E. John Wherry, PhD
Chimeric antigen receptor (CAR) T-cell therapy for hematological malignancies took a huge step forward this summer with the FDA approval of Novartis’ tisagenlecleucel (Kymriah) for relapsed/refractory B-cell precursor acute lymphoblastic leukemia (ALL) in children and young adults. However, a team of scientists at the University of Pennsylvania is working to make CAR T cells work in solid tumor disease as well.
E. John Wherry, PhD, director of the Institute for Immunology at the Perelman School of Medicine, described successful use of CAR T cells in solid tumors as a hefty challenge given the difficulty of enabling CAR T cells to penetrate and move around effectively in a dense micro-tumor environment. In terms of advancement, CAR T-cell research in solid tumor cancer is where the research in hematological malignancies was 10 years ago, he said. Still, researchers have the advantage of being able to springboard off what was gained in understanding from the CAR T-cell work in blood disorders, and there is potential for that knowledge to accelerate progress in making CAR T cells work in pancreatic cancer, he said.
A phase I human trial is now under way at Penn to not only test the efficacy of CAR T cells in pancreatic cancer but also to serve as an observation platform for making discoveries in how to improve the potency of this immunocellular therapy, Wherry said. CAR T-cell therapy involves removing a patient’s immune cells and conditioning them to express proteins that can recognize specific molecules on the surface of cancer cells. Those targeted cells are then infused into the patient, where they seek out and attack cancerous cells. Wherry is working with Carl June, MD, and Shelley L. Berger, PhD, on the project, which is supported by the Lustgarten Foundation for Pancreatic Research and Stand Up to Cancer.
Making Headway With Pancreatic Cancer
Pancreatic cancer has been one of the most difficult of targets because effective therapies are lacking and the disease, which is often diagnosed late in development, progresses rapidly. For those reasons, Wherry explained, oncologists at Penn do their best to get patients with pancreatic cancer onto clinical trials as quickly as possible. That gives them a chance at receiving the most advanced medicine. There are reasons to believe that CAR T-cell therapy could be effective in this tumor environment, he said, and that makes it worthwhile to pursue this avenue of investigation. “We just really don’t have any good immunotherapy options for pancreatic cancer, and prognosis with standard of care such as chemotherapy has not dramatically improved in recent years,” he noted.
Wherry identified multiple challenges with making CAR T cells work in pancreatic cancer. So far, this type of therapy works better with bloodborne disease because the collateral damage that the CAR T cells cause can be managed. Cells that are targeted to go after B lymphocytes will be tolerated because the body can live for a time with a low count of B lymphocytes. “You can get rid of an entire cell type in your body that includes both cancerous and noncancerous cells, and you’re perfectly fine,” Wherry said. “You have some replacement therapy for antibodies, but that makes it relatively easy to target these cell malignancies. You just get rid of all B cells, and that’s worked very effectively in ALL and has also led to some sustained remissions in patients with chronic lymphoblastic leukemia [CLL].”
But that’s not the case with solid tumors, where the CAR T cells may be directly attacking the cells of an organ that is critical to the functioning of the body. In solid tumors, the target cells are harder to distinguish from healthy cells in terms of available biomarkers. Biomarkers that distinguish the cancer cells are also found in healthy cells, creating the potential for overkill by CAR T cells that are targeted too broadly. “In solid tumors, our markers are not as good, so we have a challenge in figuring out what to target. We have to work in a therapeutic range to figure out which targets are going to give us enough on-target effect with minimal side effects for wherever else that target might be expressed,” Wherry explained.