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Frequency of Certain Immune Cells in Blood May Predict Response to Pembrolizumab in Metastatic Melanoma

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Key Points

  • Researchers found that patients who experienced clinical benefit, as measured by RECIST 1.1 complete response, partial response, or stable disease after four cycles of treatment with pembrolizumab, had a higher frequency of CD8+PD-1+Bim+ T cells in the first blood sample at 12 weeks than patients with radiographic disease progression.
  • The frequencies of these cells decreased significantly after the first 12 weeks of treatment in the blood of responders compared with nonresponders.
  • The increased frequency of CD8+PD-1+Bim+ T cells in responders may reflect an increased number of target T cells for PD-1 blockade with pembrolizumab, which may explain the positive clinical outcomes in these patients.

Among patients with metastatic melanoma treated with the immunotherapy drug pembrolizumab (Keytruda), those whose cancer responded to the treatment had a higher frequency of T cells that were positive for the proteins CD8, PD-1, and Bim (CD8+PD-1+Bim+ T cells) in blood samples taken immediately before starting pembrolizumab than those who had disease progression, according to data presented at the CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference (Abstract A007), held September 16–19 in New York.

Pembrolizumab, which targets the protein programmed cell death protein 1 (PD-1), was approved by the U.S. Food and Drug Administration for treating metastatic melanoma in September 2014. Some patients with metastatic melanoma have remarkable responses to pembrolizumab, whereas others do not respond at all, according to Roxana S. Dronca, MD, Medical Oncology Consultant and Assistant Professor of Oncology at the Mayo Clinic.

Biomarker for Immunotherapeutic Success

“The discovery of a biomarker predictive of response to pembrolizumab would inform clinical decision-making,” said Dr. Dronca. “Not only would it help to identify those patients with metastatic melanoma [and possibly other malignancies] who are most likely to benefit from the immunotherapy, but it would also potentially help to identify those patients who are acquiring resistance to the agent during the course of treatment, thereby exposing fewer patients to inadequate treatments and their associated toxicities and costs.”

“Our results indicate that measuring the frequency of CD8+PD-1+Bim+ T cells in the peripheral blood of patients with metastatic melanoma may provide a way to predict or monitor responses to pembrolizumab,” she added. “A great advantage of the approach lies in the ease of serial peripheral blood testing compared with repeated invasive tissue biopsies. We are currently validating these results in a larger prospective cohort of patients with metastatic melanoma and lung cancer with multiple serial peripheral blood samples and standardized tumor assessment.”

Study Details

Dr. Dronca and colleagues analyzed a series of blood samples from 38 patients with metastatic melanoma using flow cytometry. For each patient, a blood sample was obtained immediately before starting pembrolizumab treatment. For 18 of the patients, further samples were obtained every 12 weeks at the time of tumor evaluation by radiographic imaging.

The researchers found that patients who experienced clinical benefit, as measured by RECIST 1.1 complete response, partial response, or stable disease after four cycles of treatment, had a higher frequency of CD8+PD-1+Bim+ T cells in the first blood sample at 12 weeks compared with patients with radiographic disease progression. The frequencies of these cells decreased significantly after the first 12 weeks of treatment in the blood of responders compared with nonresponders.

“We previously showed that Bim is a downstream signaling molecule in the PD-1 signaling pathway and that levels of Bim reflect the degree of PD-1 interaction with its ligand PD-L1,” said Haidong Dong, MD, PhD, Associate Professor of Immunology at the Mayo Clinic. “We hypothesize that the increased frequency of CD8+PD-1+Bim+ T cells in responders reflects an increased number of target T cells for PD-1 blockade with pembrolizumab, which may explain the positive clinical outcomes in these patients.”

According to Dr. Dronca, limitations of the study include the relatively small cohort of patients and the fact that only one version of anti–PD-1 antibody, pembrolizumab, was evaluated.

This study was supported by the National Institutes of Health and the Cancer Research Institute. Dr. Dronca was the Mayo Clinic Principal Investigator on the pembrolizumab Expanded Access Program (EAP), on which most patients on this study were treated. With the approval of the sponsor, Merck Sharp & Dohme Corp., the patients were offered participation in a distinct biomarker substudy, which was designed and led by the Mayo Clinic. Dr. Dong is an inventor of technology related to this research. 

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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