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FINDING CURES TOGETHER<sup>SM</sup>

Pembrolizumab Treatment Causes Immune Cells in Blood to Gain Characteristics of Reinvigoration

9/16/2015

​NEW YORK — Treating patients with metastatic melanoma with the immunotherapy drug pembrolizumab (Keytruda) caused immune cells called CD8-positive (CD8+) T cells in the patient's blood to express markers of reinvigoration, according to data presented at the CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference, held Sept. 16–19.

Alexander Huang, MDPembrolizumab, which was approved by the U.S. Food and Drug Administration (FDA) for treating metastatic melanoma in September 2014, targets the protein PD-1. Preclinical mouse studies have shown that certain CD8+ T cells have very high levels of PD-1, which acts as a brake on the cells by providing an inhibitory signal, and that blocking PD-1 with pembrolizumab takes the brake off, helping reinvigorate the CD8+ T cells, according to Alexander Huang, MD, a clinical fellow in the Division of Hematology/Oncology at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia.

"Despite our understanding of how pembrolizumab-type drugs work in mice, we lack precise information about its effects on the human immune system," Huang said. "Our goal was to examine immunologic changes that occurred when patients with melanoma were treated with pembrolizumab in an easily accessible body tissue, the blood.

"We were excited to see clear changes in the functional characteristics of CD8+ T cells indicative of reinvigoration," he added. "These findings give us more insights into how pembrolizumab might be working in patients and also could eventually form the basis of a noninvasive biomarker test to predict who might and who might not respond to the immunotherapy."

Huang and colleagues analyzed a series of blood samples from 39 patients with metastatic melanoma using 16-parameter flow cytometry. For each patient, the first blood sample was obtained right before pembrolizumab treatment was initiated and then samples were obtained every three weeks right before the patient received the next pembrolizumab infusion, until 12 weeks after starting pembrolizumab treatment.

The researchers focused on changes in levels of proteins characteristic of reinvigoration in CD8+ T cells positive for PD-1 (CD8+PD-1+ T cells). Increased levels of the protein granzyme B, which is a marker of the killing capacity of a CD8+ T cell, and the protein Ki67, which is a marker of cell proliferation, were detected in CD8+PD-1+ T cells in blood samples obtained after pembrolizumab treatment had started.

In addition, the frequency of CD8+ T cells positive for granzyme B was greater in blood samples obtained after pembrolizumab treatment had started compared with blood samples obtained before pembrolizumab treatment initiation.

"Our next steps are to combine the immunologic data we have generated for each patient with the clinical data, to see if immunologic response is linked to clinical response, in particular, objective response and progression-free survival," said Huang. "This will be key to determining whether our data could eventually form the basis of a noninvasive biomarker test predictive of response to pembrolizumab."

According to Huang, the limitations of the study include a lack of paired tumor samples to determine the effect of pembrolizumab in the tumor. It is also unclear at this point whether these reinvigorated T cell subsets are actually targeting the tumor or are just a marker of immunologic response, he added.

Huang is mentored by E. John Wherry, PhD, director of the Institute for Immunology at the Perelman School of Medicine.

This study was supported by funds from the National Institutes of Health and Merck. Huang declares no conflicts of interest.

Further information about melanoma can be found here and further information about the FDA approval of pembrolizumab can be found here.

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