It’s a paradox: The immune system’s cancer-fighting T cells target and infiltrate tumors, but often they stop working and let the cancer grow.
Trained as a surgeon, Robert Eil, M.D., had minimal background in immunology. That didn’t stop him from making a pivotal observation about the paradox during his research fellowship at the National Cancer Institute. Eil took note of differences among T cells in the number and type of specialized proteins that transport potassium into and out of the cell.
Follow-up experiments revealed that potassium concentrations soar within tumor tissue as dead and dying cancer cells spill their contents. Eil and colleagues discovered that the elevated potassium levels can halt the cancer-fighting activity of T cells. “If we increased the concentration of potassium in the media enough, it almost completely shut off the cytokine production of T cells,” he says. “The T cells are alive, but they don’t work, they are not making cytokine.”
The findings pointed the way to new strategies for cancer immunotherapy — and earned Eil first authorship of a paper in Nature. “I took that ball and ran with it as far as I could. And I’m still running with it,” says the assistant professor of surgery in the OHSU School of Medicine.
Neither cancer nor surgery were on his mind when he began medical school at OHSU. But oncology soon grabbed his interest as he considered the field’s rapidly advancing science and ability to quickly translate discoveries into new therapies for patients. He was ready to commit to medical oncology — until his first operating room experience during a surgery rotation took him in another direction.
“I just absolutely loved it,” he says. “The first operation I saw as a medical student was a liver resection for cancer. It’s a massively invasive procedure. It was just such a powerful thing to see the patient leaving the hospital cancer-free.”
Following his surgery residency at OHSU, Eil completed a clinical fellowship in surgical oncology at Memorial Sloan Kettering Cancer Center in New York.
‘Patients are great motivators. They make our science more goal-directed, more focused.’
At OHSU, he specializes in caring for patients with cancers of the liver and pancreas, which are among the most challenging and deadly.
“What keeps me coming back is the patients,” he says. “You develop a close relationship over a very short period of time like no one else does in their life. You get to take care of them through the recovery and be a part of their care for years ongoing. For most highly trained subspecialists that is not the case.”
In the lab, Eil and colleagues are pursuing a number of new treatment strategies based on his T cell findings. Their leading idea is to genetically alter T cells so that they can remain active in the high-potassium microenvironment of a tumor. Engineered T cells are already being used in cancer treatment. In CAR T cell therapy, for example, T cells are collected from the patient’s blood and then genetically modified to make a chimeric antigen receptor, or CAR. This protein binds to specific proteins on the surface of cancer cells. That equips the modified T cells to target and kill the cancer cells.
T cells can also be modified with upgraded genes for ion transporter proteins that can more effectively move excess potassium out of the cell or prevent excess from entering. “We can introduce synthetic genes or overexpress endogenous genes to augment their function,” Eil says.
In mouse experiments, Eil and colleagues have shown that the approach shrinks tumors and boosts survival. They have also started testing the approach using human T cells collected from the blood or from tumors of patients with cancer. The researchers are doing experiments to pin down the most promising ion transporter gene candidates and T cell types. The in vitro results with human T cells have been promising, Eil says.
“Not every transporter works the exact same way in human versus mouse T cells. There are wrinkles to iron out,” he says. “But the proof of principle is definitely there.”
The research is drawing significant attention. Eil was one of three researchers across the U.S. awarded Transformative Cancer Research Grants from the AACR-MPM Oncology Charitable Foundation. And he was one is one of seven early-career scientists across the nation selected for a career development award from the Pancreatic Cancer Action Network.
Leading a research laboratory while also working as a cancer surgeon is a difficult balancing act. Eil says he couldn’t do it without the support of colleagues and family. He’s adamant that taking care of patients makes him a better scientist.
“I think it focuses what I’m trying to do more on what is truly going to be a therapy that helps the patient and not some exercise in discovery or self-indulgence about what I think is interesting or curious,” he says. “Patients are great motivators. They are great teachers. They make our science more goal-directed, more focused.”
Ionic immune suppression within the tumour microenvironment limits T cell effector function by Robert Eil, Suman K. Vodnala, David Clever and others. Nature (Sep. 14, 2016)