional and non-functional immune responses.  Now we have a baseline for how patients respond and don’t respond, and we can begin learning how to use combination therapies to affect the immune response cycle.”

Study Results

Of the 175 patients enrolled, 21% showed partial or complete response, with some being rapid and durable.  Across all tumor types, 46% of patients with high PD-L1 expression on non-tumor cells showed a partial or complete response. Also notable was the finding that smokers responded better to the drug than nonsmokers. This could provide insight into how smokers and nonsmokers respond differently to drugs.

Dr. Herbst said the drug is in phase II and III trials at Yale.

Also published in the same issue of Nature were additional findings from this same trial including advanced bladder cancer patients who did not respond to other treatments.2

This expansion arm study was co-authored by Thomas Powles, MD, of Queen Mary University Hospital of London with Daniel P. Petrylak, MD, Professor of Medicine and Urology at Yale Cancer Center, and Joseph Paul Eder, MD, Professor of Medicine at Yale Cancer Center. Dr. Petrylak had presented the findings earlier this year at ASCO’s Annual Meeting. ■

Disclosure: Disclosure information for the study authors is available in the online version of the paper at Nature.com.

References

1. Herbst R, Soria JC, Kowanetz M, et al: Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515:563-567, 2014.

2. Powles T, Eder JP, Fine GD, et al: MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515:558-562, 2014.



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