Chimeric antigen receptor (CAR) T cell therapy is now moving toward effectiveness against solid tumors, based on recent work in mouse models. CAR T cell therapy has already had successes against aggressive blood cancers.1
Researchers genetically engineered human T cells to produce a CAR protein that recognizes a glycopeptide found on various cancer cells but not normal cells, and then demonstrated its effectiveness in mice with leukemia and pancreatic cancer. For CAR T cell therapy, T cells are collected from the patient’s blood and genetically engineered to express the cell-surface proteins chimeric antigen receptors, which recognize specific molecules found on the surface of cancer cells. The modified T cells are then infused into the patient’s bloodstream, where they target and kill cancer cells.
“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 Avery Posey, PhD, an instructor at the Perelman School of Medicine of the University of Pennsylvania, Philadelphia, and first author of the study. “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.”
Previously, CAR T cell therapy has not been effective against solid tumors because they target molecules found on the surface of both normal cells and cancer cells, resulting in serious side effects.
The researchers were motivated by a research colleague’s diagnosis of end-stage cancer. She was well known for her scientific discoveries and lifelong contributions in the field of cancer genetics. “She knew of our work and asked if there were any promising treatments we had that might be able to help her,” said Laura Johnson, PhD, co-senior author of this study. “This really polarized our team, in a worldwide collaboration, to find and fast-track a potential treatment for her cancer to the clinic.”
The patient’s tumor presented a significant challenge: It had none of the markers that are present on several of the other cancers Johnson and her team had worked on. That drove this study, as the Tn-MUC1 glycoprotein that they targeted turned out to be present on her tumor and on every other tumor also tested. Tn-MUC1 glycoprotein is an abnormal glycoform of MUC1, in which the unique patterns of sugars on a protein on the cell surface is changed. The researchers developed novel CAR T cells that express the monoclonal antibody 5E5, which specifically recognizes the sugar modification that is abundant specifically on cancer cells.
The 5E5 antibody recognized multiple types of cancer cells, including leukemia and ovarian, breast, and pancreatic cancer cells, 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.”
“Unfortunately, our colleague passed away before this could reach a clinical treatment, but she was happy that even if it couldn’t help her, this finding might be able to help other patients in the future,” Johnson said. Although the 5E5 CAR T cells were promising in mouse studies, more work is needed in advanced mouse models before it can move into its first in-human studies.
1. Posey AD, Schwab RD, Boestaeanu AC, et al. Engineered CAR T cells targeting the cancer-associated Tn-glycoform of the membrane mucin MUC1 control adenocarcinoma. Immunity 2016;44(6):1444-1454.