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Engineered T Cells Improve Pancreatic Cancer Outcomes in Mice.

Pancreatic cancer is the most fatal cancer; it is usually discovered late, and is extremely difficult to treat once diagnosed. More than 85% of patients diagnosed with advanced cancer of the pancreas die on average within 6-10 months after diagnosis. On April 16th, at the American Association for Cancer Research annual meeting, researchers from the Fred Hutchinson Cancer Research Center in Seattle, Washington, presented their latest research on a form of immunotherapy that employed engineered T cells in mice. The T cells recognized the pancreatic cancer cells within a few days of infusion. The study, led by Sunil R. Hingorani, M.D., Ph.D., director, Center for Accelerated Translation in Pancreas Cancer and Deputy Director, Solid Tumor Translational Research, Philip Greenberg, M.D., head of immunology and research associate Ingunn Stromnes, Ph.D., reported increased survival from pancreatic cancer by more than 75%. While immune therapies show promise for treating hematologic malignancies, success with treating solid tumors has been less so. “Before, we could often kill the pancreatic cancer cells in a dish, but not in the actual organ where the tumor arises,” said Hingorani. Pancreatic ductal adenocarcinomas (PDA) which account for more than 90% of pancreatic cancer cases – are especially difficult because they form tough physical barriers around tumors. They survive with a limited blood supply thus thwarting chemotherapy, since the drugs cannot penetrate the tumors when administered via the bloodstream. In addition, PDAs employ an immunecloaking device that prevents immune cells from recognizing the cancer. Also, pancreatic tumors can grow quite large before patients notice something is wrong. They also metastasize quickly. Hingorani said the team’s engineered T cells, which express affinity-enhanced T cell receptors, overcame both the elevated interstitial pressures and immune suppression to infiltrate the PDAs and induced tumor cell death. First, the researchers dosed the mice with Cytoxan, which depleted some of the animals’ natural T cells while creating space for the engineered cells to grow, then delivered the engineered cells to them by intravenous infusion. Eight days later, many of the immune cells found the tumor and showed anticancer activity. Hingorani said that on average, the mice that received T cells engineered to recognize a noncancerous protein survived 54 days after their cancer became detectable. Those that received the mesothelin-directed cells lived an average of 96 days, a 78% increase. However, the T cells started to vanish in two to four weeks after infusion; a periods far too short to thwart the growth of the cancer. When they discovered that tumor cell death was only temporary, they found that anti-tumor activity continued by administering additional infusions. “If repeated every two weeks the infusions significantly prolonged survival in mice,” said Hingorani. “I do like this approach,” said Elizabeth M. Jaffee, M.D., The Dana and Albert “Cubby” Broccoli Professor of Oncology and Deputy Director, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine. Jaffee acknowledged that T cell therapy only works when the body generates active T cells that can recognize cancer antigens on the cancer and also get into the tumor microenvironment which does not happen with pancreatic cancer. “Most pancreatic cancer patients do not generate effective T cells on their own, so they must be modified to be effective as vaccines or other agents. Engineered T cells can overcome this problem in theory, but it is still not clear what tumor antigens are most important for T cell recognition,” said Jaffee. “There are lots of studies working on shared antigens and others working on mutationally expressed antigens, but we do not have a lot of data on which of these if any are most important for T cell recognition and killing of the cancer cell.” Hingorani said after surveying a number of possible antigen targets, they ended up with one that had been studied before; mesothelin; a tumor differentiation antigen normally present on the mesothelial cells lining the pleura, peritoneum and pericardium, and expressed in several human cancers including pancreatic cancer. “I think an unsurprising aspect of the study is that we ended up using mesothelin specific T cells,” said Hingorani. “The really interesting aspect of the study is that it actually worked.” Jaffee said that even with an effective antigen target, there is another major problem that must be solved for T cell therapy to be effective; getting the T cells into the tumor microenvironment.