Predicting checkpoint blocker response

BOSTON—Scientists at Dana-Farber/Brigham and Women’s Cancer Center (DF/BWCC) have identified biomarkers in melanoma that could help improve immunotherapy treatments to maximize the benefits for patients while reducing the likelihood of severe side effects, giving a leg up to personalized medicine approaches.

These biomarkers still need to be validated in future clinical trials to fully assess their utility, but findings reported recently in Science Translational Medicine suggest that the current practice of combining two different types of immune checkpoint blocker drugs in advanced melanoma patients may be the best course in some instances, but not in others. This is because the immune makeup of some melanoma tumors may cause them to be resistant to one class of checkpoint inhibitors.

“By looking at how melanoma is avoiding immune detection, we may be able to identify patients who may do just as well with a single agent, with no loss of efficacy but improved tolerability,” said Dr. Scott Rodig, an oncologic pathologist at DF/BWCC and first author on the report. The study revealed that patients whose tumors are deficient in a protein needed for the immune system to recognize cancer cells are unlikely to benefit from ipilimumab, an immunotherapy drug that blocks the CTLA-4 checkpoint but also has potentially severe side effects. Therefore, identifying such patients with a biomarker test prior to treatment could spare them the adverse effects.

As DF/BWCC notes, the outlook for patients with advanced melanoma has dramatically improved in recent years because of immune checkpoint inhibitor therapies that can mobilize the immune system to attack cancer. Typically, patients with advanced melanoma receive a combination of two different checkpoint inhibitor types: one (such as ipilimumab) targets the CTLA-4 checkpoint while the other, including nivolumab and pembrolizumab, targets the PD-1 checkpoint.

Patients with advanced melanoma tend to have better outcomes when they receive drugs that block both the CTLA-4 checkpoint and the PD-1 or PD-L1 checkpoints, said Dr. F. Stephen Hodi, director of the Melanoma Disease Center at Dana-Farber and senior author of the report. When treated with the combination, more than 50 percent of patients will have tumor shrinkage, and some of the responses will be quite prolonged, he said. But this benefit can come at a steep cost—roughly half of patients will have severe side effects, such as inflammation of the gut or of the liver and pancreas.

The new study was inspired by recent research by Dr. Margaret Shipp at Dana-Farber that showed Hodgkin lymphomas frequently avoid immune detection by eliminating their MHC class I proteins. MHC class I proteins are found on the surface of most cells in the body. Their function is to bind fragments of foreign proteins, including those stemming from cancer cells, and present them to T cells, which then mount a mass attack on the invader. But if cancer manages to somehow dial down the abundance of MHC class I proteins, the immune system won’t recognize the cancer as foreign and respond against it. In Hodgkin lymphoma, the tumor cells accomplish this feat by deleting a key gene required for expression of the MHC class I proteins.

Running on the hypothesis that something similar might be at play in melanoma, the authors of the study used data from two clinical trials of immunotherapy for advanced melanoma that included measurements of MHC class I proteins and other immune cells and immune regulators. They found that partial or complete loss of MHC class I proteins was common in untreated melanoma patients, and those patients had poor responses to treatment with ipilimumab, the drug that blocks the CTLA-4 checkpoint.

“CTLA-4 is exquisitely sensitive to even partial loss of these MHC class I proteins,” said Rodig. It results in the melanoma being highly resistant to ipilimumab treatment and the cancer continuing to grow, because even though the immunotherapy drug was releasing the CTLA-4 brake on the immune system, the melanoma cells weren’t recognized due to the lack of MHC class I proteins to “present” the cancer fragments to the T cells. These findings may explain why most melanoma patients don’t respond to single-agent ipilimumab.

However, the researchers also observed that the deficiency of MHC class 1 proteins did not make melanoma tumors resistant to the other type of checkpoint inhibitor, drugs like nivolumab, a PD-1 inhibitor. That is because responses to those drugs activate an immune substance known as interferon-gamma, which in turn activates both MHC class I-dependent and MHC class I-independent immune pathways and thereby promotes anti-tumor activity when MHC class I levels are reduced by the tumor. Indeed, the data from the clinical trials showed that patients whose tumors had higher pre-treatment levels of interferon-gamma had better outcomes when treated with nivolumab or a combination of nivolumab and ipilimumab, but not ipilimumab alone.

These results, the authors conclude, reveal that the clinical efficacy of anti-CTLA-4 drugs like ipilimumab is “dependent on robust, pre-existing expression of MHC class I proteins by tumor cells.” By contrast, the efficacy of anti-PD1 checkpoint blockers like nivolumab depends on “pre-existing interferon-gamma-mediated inflammation within the tumor microenvironment.” Combining the two types of checkpoint blockers “provides a further immune stimulus over individual therapies alone and, in addition, overcomes the limitations of each,” they noted.

The researchers commented that in the future, “it would be ideal to have clinical trials in which treatment options are determined in accordance with the results of tissue-based biomarker studies.”