PREDICTIVE FACTORS OF IMMUNOTHERAPY RESPONSE

Matching the size of a tumor to the body’s immune response could help physicians tailor immunotherapy treatments for patients with metastatic melanoma. Researchers found that patients who didn’t respond to treatment had an imbalance between the size of their tumor and how exhausted their immune cells were. The study, published by Huang et al in Nature, provides clues that could help identify patients whose tumors aren’t responding to certain immunotherapy drugs sooner, and possibly explain why.

Some immunotherapy drugs, such as pembrolizumab (Keytruda), work by blocking molecules on the surface of immune cells or tumor cells that act as a set of “brakes” on the immune system. Blocking these molecules (including PD-1 [programmed cell death protein 1], which pembrolizumab targets) releases these brakes, allowing immune T cells to attack cancer cells.  

“We found that the size of the pretreatment tumor determined how strong a T-cell response was needed in response to the drug to shrink a patient's tumor,” said E. John Wherry, PhD, from the University of Pennsylvania, who led the study. He explained, “the bigger the tumor, the more T-cell ‘reinvigoration’ was needed by the drug.”

Study Findings

Over half of all patients treated with immunotherapy for melanoma that has spread don’t see their tumors respond for the long term. The study team tested the blood of 47 patients with late-stage melanoma, before and after treatment with pembrolizumab. They identified changes in circulating T cells and measured whether exhausted T cells had been reinvigorated by the drug.

The team compared this finding with the size of the tumor at the start of treatment. They found that patients whose tumor didn’t respond had an imbalance between the intensity of T-cell reinvigoration and the size of their tumors at the start of treatment.

“This research helps answer some of the critical questions around why some patients don't respond to anti–PD-1 inhibitors and why some do,” said coauthor Jedd Wolchok, MD, PhD, from Memorial Sloan Kettering Cancer Center.

Dr. Wolchok believes the study is important because it identified three different ways in which PD-1–blocking drugs can fail:

• If the drug doesn’t reinvigorate exhausted T cells
• If an immune response is simply not strong enough for the size of the tumor, or
• If the drug is off-target.

Tim Elliott, PhD, FBS, FMedSci, Professor of Experimental Oncology at Cancer Research UK’s Southampton Centre, called the study “interesting” and said it “suggests some possible ways of improving immunotherapy treatments.… The kind of scoring system that this study has developed could be used early on in immunotherapy treatment to predict how likely it is to work,” he added.

When the team looked back through the data, they could predict treatment failure 3 to 6 weeks into treatment—6 weeks earlier than in previous clinical trials. “This is important, as it could pinpoint quickly those in whom the treatment isn’t working, so doctors can decide whether another drug needs to be used,” said Dr. Elliott.

But Edd James, PhD, Associate Professor of Cancer Immunology at Cancer Research UK’s Southampton Centre, pointed out that the predictive power generated by this study only came after treatment. “Obviously, it would be better to be able to predict a patient’s response to a treatment before it begins, but the information gained from this study may be useful in identifying such a marker in the future. How these findings can be applied to other cancer types now needs to be investigated,” he added.