A life after the first successful pediatric CAR T-cell Therapy

When Tom and Kari Whitehead’s five-year-old daughter Emily was diagnosed with acute lymphoblastic leukemia a decade ago, the news hit them like an earthquake: they were devastated. At the same time, they took solace in statistics. Emily’s type of cancer had a 90% cure rate. The chemotherapy was rough, Tom recalls. “Most kids don’t get as sick as Emily did,” the doctors told him. Emily also almost lost her legs from an infection. But then she became part of the 90%, she went into remission. Her parents were thrilled and relieved. It didn’t last. 16 months later she relapsed.

The next few months were harrowing. The only option to save Emily’s life, was a bone marrow transplant – which only carried a cure rate of about 30%. While Emily waited for donor marrow, her cancer spread aggressively. She got so sick that doctors recommended hospice.

But then something remarkable happened. Emily had been waiting for her transplant at Penn State Health Children’s Hospital in Hershey, Pennsylvania, but she had also been treated at Children’s Hospital of Philadelphia (CHOP). Refusing to give up hope, Tom called Emily’s doctors at CHOP to ask a final time, whether there were any clinical trials of experimental therapies available for Emily.

On the very day he called, CHOP had gotten the green light from the Food and Drug Administration to launch a clinical trial of a new type of cell therapy called CAR T. Emily became the first patient ever to receive it. She almost died from the side effects, but 23 days after receiving the cells, Emily was cancer free. She remains that way today.

CAR-T cell therapy

CAR-T cell is short for chimeric antigen receptor T-cells, which are immune cells that have been extracted from individual patients, genetically engineered to fight cancer, and then infused back into patients.

Since cancers arise from cells that are technically “self,” a person’s normal T-cell response against cancerous cells is generally weak. To ramp up a patient’s T- cell response, researchers hijack the normal function of viruses to engineer a missile attack on cancer; they replace several genes in a virus with a gene that codes for a protein on the surface of the patient’s cancer cells - a so called a viral vector.

Today, there are six types of CAR-T cell therapy on the market and several others in development. While Emily is a success story, immense challenges with the therapy remain.

Even though more than 80% of treated patients go into remission, about half of them eventually relapse, according to the National Cancer Institute. Moreover, available therapies only target blood cancers - there are still no effective CAR-T cell therapies to treat solid tumors of breast, brain or other cancers. And misinformation and the high-cost of treatment are still hurdles that prevent many patients from accessing it, says Tom.

But as technology advances and knowledge grows, CAR-T cell therapy continues to improve, says Stephan Grupp, M.D., Ph.D., Emily’s oncologist at CHOP, where he is chief of the cellular and transplant section and inaugural director of the Susan S. and Stephen P. Kelly Center for Cancer Immunotherapy.

Ongoing studies of patients in long-term remission, for example, are helping researchers understand what differentiates them from those that relapse, says Grupp. And researchers have already made great strides in manufacturing CAR-T cells more quickly, which will potentially boost access and success rates. Other researchers are experimenting with different types of T-cells that might one day enable ready to use “off the shelf” cell therapies for many different types of cancers.

“From my perspective, there are going be some amazing breakthroughs in the next five years,” says Grupp. 

Engineering cells: how it’s done

Since Emily’s treatment in 2012, thousands of cancer patients worldwide have received CAR T cells. Depending on the cancer, 80 to 97% of them go into remission. But after five years, that number drops to 45-50%.

The last decade of studies suggest that one contributing factor is the lifespan of the CAR-T cells. In some relapsed patients, researchers find little evidence of them in the bloodstream beyond a few months, says Grupp, which may be influenced by the manufacturing process, he adds.

It currently takes an average of 22 days between extracting cells from a patient and reinfusing the engineered cells back into their bloodstream.

“The longer the T cells are outside the body, the more opportunity to mess them up.” And conversely, “the less time the T cells are outside of the body, the higher the quality when they go back into the patient,” says Grupp. A faster turnaround time might lead to longer-lived and more active T-cells.

He and other research groups have already reduced manufacturing time to one week. But the protocols will need to pass regulatory approval to become standard procedure. Grupp thinks this will happen “fairly soon” and will even shrink to two to three days in a few years.”

A shorter wait time will also help in other ways. Tom personally knows of patients who died, or kids who contracted a life-threatening pneumonia infection, while waiting for their cells.

The future of CAR-T

Advances in technology are also helping to speed up the manufacturing process. Each step requires a quality control check. After incubating the cells with the viral vector, for example, scientists must measure how many of a patient’s T-cells have taken up the vector and how many copies of the new gene they carry.

Among other side effects, too many copies can cause a patient’s immune system to overreact and unleash a cytokine storm - an all-out assault on the new cells, which can kill a patient.

Labs rely on PCR to maximize quantitative insights for reliable CAR T-cell manufacturing and ensure quality during the process. Digital PCR (dPCR) can precisely quantify nucleic acids in a sample and deliver the confidence for characterizing the viral vector purity and vector copy number critical to generating CAR T-cells.

In a joint study, scientists at QIAGEN and the Center for Breakthrough Medicines in King of Prussia, Pennsylvania, showed that digital PCR with QIAcuity can quantify the amount of viral vector in a sample in as little as 2 hours compared to digital droplet PCR, another commonly used PCR assay which can take up to 7 hours - with comparable precision and sensitivity.

More broadly, scientists are making strides towards developing CAR-T cells to treat other types of cancers. Last year, researchers at Stanford Medicine, for example, reported results from treating four children with diffuse intrinsic pontine glioma (DIPG) — an aggressive brain tumor that has a five-year survival rate of less than 1%. Although all eventually died from their disease, patients showed encouraging signs that the experimental CAR-T cell therapy had an effect; one patient’s neurological symptoms disappeared for months. By tweaking the therapy and dosage further, the researchers hope for better results in other patients.

Other groups are looking at using T cells from donors to mass-produce an off-the-shelf option that would be available immediately. Researchers led by Katy Rezvani, M.D., Ph.D., at MD Anderson Center in Houston, for example, are adding CAR genes to natural killer cells — another type of immune cell — extracted from donated umbilical cord blood. A single cord blood donation can provide hundreds of doses of CAR NK cell therapy. The team is exploring the potential of CAR NK cells to treat many types of cancers.

Helping patients: still a priority

Emily’s remission after her CAR T cell therapy wasn’t the end of her family’s cancer story. Since its founding in 2015, the Emily Whitehead Foundation (EWF) has connected countless families with experts and has raised over $2 million towards research. In fact, EWF contributed funding for the study of CAR-T cells in DIPG. “We are very proud to be part of that,” Tom adds.

“We just wanted to do whatever we could to help families have the same success that we had,” says Tom.

How the Whiteheads find time for their advocacy work while working other jobs is a mystery to anyone who knows them. Kari works at Penn State University and Tom for First Energy of Pennsylvania. He is a lead line man—a first responder when there is an electricity outage. The job demands 50 hours of his time a week and can be unpredictable. When the power goes out, he is first in line to investigate and sometimes has to deal with angry customers in the middle of the night.

But the media attention has had its upsides. Recently an annoyed customer approached Tom while he was working to restore power to her house. She started attacking him verbally because of the delay, he says. But as she shone her flashlight into his face, she recognized him. “’You’re Tom Whitehead,” she said. Her face softened, she became chatty and then offered him coffee.

Tom doesn’t plan on stopping his advocacy work for EWF anytime soon.

He continues to share his family’s story and is currently expanding the foundation; his goal is to raise at least $1 million a year for research. Because the most rewarding thing of all, he says, is seeing the outcome. He recently helped a child in India get treatment in the U.S. The parents called and said:

“Because you took my call, my child is alive. When you save a child, you save a family. We’re going to keep working until the therapy is globally accessible.”