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Study: Immune-cell numbers predict response to combination immunotherapy in melanoma

A nestudy indicates w that 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.

The findings, by researchers from University of California, San Francisco (UCSF), joined by physicians from UCSF Health, provide a novel predictive biomarker to identify patients who are most likely to respond well to a combination of immunotherapy drugs known as checkpoint inhibitors, and to protect those who won't respond from potentially adverse side effects of combination treatment.

Published online in Journal of Clinical Investigation (JCI) Insight, the study describes an assay that measures the abundance of immune cells that infiltrate melanoma tumors, reveals that patients who had lower levels of immune cells called T cells within their tumors benefitted most from two immunotherapy drugs in tandem, and that the measurements could allow clinicians to predict patients who would most benefit from combination immunotherapy.

"Combination immunotherapy is super-expensive and very toxic," noted Adil Daud, director of Melanoma Clinical Research at the UCSF Helen Diller Family Comprehensive Cancer Center and senior author of the 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."

T cells patrol our body for signs of infection or other diseases, recognizing culprit cells via telltale proteins on their membranes. Our body's normal cells carry certain proteins on their coats that act as "checkpoints," making them invisible to T cells.

It turns out many cancer cells adopt the same trick by cloaking themselves with one of those same proteins, called PD-L1, causing T cells, which carry a complementary protein called PD-1, to mistake them as harmless.

PD-L1 thus acts like a fake identification card, allowing cancer cells to live and multiply without being detected by the immune system.

Immunotherapy drugs called checkpoint inhibitors work to uncloak cancer cells by throwing a wrench in their disappearing act: these drugs block PD-L1 or PD-1, allowing T cells to recognize cancer cells as detrimental and kill them.

There are four checkpoint inhibitors approved by the U.S. Food and Drug Administration (FDA): ipilimumab, nivolumab, pembrolizumab and atezolizumab.

These drugs have been very successful in some cases, but they help only about 20 to 40 percent of patients. One of the ways doctors have improved their efficacy is by using multiple drugs at the same time. But the toxic side effects of these drugs can add up.

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 nivolumab.

These cells had high levels of both PD-1 and CTLA-4, another well-known immune checkpoint protein, which is targeted by immunotherapy drugs such as ipilimumab.

In the new study, 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, they 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," Daud was quoted as explaining in a news release from UCSF. "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."

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