T Cell Therapy Shows Promise in Solid Tumors
Chimeric antigen receptor T cell therapy targets advanced forms of leukemia and lymphoma.
By using mice, researchers were able to demonstrate how chimeric antigen receptor (CAR) T cell therapy can target solid tumors.
Recent clinical trials have demonstrated that CAR T cell therapy dramatically improved the outcomes of patients with advanced forms of leukemia and lymphoma. But, studies that used this form of therapy to treat solid tumors found little success because it targeted molecules on the surface of both normal cells and cancers cells, causing serious side effects.
To overcome this, researchers decided to genetically engineer human T cells to produce a CAR protein that recognizes a glycopeptide found on different cancer cells, but not normal cells. Through this approach, the therapy demonstrated its efficacy in mice with leukemia and pancreatic cancer.
The findings were published in Immunity.
“This is the first approach using a patient's own immune cells that can specifically target this class of cancer-specific glycoantigens, and this has the great advantage of applicability to a broad range of cancers,” said first study author Avery Posey. “Future cancer immunotherapies combining the targeting of cancer-specific carbohydrates and cancer proteins may lead to the development of incredibly effective and safe new therapies for patients.”
Finding a solution to the problem quickly was reinforced when a colleague of the team was diagnosed with end-stage cancer.
“She knew of our work and asked if there were any promising treatments we had that might be able to help her,” said co-senior study author Laura Johnson. “This really polarized our team, in a worldwide collaboration, to find and fast-track a potential treatment for her cancer to the clinic.”
However, the patient’s tumor was a challenge because it had none of the markers that were present on several of the other cancers the research team had worked on.
“This was truly what drove the work that resulted in the CAR in this study,” Johnson said. “It was the only marker we could find on her tumor; and it turns out, on just about every other tumor we tested, too.”
Researchers identified the cancer cell marker as a specific change in protein glycosylation. The team developed novel CAR T cells that expressed the monoclonal antibody 5E5, which specifically recognized a sugar modification, Tn glycan on the mucin 1 (MUC1) protein, that is found in abundance on cancer cells.
The 5E5 antibody was able to recognize several types of cancer cells such as leukemia, breast, ovarian, and pancreatic but not normal tissues.
“This is really the first description of a CAR that can target multiple different solid or liquid tumors, without apparent toxicity to normal cells,” Johnson said. “While it may not be a universal CAR, it is currently the closest thing we have.”
When the 5E5 Car T cells were injected into mice with pancreatic cancer or leukemia, it reduced tumor growth and increased survival.
At the end of the study, 113 days after treatment with 5E5 Car T cells, all 6 mice with pancreatic cancer were alive. However, only one-third of mice treated with CAR T cells that did not target Tn-MUC1 survived until the end of the study.
Researchers noted that more work needs to be done to determine the safety and efficacy of the treatment using advanced mouse models that can more accurately predict the effects in humans.
“So while we are hopeful, no one ever knows if a cancer treatment is truly going to work, and be safe, until it actually goes to treat patients in the clinic,” Johnson said.
However, researchers plan to continue to develop their CAR T cell therapy and test its safety and efficacy for different types of metastatic cancer in upcoming clinical trials.