Dr. Zhubin Gahvari is among the UW Health | Carbone Cancer Center researchers examining how to make CAR T-cell and T-cell Receptor therapies, which involve use of modified white blood cells, be an effective treatment against the most common cancer types.
“Blood cancers are a small piece of the pie—they make up about 10% of the cancer diagnoses in the United States,” said Gahvari, a hematologist. “There are huge groups of people with breast cancer, prostate cancer, lung cancer, gastrointestinal cancers… How many more people could we help if we get these treatments over the finish line?”
How they work
T-cells are a type of white blood cell that helps the body fight disease and kill abnormal cells. Cancer grows and spreads because it can evade this natural immune response.
CAR T-cell, or chimeric antigen receptor T-cell, therapy works by modifying T-cells to seek specific targets on the surface of cancer cells so they can bind to and destroy them. T-cell Receptor therapy is similar but targets markers within cancer cells, which helps specialize their focus. These modified T-cells can be made from taking blood samples from a cancer patient, or by using donor blood.
These therapies have worked very well in treating blood-based cancers because those cancer cells express more unique markers that are easier to target. With solid tumors that are associated with organ system cancers, that environment is more complex. It’s harder to identify a good, unique target for those modified T-cells to aim for that is not also expressed by healthy cells. That target might not be uniformly expressed by all the cancer cells, either. Another issue is how to get those T-cells to penetrate tumors and still have enough strength to attack and kill the cancer cells inside the tumor.
“Solid tumors are notorious for weakening the immune system that gets there, weakening these CAR T-cells and other immunotherapies and making them less effective,” Gahvari said.
Overcoming challenges
Gahvari has seen the life-saving impact that other forms of immunotherapy have had in major cancer types over the past decade. Checkpoint inhibitors, which are used to rev up the body’s natural immune response to fight cancer cells, have given new hope even among patients with grim diagnoses.
“There’s people who have had years of life with metastatic solid tumor cancers that, previously, we didn’t have any options for,” Gahvari said. “These medicines have disrupted the standard of care in so many tumor types where they’ve gone from end of the line treatment to now frontline recommendations for treatment.”
Researchers are investigating multiple ideas to overcome the barriers currently faced in T-cell therapies, including evaluating which markers on cancer cells offer the best targets, how to let the modified T-cells “rest” until they reach the cancer cell, and how to pattern cell therapy dosages and combine with other medications like chemotherapy to increase success.
“I don’t think it’s a situation where it’s just going to be one thing that fixes all of the issues,” he said. “It’s rather attacking all these linked but separate problems. The hope and the expectation are that we’ll get there eventually, and that’s when exciting things happen.”
Currently, Gahvari is overseeing two phase I clinical trials at Carbone Cancer Center involving T-cell therapies. One tests use of CAR T-cells that targets the protein mesothelin on cancer cells, and this is being evaluated for patients with ovarian cancer, the rare lung and chest cavity cancer called mesothelioma, and the rare bile duct cancer called cholangiocarcinoma.
The other clinical trial tests the use of T-cell Receptor therapy that targets cancer cells with a specific mutation of the KRAS gene, which can occur in patients with colorectal, pancreas and non-small cell lung cancers, as well as select other cancer types.
Gahvari enjoys the collaborative nature of this research, combining blood cancer specialists with researchers focused on solid tumor cancers to evolve the next breakthrough in cancer care. He also praised the patients in these trials who help advance new treatments, even if it may not benefit them personally.
“I think the patients and their families who are willing to take a chance with this new therapy that’s promising but may not work for them, but it could be the difference in making this therapy work for everyone else, is very brave and courageous, and it’s inspiring to be a part of that journey,” he said.