When chemotherapy failed to stave off the cancer cells living in her body, 6-year-old Emily Whitehead was left with one option.
Nearly a year earlier, Whitehead was diagnosed with acute lymphoblastic leukemia, a blood cancer that chemotherapy successfully treats in most patients. But two relapses meant that Whitehead, who was seeking care at the Children’s Hospital of Philadelphia, would need to find an alternative.
At the time, researchers at Penn Medicine had spent over a decade developing CAR T-cell therapies for cancer — an approach where a patient’s natural attacker T cells, not recognizing the cancer cells, are removed from the body and engineered to include a chimeric antigen receptor that can recognize the cancer cells. By 2010, the researchers had treated the first adult patient with the therapy for chronic lymphocytic leukemia.
But before Whitehead, now a College senior, no child had received the novel treatment. In 2012, she became the first pediatric patient to receive T-cell therapy. She has not relapsed since.
Five years later, the first CAR T-cell therapy, pioneered by a collaboration between Penn and pharmaceutical company Novartis, was approved in the United States by the Food and Drug Administration for acute lymphoblastic leukemia in children.
This past summer, China’s National Medical Products Administration approved the world’s first CAR T-cell therapy for the treatment of a solid tumor. Despite clinical trials — partly led by a Penn startup — the technology has yet to be approved to treat solid tumors in the United States.
The Daily Pennsylvanian spoke with Penn researchers about where that progress currently stands and what they’re doing to overcome barriers.
“The big difference between liquid tumors and solid tumors is, in solid tumors, you basically have a new organ forming,” School of Veterinary Medicine Cancer Center Director Ellen Puré said.
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Perelman School of Medicine Department of Microbiology professor Joseph Fraietta compared the solid tumor microenvironment to a “sewer.”
“CAR T cells have to function within that sewer,” he said. “Even if they can get past these very formidable physical barriers and infiltrate into the tumor bed, in the tumor microenvironment, they’re met with various sundry immunosuppressive mechanisms.”
Puré added that while immunosuppressive cells form the bulk of the tumor microenvironment, cancer cells “remodel” the extracellular matrix with the formation of a desmoplastic matrix, a network of connective tissue. This tissue, which includes immune-suppressing cells like cancer-associated fibroblasts, creates a barrier around the cancer cells.
In the past, CAR T cells have not been able to penetrate the tumor wall to reach and destroy cancer cells. Fraietta noted that while it has taken longer to move from liquid tumor to solid tumor applications than expected, researchers are “turning the corner with solid tumor therapy.”
“Rather than try to go after the tumor cells themselves — the way every CAR T cell used to work — we decided to make a CAR T cell that would go after the cancer-associated fibroblast,” Puré said.
These CAR T cells target the fibroblast activation protein on CAFs, depleting the CAFs.
But the approach had an “unexpectedly” larger effect on the entire matrix as well, Puré said. The desmoplastic matrix, or the tissue surrounding the tumor, “just melted away.”
Nearly 90 to 95% of all human tumors express FAP, Puré explained. This makes the protein an appealing and nearly “universal target.”
Fraietta is also designing new ways to get past the solid tumor barrier.
In a current clinical trial, Fraietta and his team are putting a lab-designed virus into patients that, as a “first line of attack,” is programmed to “selectively replicate within the tumor.”
The virus is “going to break down some of the physical barriers” and “start killing the tumor even before the CAR T cells get in there,” he said.
An added bonus of this system is that it can “wake up” the body’s own immune system, adding another layer of antitumor activity besides the engineered CAR T-cell therapies.
Fraietta’s therapy relies on the production of CAR T cells outside the body, or “ex vivo,” like the treatment Whitehead received over a decade ago.
Currently, patients who receive CAR T-cell therapy undergo lymphodepletion, a process in which chemotherapy drugs are used to deplete existing immune cells and make way for the new, engineered T cells.
Puré’s lab is working on developing an “in vivo” system where artificial packages known as lipid nanoparticles carry instructions to T cells already in the body — allowing the T cells to make the CARs themselves.
An “in vivo” approach where the patient’s own T cells don’t have to be removed, harvested, and grown — and where lymphodepletion is not necessary — could be gentler on their body and lower costs of the therapy, Puré explained.
Other Penn researchers are studying CAR T cells from different angles, including how to track their activity in the body.
Most indications of a cancer therapy’s success are determined through blood samples or biopsies. But “what is in the blood does not match what’s in the tumor” when it comes to the CAR T-cell population, according to radiology professor Mark Sellmyer.
He added that a biopsy offers only limited information based on a “small, teeny tiny chunk” of the tumor.
Sellmyer’s research involves imaging as a way to provide a more robust understanding of where CAR T cells move and whether the therapy is successful.
Currently, he is working on a clinical trial that involves a two-step imaging process: first, the CAR T cell is designed to express a target for a radiotracer. Then, after CAR T cell delivery, the radiotracer can be injected to track where they move.
Sellmyer’s team is working to confirm the success of their approach in liquid tumors before tracking therapies that target the heterogeneous landscape of solid tumors.
Puré also has plans to bring her ideas to patients. However, she noted that the process of bringing her ideas from bench to bedside has been slowed by funding obstacles.
The funding to the Center for Cellular Immunotherapies was reduced when her team was “well on” their way to preparing an Investigational New Drug application, Puré explained. As a result, they had to put the application on hold.
Puré attributes this to “what went on in science and scientific funding about a year and a half ago” and is currently working on finding alternative funding sources.
As researchers continue finding ways to improve CAR T-cell therapies, Whitehead has become involved in supporting the growth of the field and “improving immunotherapy access and education,” she told the DP — particularly through the Emily Whitehead Foundation.
Whitehead said her foundation fundraises in multiple ways, with events such as golf tournaments and a “Believe Ball.” The money is distributed to various causes, including research and patient advocacy.
She added that while CAR T-cell therapy is “not as accessible” as it could be, the treatment has gradually appeared in more hospitals.
“There’s still a long way to go, but so far, it’s on the right track,” Whitehead said.
This story is the second part in a two-part series about CAR T-cell research at Penn.
Staff reporter Mariacristina Calcagno covers science and health and can be reached at calcagno@thedp.com. At Penn, she studies biochemistry and economics.
