Whether a melanoma patient will better respond to a single immunotherapy drug or two in combination depends on the abundance of certain white blood cells within their tumors (JCI Insight 2017;2(14):e93433). The findings provide a novel predictive biomarker to identify patients most likely to respond well to a combination of checkpoint inhibitors-and to protect those who won't respond from potentially adverse side effects of combination treatment.
"Combination immunotherapy is super-expensive and very toxic," said Adil Daud, MD, Director of Melanoma Clinical Research at the UCSF Helen Diller Family Comprehensive Cancer Center and senior author of the new study. "You're putting patients at a lot of extra risk if they don't need it, and you can adjust for that risk by knowing in advance who can benefit."
The study describes an assay that measures the abundance of immune cells that infiltrate melanoma tumors. The findings revealed that patients who had lower levels of T cells within their tumors benefitted most from two immunotherapy drugs in tandem. The measurements could provide clinicians with a means to predict patients who would most benefit from combination immunotherapy, the authors said.
"This is clinical research at its best," said UCSF's Katy Tsai, MD, a medical oncologist and lead author of the report. "We have identified something as a predictive biomarker in melanoma, and we're hoping to validate it in other tumor types as well."
In a previous study, Daud and colleagues homed in on what makes some individuals respond well to checkpoint inhibitors that block PD-1, finding that patients whose tumors harbored high populations of T cells known as partially exhausted CD8+ cells responded well to treatment with nivolumab. Intriguingly, these cells had high levels of both PD-1 and CTLA-4, which is targeted by immunotherapy drugs such as ipilimumab.
In the new report, the researchers studied tumor samples from 102 melanoma patients, extracted T cells from the samples, and used cell sorting equipment to estimate the relative proportion of immune cells in the samples. The patients then underwent treatment either with only nivolumab, or with both nivolumab and ipilimumab. Finally, the researchers ran statistical tests to discover correlations among patient demographics, immune cell populations, and drug responses.
The team found that patients with high levels of exhausted T cells benefitted significantly from treatment with only a single drug. On the other hand, women and those who had liver metastases had lower number of immune cells patrolling their tumors, and responded well to the combination treatment.
"You're pushing on two different gas pedals-PD-1 and CTLA-4," said Daud, a member of UCSF's Parker Institute for Cancer Immunotherapy. "If you're one of those patients with a low number of exhausted T cells, you have a better likelihood of benefitting from both drugs."
The team will next explore why women have fewer T cells-and in turn, a diminished response to single immunotherapy drugs-and whether these factors could be related to age, estrogen levels, or pregnancy.
The cell-counting assay developed by the researchers is time- and resource-intensive, especially because it requires fresh tumor samples and elaborate cell-sorting machines, and it is only available at UCSF. To get around these limitations, the team is now working on a more broadly applicable test that would measure the levels of PD-1 and CTLA-4 proteins-both present on T cells-in tumors and use that as a surrogate marker for immune cell count.
"In 6 months to a year, we should have an assay that works using fairly common, less-expensive techniques," said Daud. "And it could work on fresh, frozen, or paraffin-embedded tumor blocks." With this easier test, the researchers hope to expand their study of immune cell infiltration to other cancer types and to bigger groups of patients, both from different areas of the U.S. and internationally.