New research offers hope for rare, devastating eye cancer

Tumors vary between patients and even within the same patient, so a treatment that works for one tumor may not work for another, even if both tumors have the same type of cancer.

Researchers in Pittsburgh tackled this problem with uveal melanoma, an eye cancer that affects only five in a million people, but is half as likely to spread to other parts of the body, often the liver. To do. According to one researcher, once uveal melanoma spreads, the median survival time is less than 7 months. 2018 survey Published in JAMA Ophthalmology.

“We chose this because it was one of the few cancers for which nothing had been approved 10 years ago when this study started,” said UPMC Hillman, who led the study. said Uday Kanmura, who directs the Solid Tumor Cell Therapy Program at the Cancer Center. Pittsburgh.

Scientists believe that the reason uveal melanoma is so difficult to fight is because something helps the tumor block T cells, an important part of the body's immune system, that develop in the bone marrow. I've been guessing for a long time. However, a previous study by Kammula et al. showed that there are indeed His T cells inside uveal melanoma tumors and that the T cells are activated.

problem? The cells do not proliferate and remain dormant, without reaching numbers large enough to overwhelm the tumor.

The culprit appears to be somewhere within the tumor's ecosystem of cells, molecules, and blood vessels, formally known as the tumor's “microenvironment.” Mr. Kanmura likens this ecosystem to the infrastructure that supports a city. Something within that infrastructure helps protect uveal melanoma tumors by preventing important T cell proliferation.

“Ultimately, if we want to eradicate cancer, we have to eliminate this infrastructure,” says Kanmura.

Tools to predict success

He and his colleagues have had some success using a treatment known as adoptive cell therapy. developed It was studied by Steven Rosenberg at the National Institutes of Health in the 1980s.

Treatment involves removing T cells from the tumor that are no longer able to proliferate. Scientists then remove those T cells and culture them in a laboratory dish outside the body. They treat patients with chemotherapy to destroy the last cells of the old immune system. Finally, when her lab-grown T cells are reinfused into the patient's bloodstream, the much larger number of cells begin attacking the tumor.

In this treatment, T cells are often referred to as tumor-infiltrating leukocytes (TILs).

Kammula said his team found that tumors partially or completely shrank in about 35% of treated patients. But they wanted to know why it doesn't work most of the time, and whether there's a way to predict in advance when it will succeed.

To find out, researchers analyzed samples of 100 different uveal melanomas that had spread to different parts of the body from 84 patients, trying to examine all of the tumors' genetic material.

“We basically put the tumor biopsy in a blender that contains the stroma. [supportive tissue], blood vessels, immune cells, tumor cells. Everything was there,” said Kanmura, explaining that he then analyzed all of the tumor's genetic material.

They discovered 2,394 genes that could help make tumors more amenable to treatment. Some of the genes were considered “common suspects” by experts, while others were unexpected. Using this long list of genes, scientists searched for characteristics they shared.

Genes are primarily involved in protecting the body from viruses, bacteria, and other foreign invaders by eliminating invaders and helping tissues heal. Kammula and the study's lead author, Shravan Leonard-Murali, a postdoctoral fellow in his lab, used different activity levels of these genes to develop a clinical tool.

This tool, known as a biomarker, assigns a score to uveal melanoma tumors based on their likelihood of responding well to treatment, which involves removing T cells, growing them outside the body, and reinjecting them.

Kammura said that so far, the biomarkers have been “very good” at predicting when treatments will be effective, but that “these findings are not supported by ongoing clinical trials. We need to confirm,” he added.

“Honestly, I thought this was some sort of masterstroke,” said Eric Tran, an associate member of the Earl A. Chiles Research Institute, a division of Providence Cancer Institute in Portland, Oregon. Mr. Tran did not participate in this study.”

Although it is important to verify these results, he said: From my perspective, I think such a strategy could be applied to other cancers as well. ”

Ryan J. Sullivan, an oncologist at Massachusetts General Hospital and an associate professor at Harvard Medical School who was not involved in the study, called the team's work “timely.” The team [tool] It seems to predict which patients will benefit. ”

The UPMC team is already investigating the potential broader applications of both the treatment and the biomarker in a second clinical trial in more than a dozen different cancers.