New study offers hope for a rare and devastating eye cancer
After more than a decade studying a rare eye cancer that produces some of the hardest-to-fight tumors, researchers from University of Pittsburgh Medical Center have found a treatment that works on some patients and, more importantly, a tool that can predict when it is likely to succeed.
The work, published in Nature Communications, is being validated in a clinical trial involving at least 30 patients. It could pave the way for similar methods designed to overcome one of the enduring frustrations of cancer care.
Because tumors differ, not only between patients but even inside the same patient, a treatment that works on one mass may fail on another, even when both are of the same cancer type.
The researchers in Pittsburgh tackled this problem in uveal melanoma, an eye cancer that afflicts only 5 people in a million, but that half the time spreads to other parts of the body, often the liver. The median survival once uveal melanoma has spread has been less than seven months, according to a 2018 study in the journal JAMA Ophthalmology.
“We chose this because it was one of the only cancers that 10 years ago when we started, there was nothing approved for it,” said Udai Kammula, who led the study and directs the Solid Tumor Cell Therapy Program at UPMC Hillman Cancer Center in Pittsburgh.
Scientists had long speculated that the reason uveal melanoma is so tough to fight is that something helps the tumor keep out T cells, a key part of the body’s immune system that develops in bone marrow. However, previous studies by Kammula and his colleagues showed that uveal melanoma tumors actually have T cells inside, and they are turned on.
The problem? The cells lie dormant instead of multiplying and reaching numbers large enough to overwhelm the tumor.
The culprit appears to reside somewhere inside the tumor’s ecosystem of cells, molecules and blood vessels, known formally as the tumor’s “microenvironment.” Kammula compares this ecosystem to the infrastructure that supports a city. Something in that infrastructure helps protect uveal melanoma tumors by preventing the critical T cells from multiplying.
“Ultimately, if we’re going to get rid of cancer, we have to get rid of this infrastructure,” Kammula said.
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A tool for predicting success
He and his colleagues have had some success using a treatment known as adoptive cell therapy, which was developed in the 1980s by Steven Rosenberg at the National Institutes of Health.
The treatment involves removing the T cells from the tumor, where they have been unable to proliferate. Scientists then take those T cells and grow them outside the body in a lab dish. They treat patients with chemotherapy to kill off the last of their old immune systems. Finally, they reinfuse the lab-grown T cells into the patient’s blood stream and the cells, now in much greater numbers, go on to attack the tumor.
In this treatment, the T cells are often referred to as tumor-infiltrating leukocytes, or TILs.
Kammula said his team has found that tumors shrink partially or completely in about 35 percent of patients who receive the treatment. But they wanted to know why it doesn’t work in the majority of cases, and whether there might be some way to predict beforehand when it will succeed.
To find out, the researchers analyzed samples from 100 different uveal melanoma tumors that had spread to different parts of the body in 84 patients, seeking to examine all of the tumors’ genetic material.
“We basically put the tumor biopsy in a blender that had the stroma [supportive tissue], the blood vessels, the immune cells, the tumor cells. It had everything,” Kammula said, explaining that they then analyzed all of the tumor’s genetic material.
They found 2,394 genes that could have helped make the tumor susceptible to treatment, some of them genes that experts would regard as “the usual suspects” and others that were unexpected. Using this long list of genes, the scientists searched for characteristics that they shared.
The genes were predominantly involved in helping the body defend itself against viruses, bacteria and other foreign invaders by removing the invaders and helping tissue heal. Kammula and the study’s lead author, Shravan Leonard-Murali, a postdoctoral fellow in the lab, used the different activity levels of these genes to develop a clinical tool.
The tool, known as a biomarker, assigns a score to a uveal melanoma tumor based on the likelihood that it will respond well to the treatment ― removing T cells, growing them outside the body, then reinfusing them.
So far, Kammula said, the biomarker has been “extremely good,” in predicting when the treatment will be effective, though he added, “these findings will need confirmation in the current ongoing clinical trial.”
“I thought it was somewhat of a tour de force, honestly,” said Eric Tran, an associate member of the Earle A. Chiles Research Institute, a division of Providence Cancer Institute in Portland, Ore. Tran did not participate in the study.
He said that while it will be important to validate these results, “I was certainly encouraged by their studies. And from my perspective, I wonder if that sort of strategy can be deployed in other cancers.”
Ryan J. Sullivan, an oncologist at Massachusetts General Hospital and associate professor at Harvard Medical School who was not involved in the study, called the team’s work “timely” and said “it is even more significant that they appear to have a [tool] that appears to predict which patients will benefit.”
The team at UPMC is already investigating possible wider application of both the treatment and the biomarker in a second clinical trial that involves a dozen different cancers.
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