Bill Ludwig was out of options. The retired New Jersey resident had gone through so many rounds of chemotherapy for his cancer that he’d lost count. A clinical trial at the National Institutes of Health had almost killed him. After nearly 10 years of battling leukemia, Bill couldn’t handle a bone marrow transplant.
“I asked God every night to give me the strength to fight one more day. I didn’t ask him to cure me because there was no cure. So, I asked him for the strength to fight,” Bill says.
Then, Bill was given one more weapon in the battle. It was 2010, and his oncologist at Penn Medicine’s Abramson Cancer Center, Alison Loren, MD, was one of the investigators on a new clinical trial for patients with the same type of leukemia as Bill.
As it turned out, Bill’s last defense was inside him all along. Called CAR T-cell immunotherapy, the investigational treatment involves programming patients’ own immune cells to recognize and kill cancer cells. It’s the first treatment of its kind, pioneered at Penn, and Bill would be the first patient to undergo it.
At the time, researchers didn’t know what to expect. “We have no idea what it’s going to do or how it’s going to work,” Dr. Loren told Bill.
Bill had been Dr. Loren’s patient for nine years, and she says by 2010, with all the side effects from years of treatment, this could be the best chance to greatly improve his quality of life. Bill agreed.
Back to the Beginning
Nine years earlier, in December of 2000, Bill was scheduled for routine blood work before a hernia repair surgery. When he arrived for surgery a week later, the surgeon told him that his blood samples had shown an elevated white blood cell count.
The surgeon wouldn’t make a diagnosis, but suspected that he had leukemia. During surgery, he would take a biopsy for analysis and have the results at Bill’s follow-up appointment.
There, the surgeon confirmed his hypothesis: Bill had chronic lymphocytic leukemia, or CLL, a type of cancer that involves white blood cells called B-cells. In CLL, the immune system doesn’t recognize the cancer cells as cancerous. Instead, it recognizes them as normal B-cells. The surgeon referred Bill to a local oncologist, and that physician concurred.
Going the Distance: Choosing Penn Medicine
When Bill and his wife, Darla, arrived home after the appointment with the local oncologist, they called Penn Medicine—50 miles away.
“I’ve heard stories of people going over the bridge from New Jersey and into Philadelphia for medical problems. They seemed quite pleased. If somebody tells you that you have a disease, you want the best doctors.” Bill says. “Plus, Penn is a teaching institution. They had the possibility of having the newest, brightest brains.”
(From left to right) Dr. Levine, Bill Ludwig, Darla Ludwig and Dr. June
Over at Penn Medicine, immunologist Carl June, MD, was building on years of research showing the immune system could target, and destroy, cancer. For a decade, June’s lab had been genetically altering a type of immune cell called a T-cell so the cells would recognize and attack leukemia cells. They successfully showed the process worked in the lab and in mice.
“But a lot of things effective in mice don’t work in people,” says David Porter, MD, an oncologist at Penn who was leading the research and working with June.
In 2006, Dr. Porter began drafting the clinical trial. But the group was not ready to actually treat patients until 2009. In August 2010, the investigators identified their first patient: Bill Ludwig.
Prior to enrolling in the trial, Bill’s care involved rounds of chemotherapy every few months when his white blood cell count grew too high. The cycle took its toll. When Dr. Loren raised the prospect of the CAR T clinical trial in early 2010, she says Bill was “very open, trusting, and willing to try. He was really brave to do it”—especially considering the previous clinical trial that had almost killed him.
“It could work or it could not work. But that’s the only thing I had left,” Bill says.
Clinicians collected T-cells from Bill’s blood using a procedure called leukapheresis. A machine spun out Bill’s T-cells, and those cells went to the lab of Bruce Levine, PhD.
Dr. Levine’s lab injected the T-cells with a virus that included the CAR gene. This new gene became a part of the T-cells’ DNA, and the cells continued to reproduce with that gene on their surface. This meant that Bill’s own T-cells could now recognize the cancerous B-cells and know to take the next step: destroy them.
Two weeks later, the cells had grown 700 fold, and were ready to be reintroduced to Bill’s blood stream, where they would grow even faster.
“When they recognize there are cells to kill, it activates them to reproduce,” Dr. Porter explains. “You can get thousands of cells for every one that you put in. At one point, we estimated the cells were growing 1,000 to 10,000 fold in the body.”
Waging War on Cancer: Fighting from Within
Bill Ludwig with his nurses during treatment
In July of 2010—on his wedding anniversary—Bill checked into the hospital. He describes a vastly different therapy experience than the hours he’d spent attached to chemotherapy infusions.
“They put the line in and brought me the first infusion bag. Three minutes later, they were done.”
Throughout the week, he received two more infusions and planned to go home the day after the final one—Friday. As the first patient, nobody knew what to expect, but the team was excited to find out.
Shortly after his last T cell infusion, Bill became increasingly ill.
“I went from one day to the next like a roller coaster,” he says. He was having a rapid immune response that was good for going after cancer cells but less beneficial for Bill’s overall health. As cells reproduce, they release cytokines—substances that cause fever, chills, low blood pressure, and other adverse effects.
Then one evening, a doctor came in after Darla had gone home for the night.
“You need to come back. Bring the family,” the doctor told Darla over the phone. “Bill will not see sunrise.”
Surviving to See the Sunrise
But then a remarkable thing happened. Bill did see the sunrise. He’s seen many years of sunrises since.
“Slowly but surely, I started to get better mentally and physically,” he says.
A month after treatment, Dr. Loren ordered a bone marrow biopsy to check the levels of cancer cells in Bill’s blood. A few days later, Dr. Loren came back and said she needed to take another sample.
The following Saturday morning, Dr. Loren entered Bill’s room.
“I have to give you news, and I need it to come from me,” she told him.
Bill was prepared for the worst. As he shared the next part of the story, he had to pause. Tears choked his voice.
“I owe you an apology because the first bone marrow biopsy they did on Tuesday was processed by the lab.” Dr. Loren told him that Saturday morning. “The results that came back from that test—no one could believe.”
“What do you mean?” Bill asked.
“You have no cancerous cells in your body as we speak. They’re gone. That’s the reason we did the second biopsy,” Dr. Loren told him.
She remembers having mixed emotions about breaking the news. “You become really humble about giving patients false hope. In the leukemia world, it’s unfortunately common. ... We thought the lab had mixed up his results. Anybody with CLL, you never get rid of it entirely. You can always find traces in bone marrow. The fact that his bone marrow blood count was normal was unprecedented.”
Dr. Porter remembers having a similar reaction: “We were all optimistic that this would work, but not so perfectly and potently.
After Dr. Loren broke the news, Bill sat alone in silence.
“My brain was going 100 miles an hour,” he says.
Bill couldn’t believe what he’d heard. “I was scared to death. For 10 years, I fought to wake up every morning,” he says.
A week later, Dr. Loren reviewed the therapy with Bill and Darla in her office. She explained that the researchers now knew what Bill’s adverse reaction was: cytokine release syndrome.
“Is he cured?” Darla asked of the leukemia.
“No,” Loren replied.
“Is he in remission?”
“Well, what’s his status?” Darla asked.
“We’re going to call it cancer free. We don’t know from right now forward,” Loren said. “We know right now back. No one has walked in his shoes before.”
Changing the Course of Cancer Care
Bill, Darla and their granddaughter
Fast forward to July 31, 2017—seven years after Bill went to Penn Medicine. He and Darla walked out onto their driveway, boarded their RV, and drove west toward South Dakota.
“This is the best vacation we’ve ever had because, between 2001 and 2010, our only vacation was going to Philly for treatment,” he says. “I’m the most fortunate person on the planet when it comes to leukemia.”
Bill’s luck spread to others, too. Dr. Porter says that more than 400 people have undergone similar trials at Penn and CHOP following Bill’s success—along with hundreds more at other centers.
Pharmaceutical company Novartis manufactures this gene therapy product and recently received approval from the FDA, so that initially it will be available to children and young adults with acute lymphoblastic leukemia (ALL).
Already, the therapy has spread to 11 countries, leading to remission for 83 percent of patients with ALL. A year later, two-thirds of that 83 percent remain in remission. The implications for the future of cancer care are immeasurable.
“I don’t think we could have predicted how potent it was going to be. That was beyond our wildest dreams,” says Dr. Porter, the clinical trial principal investigator at Penn Medicine. He hopes that more people can benefit and that the future holds promise for not only ALL or CLL, but other kinds of cancers as well.
Dr. Loren adds, “If [Bill] had died from those complications, who knows how many patients would never have gotten this, and it definitely wouldn’t be given to kids. All these kids owe their lives to him. If he hadn’t been willing to try, that trial easily could have closed.”
Bill and Darla looking at pictures of the major milestones of Penn's CAR T-cell therapy since Bill's treatment.
Instead, Bill and the team at Penn persevered. Recent forms of immunotherapy, such as checkpoint inhibitors, have undoubtedly revolutionized cancer treatment. However, using a person’s own immune cells to recognize and kill cancer cells opens a new chapter in cancer treatment.
“In running, no one could break the four-minute mile—until someone did,” Dr. Loren says. “And then 10 more people did it. It’s like you almost have to break a mental block. CAR T-cell therapy is really important as proof of concept that this is possible.”
Today, Bill says he appreciates his team at Penn and the years the treatment has given him—all while gushing over his granddaughter.
“She makes the world go ‘round, and just think what I would’ve missed,” he says. “I imagine that every family in the country has a family member with a cancer story. This could be the beginning of the end of some of that tragedy.”
In August 2017, Kymriah™ became the first CAR-T cell therapy to be approved by the FDA. Developed here at Penn Medicine, Kymriah™ was approved to treat patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL).
In addition to leukemia, Kymriah™ is approved to treat adult patients with diffuse large B-cell lymphoma (DLBCL) – the most common form of non-Hodgkin lymphoma (NHL) – as well as high grade B-cell lymphoma and DLBCL arising from follicular lymphoma.
Yescarta™ is another CAR therapy approved by the FDA for treatment of this disease.
Penn Medicine is the only cancer center in the Philadelphia region approved to administer both Kymriah™ and Yescarta™ for patients with DLBCL.