Scientists at Dana-Farber/Brigham and Women’s Cancer Center (DF/BWCC) have identified biomarkers in melanoma that could help tailor immunotherapy treatments to maximize the benefits for patients while reducing the likelihood of severe side effects.
“By looking at how melanoma is avoiding immune detection, we may be able to identify patients who might do just as well with a single agent, with no loss of efficacy, but improved tolerability,” says Scott Rodig, MD, PhD, an oncologic pathologist at DF/BWCC and first author on the report. F. Stephen Hodi, MD, director of the Melanoma Treatment Center at Dana-Farber, is the senior author.
While the utility of these biomarkers needs to be validated in clinical trials, the findings reported 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.
For example, the study revealed that some patients, whose tumors are deficient in MHC class I, 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 which has potentially severe side effects. A biomarker test potentially could identify such patients in advance.
In general, patients with advanced melanoma have better outcomes when they receive drugs that block both the CTLA-4 checkpoint and the PD-1 or PD-L1 checkpoints. Hodi says that more than 50 percent of patients receiving the combination will have tumor shrinkage and some of the responses will be quite prolonged. But this benefit can come at a cost—around 50 percent of patients treated with two types of checkpoint blockers will have severe side effects, such as diarrhea, rash, or inflammation of the liver and pancreas.
The new study was inspired by recent research led by Margaret Shipp, MD, chief of the Division of Hematologic Neoplasia at Dana-Farber. The research showed that Hodgkin lymphomas frequently avoid immune detection by eliminating their MHC class I proteins, which are found on most cells and are critical to the detection of cancer cells.
Speculating that something similar might occur in melanoma, the authors of the new study found that partial or complete loss of MHC class I proteins was common in untreated melanoma patients. Those patients had poor responses to treatment with ipilimumab—the drug that blocks the CTLA-4 checkpoint—because without MHC class I, the immune system didn’t recognize the melanoma cells as foreign.
“CTLA-4 is exquisitely sensitive to even partial loss of these MHC class I proteins,” says Rodig.
The result was the melanoma was highly resistant to ipilimumab treatment and the cancer continued to grow. These findings may explain why most melanoma patients don’t respond to single-agent ipilimumab.
However, the researchers observed the effectiveness of the other type of checkpoint inhibitor—drugs like nivolumab, a PD-1 inhibitor—wasn’t impaired by the loss of MHC class I in melanoma cells. 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 even when MHC class I levels are reduced by the tumor.
Indeed, the data from the clinical trials show 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.
Going forward, the researchers say, it would be ideal to have clinical trials “in which treatment options are determined in accordance with the results of tissue-based biomarker studies.”