Researchers have generated engineered T cells that home in on mesothelin, a protein produced in large amounts by pancreatic tumors. In mice, the T cells entered pancreatic tumors and destroyed cancer cells. Repeated infusions of the T cells nearly doubled survival times in the animals.

Engineered T cells that recognize the protein mesothelin on the surface of tumor cells can attack and shrink pancreatic tumors in mice, a recent study reveals. Researchers plan to start a clinical trial with human versions of the cells.

So far, checkpoint inhibitors and other immunotherapies haven't worked against pancreatic ductal adenocarcinoma, the most common kind of pancreatic cancer. Several characteristics of the tumors explain why: Their stroma serves as a barrier, and they have few blood vessels to admit drugs or therapeutic cells. In addition, the extracellular matrix in pancreatic tumors absorbs large amounts of water, creating a high internal pressure that may exclude T cells. Even if T cells do manage to slip in, the tumors suppress them in several ways, such as producing the inhibitory cytokine TGFβ.

A team led by Sunil Hingorani, MD, PhD, and Philip Greenberg, MD, of the Fred Hutchinson Cancer Research Center in Seattle, WA, tested whether T cells that target mesothelin, which pancreatic tumors produce in abundance, could overcome these obstacles. To generate these T cells, the researchers immunized two kinds of mice against mesothelin: animals that lack the protein and normal mice, which produce mesothelin in a few tissues. Both kinds of animals generated T cells with a receptor that recognized a short segment of mesothelin. The researchers then engineered mouse T cells to produce this receptor.

Next, the scientists infused the engineered T cells into mice that spontaneously developed pancreatic tumors. The T cells entered the tumors and began to kill cancer cells. However, their potency declined quickly. Within a month of the infusion, most of the tumor-infiltrating T cells had died, and many of the remaining T cells carried proteins, such as PD-1, that indicated they were no longer functional.

Aiming to overcome that challenge, Hingorani and colleagues tested whether repeated infusions of T cells would work better. When they gave mice the T cells every 2 weeks, the treatment's effectiveness didn't tail off. Tumors shrank in 63% of the mice, and the animals' overall survival increased from 54 days to 96 days, the researchers reported (Cancer Cell 2015;5:638–52). Although other tissues, such as the pleura and pericardium, produce mesothelin, the researchers saw no signs that the engineered T cells were attacking these sites.

Along with a few other recent studies, the work “changes the impression that this is an impregnable cancer and suggests there are ways to target it,” says Hingorani.

The study “makes the point that T cells can enter pancreatic cancer tumors and that their stroma and poor vascularity are not barriers,” says Gregory Beatty, MD, PhD, of the University of Pennsylvania in Philadelphia, who wasn't connected to the study. He's part of a group that recently launched a clinical trial of a slightly different approach that involves chimeric antigen receptor T cells targeted against mesothelin. “They are different strategies, but both might be efficacious,” says Beatty.

Hingorani says that he and his colleagues hope to begin a clinical trial of their engineered T cells by the end of 2016. –Mitch Leslie

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©2016 American Association for Cancer Research.
2016