By Kirsten Weir
CAR T cell therapy is one of the heroes that ushered in the age of immunotherapies, bringing long-lasting remissions and cures for patients with blood cancers like leukemias and lymphomas. But there are many more cancer foes it has yet to defeat. Designing CAR T cells to destroy solid tumors—which account for 90% of all cancers—has proved much trickier.
In CAR T therapy, a patient’s T cells are removed, altered, then returned to the body, where they seek out and kill cancer cells. In a petri dish, that process works for any type of cancer, including solid tumors. Getting it to work in the body, though, has been a different story.
“Each type of tumor has its own little ways of evading the immune system,” said Carl June, MD, the Richard W. Vague Professor in Immunotherapy at the Perelman School of Medicine and director of the Center for Cellular Immunotherapies at Penn Medicine’s Abramson Cancer Center, who led the team that developed what became the first U.S. Food and Drug Administration–approved CAR T cell therapy. “So there won’t be one silver-bullet CAR T therapy that targets all types of tumors.”
But Penn Medicine researchers are making steady progress, with an extensive portfolio of clinical trials testing the treatment in solid tumors and other approaches in the pipeline. “Our toolbox is full of new ways to engineer cells. We have all the tools required to solve the problem of solid tumors,” June said.
How Brain Cancer CAR T Homes in on Hard-to-Target Solid Tumors
Many solid tumors are naturally hostile to T cells. Part of that hostility is what June calls the medieval castle problem: “Just like castles have a moat, tumors are surrounded by scars made of collagen,” he explained. It’s tough for T cells to cross that barrier. When cells do make it past, they often find themselves surrounded by immunosuppressive cells and molecules that are primed to wipe out marauding immune cells—including T cells. “You have to teach the cells to go there and proliferate in that hostile environment,” June said.
Another challenge is that solid tumors aren’t as easy a target for CAR T cells to lock onto. CAR T cells are programmed to seek out specific proteins, or antigens, on a cancer cell’s surface. In a disease like leukemia, most cancer cells are made of a single cell type (such as B cells) that all express the same antigen. A solid tumor, however, is made up of different cell types, with different mutations, expressing different antigens. It’s more challenging to design a CAR T therapy for heterogeneous tumors like this, targeting several antigens at once.
Challenging, but not impossible. Donald M. O’Rourke, MD, the John Templeton, Jr., MD Professor in Neurosurgery and director of the Glioblastoma Translational Center of Excellence at the Abramson Cancer Center, and colleagues are currently testing a “dual target” CAR T that goes after two antigens expressed by the brain cancer glioblastoma multiforme (GBM).
GBM has long been one of oncology’s fiercest foes. Rather than growing in a well-defined ball, these tumors send out invasive projections that infiltrate nearby cells. They're virtually impossible for surgeons to remove them completely, and tumors almost always recur soon after treatment. Despite decades of research, the median survival time for GBM patients is just 15 months. “We need a therapy that can expand in the body and home in on the regions that the cancer has invaded,” O’Rourke said. “And the only thing that can do that is an activated T cell.”
Getting T cell therapies ready to test in GBM patients hasn’t been easy. On top of the other defenses that solid tumors put up against CAR T, the brain has its own mechanisms to keep T cells away, O’Rourke said. “The body isn’t designed to tolerate inflammation in the brain.” But in previous research, his team discovered that GBM seems to be more vulnerable to CAR T therapy after the cancer recurs. One patient they treated with CAR T cells for recurrent GBM lived for 36 months.
Building on those successes, O’Rourke is leading a clinical trial testing the dual target CAR in patients with recurrent GBM. To help as many of the engineered cells as possible reach their target, they’ll deliver the T cells directly into the spinal fluid. It’s the third in a series of small trials, and with each one, the researchers chip away at GBM’s stubborn barricades. The patients recognize that this new therapy is unlikely to erase their tumors completely. But their participation offers hope that they may gain more quality months or years, and allows them to be a part of finding a future cure for this devastating disease. “Each patient is a treasure trove of data,” O’Rourke said. “It’s been a slow build, but we’re learning a lot.”
Trial Gives a Boost of CAR T After Surgery for Breast Cancer
Getting CAR T cells past a tumor’s defenses is one challenge. Making sure they don’t go after innocent targets is another. A decade ago, June and colleagues including Julia Tchou, MD, PhD, a professor of Clinical Surgery and director of breast surgery research at Penn Medicine, discovered that the hard-to-treat triple negative breast cancer expresses the surface protein mesothelin. It could be a good target for T cells—except that noncancerous cells can also express mesothelin, increasing the risk of serious side effects if the engineered cells attacked healthy tissue.
Tchou and June took a creative route around that roadblock. They developed a special gel containing CAR T cells that could be painted into tissues left behind after tumor removal. In mouse models of breast cancer and pancreatic cancer, the gel showed impressive results: Residual cancer vanished in 19 of 20 mice, without affecting wound healing or causing other side effects. “The results in animals were surprisingly good,” Tchou said.
Now her team is launching a trial of patients with locally advanced or metastatic triple negative breast cancer. Rather than apply the gel, they’re injecting CAR-T cells directly into the tumors. (If all goes well, studies of the gel may follow.) Researchers biopsy the tumors before and after treatment so they can make detailed comparisons. “We’ll be able to do these really deep analyses and learn how the CAR T cells are behaving—and whether the tumor tissues are shrinking or changing,” Tchou said.
It's a small pilot, she cautions, and just one step on the long road to making CAR T a go-to for solid tumors. But the approach has potential for all sorts of tumors that are difficult for surgeons to remove completely, including cancers of the brain, lung, and pancreas. “In the future, if we can deliver this type of treatment at the site during surgery, patients might be able to avoid chemotherapy and radiation,” Tchou said. “That would be a huge breakthrough.”
Meanwhile, researchers across Penn are working on complementary approaches to make CAR T more effective, including new techniques to break down the collagen “moat” surrounding tumors, and new rapid manufacturing methods that allow T cells to be reinfused into patients in just a few days rather than several weeks. Penn Medicine is a place where such revolutions can happen—especially in the field of CAR T immunotherapy, which was born in those very labs. “When we started, there wasn’t a workforce of people who knew how to do this. Over the past 25 years, we’ve developed a huge talent base and an amazing infrastructure,” June said. “I’m optimistic cell therapies will be used for all kinds of solid cancers. The only unknown is when.”
An Age of Immunotherapies: Related Stories
Building on the Body’s Wisdom: Treatments that manipulate or repair the immune system are becoming more commonplace.
Life, Gained: Walter Styer has cherished 11 years of life after being one of the earliest patients in a trial of the first CAR T cell therapy developed at Penn Medicine.
The Immunotherapy Revolution for Autoimmune Diseases: With a deeper understanding of the immune system, there are growing possibilities to selectively turn down only the parts that malfunction—with hopes to someday cure these conditions.
Cancer Interception: Cancer vaccines are a form of immune therapy under investigation at Penn, part of a growing effort to intercept cancer before abnormal cells become malignant. (From the Spring 2023 issue of Penn Medicine magazine)
Energizing the Immune Army: A phenomenon known as “T cell exhaustion” has stymied some efforts to develop powerful immune-based therapies. E. John Wherry, PhD, describes how researchers are learning to manipulate this complex process.