Chimeric antigen receptor T-cell therapy for hematological malignancies took a huge step forward this summer with the FDA approval of Novartis
E. John Wherry, PhD
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.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.
Some success has been achieved in finding markers that are highly specific to solid tumor cells, and that accomplishment is promising for further development of CAR T cells in this context, Wherry said. There are opportunities there, but much work lies ahead. One objective of this trial is to explore the use of CAR T cells that will target mesothelin, a protein that is overexpressed in pancreatic cancer. Even if you have good markers, the dense stromal tissue that is characteristic of pancreatic cancer presents another obstacle to effectively dealing with the disease, Wherry said. “If you’ve got leukemia or lymphoma, and you put the CAR T cells into the blood, they don’t have to do any work to get to where the cancer is.” It’s much harder to get T cells to migrate to the pancreas. “It almost has a wall around it that excludes or prevents the immune cells from getting in.”
If the cells manage to penetrate the diseased tissue, the compactness of the intracellular matrix makes it difficult for the cells to move around and find their targets. That said, there has been progress in the use of drugs to soften up the tumor environment to allow the modified T cells to get in more effectively, and progress has been made in figuring out what molecular structure the T cells need to migrate to the disease site, home in on the tumor, and interact with the cancerous cells, Wherry said.
The third big challenge is ensuring that the CAR T cells still have some pep for fighting the tumor once they have penetrated to the disease site. “They come in as functional antitumor cells, but in that tumor microenvironment, they get inactivated, and they get shut off. This is a major problem. It’s one of the things that checkpoint blockade is reversing, but we still don’t understand how to make sure that the reversal is as effective and durable as possible,” Wherry said. CAR T-cell “exhaustion” is a major area of laboratory research. Efforts are being made to understand the cellular mechanisms behind the process of inactivation. Scientists know it is related to intracellular signaling and the pathways that are regulated by immune system checkpoints. Wherry said that how gene expression correlates to T-cell exhaustion is also part of the problem of fighting solid tumors with CAR T cells.
Investigators at Penn believe they have a molecular target that will be valuable in pancreatic cancer. They have a theory about managing the second problem, which is getting the modified T cells to the cancer site effectively, and during this trial, they intend to test to find out whether that hypothesis is true. Another goal is to gain a deeper understanding of how T-cell exhaustion interferes with getting T-cell boots on the ground, in combat condition, and directly where they are needed within the tumor environment.
Pancreatic cancer is such a daunting form of this disease that “all options are on the table” in terms of fighting it, Wherry says. The need for a cure is so strong that CAR T-cell therapy is worth investigating even though it may be a time-consuming challenge to develop a treatment that should be propagated. In the solid tumor environment, CAR T cells have natural limitations, so the solution is going to involve more discovery and also adaptive use of many supportive ideas and technologies to overcome the barriers, Wherry said. “We have to take from every source to try to improve these therapies. Without knowing what CAR T cells can and can’t do in the system, we’ll never generate a CAR T cell that can do better. In many ways, this is the place to start. We can get CAR T cells into the tumor. That’s a huge success.”
One goal of this trial is to develop a follow-up trial that will be even more revealing and successful, and to do that, it is necessary to pay very close attention to what works and what the limitations are, Wherry said. “This is testing how much each of those potential limitations plays a role in this process. We’re very hopeful that we’ll see T cells in the tumor microenvironment. If they can get there, then there’s the chance they can have a positive clinical effect.”
Penn has been a pioneer in CAR T-cell research, developing tisagenlecleucel, which was licensed to Novartis in 2012 as part of a global research and development alliance. But even before Novartis became involved with Penn, the school had recruited June to help lead an investigational research team to explore CAR T-cell therapy. When he arrived at the school, June was working on understanding CAR T-cell signaling, and he developed some of the first approaches to get CAR T cells into humans. The Novartis alliance followed publication of initial results in a small group of patients with CLL, to help bring those discoveries to the clinic on a larger scale, he explained.