Protein May Identify Which Melanoma Patients Most Likely to Benefit From Immunotherapy

It now turns out that Bim, a downstream signaling molecule of the PD-1 pathway, may hold the clue to which patients may be successful on immunotherapy for metastatic melanoma. 

Investigators at the Mayo Clinic published a study in JCI Insight suggesting that Bim plays a crucial role in both T-cell activation and apoptosis as regulated by PD-1 and PD-L1 interactions in effector CD8⁺ T cells. They report that measuring Bim levels in circulating T cells of patients with cancer may provide a less invasive approach to predicting and monitoring responses to anti–PD-1 therapy.

Lead study author Roxana Dronca, MD, who is with the Mayo Clinic, Rochester, Minn., explains that immune checkpoint therapy with PD-1 blockade has emerged as an effective treatment for many advanced cancers, but only a fraction of patients achieve durable responses to immunotherapy. In addition, until now, there has been no way of predicting which patients are most likely to benefit from immune checkpoint therapy.

Dr. Dronca and her colleagues collected peripheral blood from patients at the initiation immunotherapy (baseline) and again at the time of first radiographic tumor assessment (12 weeks). They collected additional samples at each subsequent radiographic tumor evaluation for patients continuing on immunotherapy. This study included 29 patients with metastatic melanoma and 20 healthy donors.

The researchers found a higher frequency of T cells that expressed the protein Bim among patients who responded to immunotherapy for metastatic melanoma compared to patients who were treated with immunotherapy, but whose disease had progressed. In previous studies, the team had demonstrated that Bim is a downstream signaling molecule in the PD-1 signaling pathway.  The researchers had also found that levels of Bim reflect the degree of PD-1 interaction with its ligand PD-L1.

“We hypothesized that the increased frequency of CD8⁺PD-1⁺Bim⁺ T cells in patients who respond to immunotherapy reflects an increased number of target T cells for PD-1 blockade with pembrolizumab [Keytruda], which may explain the positive clinical outcomes in these patients,” said senior study author Haidong Dong, MD, PhD, who is with the Mayo Clinic, in a news release.

The current study demonstrated the percentages of Bim⁺ cells among PD-1⁺CD11a^hiCD8⁺ T cells were 2.4-fold higher in the peripheral blood of patients with metastatic melanoma than in healthy donors. Dr. Dronca said a great advantage of this approach lies in the ease of serial peripheral blood testing compared to repeated invasive tissue biopsies.   

The researchers are currently validating these results in a larger prospective cohort of patients with metastatic melanoma and in patients with lung cancer using multiple serial peripheral blood samples and standardized tumor assessment.

“The potential discovery of a way to predict a patient’s response to pembrolizumab would help inform clinical decision making,” said Dr. Dronca. “It would not only help clinicians identify which patients would be most likely to benefit from the drug, but also prevent patients not likely to respond to the therapy from being exposed to unnecessary toxicities and costs.”