A Cub Scout in the Webelo Rank, a collector of rocks and gems, and an inquisitive explorer, 10-year-old Austin Schuetz is fascinated by the wonder and workings of everyday objects. And although he doesn’t grasp all of the complex details just yet, Austin knows a little bit about his own special molecular machinery, too: “Super killer” T-cells act as a living drug to find and fight any potential cancer growth inside his body.
In October of 2013, scientists at Children’s Hospital of Philadelphia and the University of Pennsylvania genetically modified Austin’s T-cells as part of an experimental clinical trial for a novel type of cancer immunotherapy. The innovative treatment, known as chimeric antigen receptor T-cell therapy, or CTL019, captivated the attention of both scientific communities and the mainstream media. As the first-ever gene therapy for cancer, the one-time treatment trains a patient’s own immune system to target and destroy leukemia cells.
In 2017, the treatment broke new ground for pediatric cancer treatment when the U.S. Food and Drug Administration approved its use for the treatment of B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse in patients up to 25 years old. The move was historic and unprecedented: In an FDA advisory panel this past July, one expert called the therapy “the most exciting thing I’ve seen in my lifetime.” With FDA approval, Novartis Pharmaceuticals will market CTL019 under the name Kymriah™ (tisagenlecleucel), and it is anticipated to reach pediatric patients through a network of certified treatment centers throughout the U.S.
The approval arrived after decades of intensive lab work and clinical trials conducted in collaboration with a team of scientists from CHOP, the University of Pennsylvania, and Novartis, along with the courage of young patients like Austin facing refractory and relapsed forms of ALL— for many of whom, as Kim puts it, the clinical trial was their “last roll of dice.”
“I look at him every day and thank God, science, and research that we have [Austin] with us,” Kim said.
How It’s Made: The Science of CTL019
One of the most common cancers in children, ALL is also one of the most aggressive. It occurs when immature white blood cells called lymphocytes crowd out normal, healthy cells in the bone marrow. About 20 percent of the 3,500 pediatric and young adult patients diagnosed with ALL each year relapse or fail to respond to conventional treatments.
Over the last 30 years, Carl June, MD, director of the Center for Cellular Immunotherapies at Penn, and his colleagues had been genetically altering a type of immune cell called a T-cell so that it could detect and destroy lymphocytes. After showing CTL019 successfully eradicated cancer cells in mice, Dr. June’s team tested the therapy in adult patients with advanced chronic lymphocytic leukemia (CLL) in 2010. As the evidence supporting immunotherapy began to build, Stephan Grupp, MD, PhD, director of the Cancer Immunotherapy Program at CHOP, was preparing to lead pioneering clinical trials for CTL019 in pediatric patients with an advanced form of ALL.
Years before her son’s diagnosis, Kim, an oncology nurse in Wisconsin, watched the remarkable story of Emily Whitehead, who was 6-years-old when her leukemia stopped responding to conventional treatment, on the news. Looking for a last chance, Emily’s family met with Dr. Grupp and made the brave decision in April 2012 for her to become the first child in the world to be treated with engineered T-cell therapy. The new treatment differs from any pediatric cancer treatment seen before.
First, patients have a small percentage of their T-cells extracted from their body through a process called leukaphresis. While the patient returns home, scientists get to work: Using a modified version of the HIV virus, they reprogram the cells with the ability to target a specific protein called CD19, found on the surface of cancerous B-cells. The bulked-up new T-cells can now recognize and attack quickly-dividing cancerous B-cells in a similar way that immune cells typically fight viruses or bacteria.
When infused back into the patient, the T-cells multiply into a brigade of hunter cells that dispatch throughout the body, binding to and killing B-cells. Tests show that an army of infused T-cells can grow to more than 100,000 new cells for each single engineered cell that a patient receives. The bioengineered cells then survive in the body for years, controlling any new cancer cells. Because they also kill off healthy B-cells, patients must come in for routine follow-ups to receive IV immunoglobulin, which provides them with the antibodies they lose during the treatment.
Pioneers: CAR-T Cell Therapy’s Earliest Patients
Emily is now 13, and her cancer remains in remission. For the pediatric patients like her who enrolled in the earliest trials, the treatment was a high-risk but high-impact gamble. Most had reached a critical moment in their disease progress.
When a biopsy revealed that it was only a matter of time before Austin suffered a full-blown relapse despite bouts of chemotherapy and a bone marrow transplant, Kim moved fast, packing the family’s bags and arranging to have Austin’s information sent to CHOP for qualification, and his cells collected by one of her colleagues in the oncology department at the hospital where she worked.
Arriving in Philadelphia, Austin became participant number 21 — a number that Kim recalls brought to earth just how investigational the treatment was.
“He ended up being No. 21, and you think, ‘Oh, my gosh, that’s not a lot of kids at all.’ We really just had to roll the dice and pray that it worked. Nothing in this path is a guarantee,” Kim said. “So I just held onto hope. We had to go for it, and just hope and pray along the way that it would work.”
After meeting Dr. Grupp and the tireless team of providers conducting the trial including Shannon Maude, MD, attending physician in the Cancer Center at CHOP, Austin received his T-cell infusion in two doses on Oct. 1 and 2, 2013. His family remained watchful for the appearance of the cytokine release syndrome (CRS) that they had been warned of: a side effect in the form of a hurricane of flu-like symptoms. Six days after his infusion, Austin began to show signs of CRS, including severe headaches and low-grade fevers. He was admitted to the hospital for three nights.
As Austin recovered, the Schuetz’s waited. News of the results from a bone marrow biopsy taken about four weeks after Austin’s infusion arrived on Halloween night, which also happened to be Kim’s birthday. The family was trick-or-treating in a Philadelphia suburb when Austin (dressed as one of the Ghostbusters) reached for a doorbell, and the phone rang. It was Dr. Maude, and her message was short and sweet: The CTL019 therapy was working.
The family returned to home Wisconsin, joining the growing number of cancer immunotherapy patients who, like Austin and Emily, now had hope for healthy, normal childhoods ahead of them. In the early stage clinical trials of CTL019, more than 90 percent of patients achieved a complete remission one month after the therapy. In a subsequent global registration trial in 2015, 83 percent of patients with advanced ALL who received a single dose achieved a complete remission.
Next Steps
As Kymriah™ enters the market over the next few years, research into more cellular therapies continues to drive forward at CHOP. Dr. Maude is leading a pilot study to evaluate humanized CART19 cells (or huCART19 cells) for patients with relapsed or refractory CD19+ leukemia and lymphoma who were previously treated with a B-cell directed engineered cell therapy product. The hope for this product is to extend the time that cells stick around and help more patients avoid the risks of bone marrow transplant.
Meanwhile, CHOP’s Immunotherapy team is also leading the development of a trial that tests Kymriah as part of first-line therapy to prevent relapse or the subsequent need for bone marrow transplant in children with treatment-resistant ALL. Investigators are also developing trials to identify other ALL populations who might benefit from immunotherapy, including patients with Down syndrome and those with central nervous system ALL.
As for Kim, her life feels full of gratitude, purpose, and very welcome cuddles from 9-year-old Austin.
“I don’t think that I could ever repay [the CHOP team] for the work that they’ve done,” Kim said. “I’m just thankful that they are dedicated to kids like mine; that they are just as invested as I am in my son’s life because they want to see this happen.”
The treatment at age 5 that allowed Austin to be so many wonderful things at age 9 — from Cub Scout to collector to cancer survivor — now gives Kim yet another thing that she happily adds to the list: Pioneer.