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CAR T-Cell Therapy

The New Frontier of Hope

Neff Newitt, Valerie

doi: 10.1097/01.COT.0000526653.15787.41
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Emily Whitehead; CAR T-cell therapy
Emily Whitehead; CAR T-cell therapy:
Emily Whitehead; CAR T-cell therapy

The promise of life was in full bloom in May 2010. At just 5 years of age, Emily Whitehead was running, playing, and indulging the very spirit of childhood. Years earlier, she'd been born a healthy 10-pound baby who grew into a robust youngster. But in the course of a single week, everything would change.

Emily's story is a dramatic one, placing her close to death at various intervals. And while the tenets of good storytelling might seek to keep all in suspense throughout that retelling, the ending to Emily's story is really the beginning to another saga that holds epic importance in oncology.

Little Emily eventually became the first pediatric patient with refractory/relapsed acute lymphoblastic leukemia (ALL) to be treated with her own re-engineered immune cells using chimeric antigen receptor (CAR) T-cell therapy developed by the University of Pennsylvania and Children's Hospital of Philadelphia (CHOP). Her heroic fight against staggering odds, the insights and devotion of her parents, and the Herculean efforts of her medical team have resulted in many more springtimes for Emily.

Their collective efforts also planted fertile seeds that brought forth greater understanding of immune cell therapy, strategies for countering side effects, and a groundbreaking FDA approval of a personalized immunocellular therapy in the form of tisagenlecleucel. Approved for use in pediatric and young adult patients with B-cell ALL whose disease has not responded to initial treatment or has relapsed, it is the first therapy based on gene transfer approved by the FDA. In short, Emily's medical journey has lead to a milestone marking a new era of cellular therapies that take advantage of a patient's own immune system.

In an Aug. 30 statement, the FDA called this approval nothing short of “historic.” It is a sentiment echoed by David Porter, MD, a member of the team that developed CAR T-cell therapy, and Professor in Leukemia Care Excellence and Director, Blood and Marrow Transplantation at the Hospital of the University of Pennsylvania.

“It is the beginning of a new approach to cancer treatment that hopefully will lead to an entire new field,” said Porter, who added he has felt humbled to be involved in such a momentous movement. “I believe we will look back and say this was historic; this was the first time this has ever happened.”

Emily's Journey

Emily had no apparent health issues until the day before she was diagnosed, said her father, Thomas Whitehead of Philipsburg, Pa. “We had noticed her gums bleeding a couple of times and when she took her bedtime bath, we saw there were 21 bruises on her body. That was our first sign that something was wrong.” The next day, Emily's mother, Kari, a researcher at Penn State University, Googled the symptoms that also included some knee pain Emily had mentioned, and results came up symptomatic of leukemia.

Emily Whitehead
Emily Whitehead:
Emily Whitehead, and her parents, Tom and Kari, traveled to CHOP in May 2017, during which time Emily received results confirming her cancer has remained in remission for more than 5 years.
Emily Whitehead; Stephan Grupp, MD, PhD
Emily Whitehead; Stephan Grupp, MD, PhD:
Stephan Grupp, MD, PhD, meets with Emily Whitehead and her parents during the May visit. Photos courtesy Children's Hospital of Philadelphia

“Let's not panic,” Whitehead told his wife. “We'll take her to the pediatrician tomorrow.” Overnight, Emily developed severe pain and when she was seen by the pediatrician the next day she was directed to the emergency department of the adjacent Clearfield Hospital. After a blood test, the diagnosis was made: Emily had leukemia. She was then transferred to the Penn State Children's Hospital, Hershey, Pa., where she was put on a morphine pump.

“They told us she had ALL, and that it was the most curable kind of cancer,” recalled her father. “They said, ‘If your child is going to have cancer, this is the one you want her to have.’ But we've learned differently. There is no good cancer.”

Though chemotherapy is usually extremely effective for pediatric patients with ALL, Emily proved to be the exception. Whitehead recounted, “After two outpatient chemo sessions, I called the medical center and said, ‘I know we're new to this, but when I touch Emily's legs she screams in pain. Is that normal?’”

It wasn't. The Whiteheads were directed to take their daughter back to the hospital where doctors told them, “Today cancer is not your problem. Today you have to try to save her life. Emily has infections in both legs and we may have to amputate.” Whitehead said the chemo had “knocked out” Emily's immune system and necrotizing fasciitis had developed in her left thigh and right calf. It was then that his daughter's fighting spirit emerged in full force. She battled through surgery—legs intact.

Emily spent the rest of her induction period at the hospital, and the chemo gave her a fickle gift of remission. But 16 months later, during a routine blood check, the news was bad. “This almost never happens when children respond to chemotherapy,” doctors told the Whiteheads, “but it appears Emily is relapsing.” A bone marrow test the next day confirmed the relapse.

When doctors suggested more chemo and a bone marrow transplant, the Whiteheads first opted for a consultation at CHOP where they were reassured that the treatment plan was appropriate. So the family returned to Hershey, closer to home, to await the procedure. Though a donor was successfully identified and available a few weeks hence, Emily's condition worsened so rapidly that she was no longer a candidate for the transplant.

The Whiteheads went back and forth between Hershey and Philadelphia, trying to determine the best course of action, which included more chemo and a possible trial for a new medication (which they ultimately believed was not in Emily's best interest). They had also been told about a CAR T-cell therapy (CTL019, now FDA approved as tisagenlecleucel) trial on the horizon, but the doctors said it would commence too late for Emily. After returning yet again to Hershey, more chemo was delivered. But her home medical team finally hoisted the white flag. “They told us, ‘We have no more weapons to use to fight Emily's illness. Take her home and enjoy the days you have left with her,’” her father remembered.

It was then that Thomas Whitehead became—for want of a better term—almost supernaturally enlightened. He recalled that a great many decisions had to be made in a short space of time and said he once went 60 hours without sleep while dealing with the stress of the demands of immediate, life-and-death decision-making. But then there were two nights when he did fall asleep. And he had dreams—prophetic in character—that would inform the decisions still to come. He saw in his dream that Emily would be treated at CHOP (“...it had to be in Philadelphia...”) and contrary to reasonable medical expectations, he also saw that she would survive. “I knew taking her home to die was not an option,” he declared.

Going on the belief that this knowledge was more than mere hopefulness, the Whiteheads called CHOP and said, “We're coming there, no matter what you can or can't do. We aren't going to let it end like this.”

On the other end of the line was Susan R. Rheingold, MD, Medical Director of the Oncology Outpatient Clinic and an attending physician with the Cancer Center at CHOP, and with whom the Whiteheads had earlier consulted. “She said, somewhat incredulously, ‘I can't believe you are calling at this moment. The very last email I read said we are allowed to treat our first pediatric ALL patient with CAR T cells. It is all moving ahead much faster than we expected,’” told Whitehead. Emily would become that patient.

Emergence of CAR T Cells

A year before Emily became part of this immense research and clinical effort, three adult patients at Penn with chronic lymphocytic leukemia (CLL) were considered hopeless in terms of medical intervention. At the same time, Carl June, MD, Professor of Immunology in the Department of Pathology and Laboratory Medicine in Penn's Perelman School of Medicine and Director of the Center for Cellular Immunotherapies in the Abramson Cancer Center, joined by Porter and other investigators, already believed in the concept of CAR T-cell therapy. “We embraced it,” said Porter, “because it worked well with mice in the lab. But it was only cautious optimism; we'd all seen study after study that proved curing a lot of mice with leukemia doesn't necessarily result in curing humans.”

However, the investigation moved forward and the three adult CLL patients were treated. Two of the three achieved rapid complete remission, eradicating several pounds of tumor within a few weeks. “We expected some progress, expected to learn more about developing this therapy. But none of us exactly expected the rapid, dramatic response that we saw,” noted Porter. “The results were staggering. Shocking. Two of these three people—who were actively dying of leukemia and who had no other options—went into remission, and are now long-term survivors. This was effective where nothing else had been. It led to so much excitement, realizing that this really might work, really might eradicate leukemia. We had never seen any therapy like that. We all knew we were at the beginning of something really big—not just a new treatment, but a new approach to treatment.”

It was at about the same time that Porter's friend and colleague, Stephan Grupp, MD, PhD, Professor of Pediatrics at Perelman School of Medicine at Penn, and Director of the Cancer Immunotherapy Frontier Program at CHOP, was very interested in testing this therapy further. “Steve was interested in treating children with ALL,” said Porter, explaining that both ALL and CLL are B-cell malignancies that have the same target, CD19. “Given the things we were learning about it in adults, added to some additional safety data, we felt we had some understanding of what to expect. So it was not a giant leap to be able to use it in children.”

Grupp himself was no stranger to CAR T-cell research, having been involved in the area since 2000. “Several things were investigated all at once,” Grupp told Oncology Times. “We started with CLL and added on ALL and then non-Hodgkin lymphoma. All had the same targets, so it made a ton of sense. Of course, in the beginning we had no idea that anyone would respond to this at all.”

From a scientific standpoint, Grupp has found the work “... incredibly elating. But when you realize you have something in front of you that could be this important for this group of patients, the responsibility is almost overwhelming. How do you move this forward as quickly as possible? How do you get through roadblocks? Is it even conceivable that you could transfer a treatment like this that is so highly individualized to a drug company process and make it something that could eventually be FDA-approved? If you asked me that 3 or 4 years ago I would have said, ‘Oh my God, that seems impossible.’”

In fact, the whole area of effort could have collapsed in the midst of Emily's journey, and nearly did.

Emily's Battle

“We transferred to CHOP on March 1, 2012, met Dr. Grupp, and he explained about the CAR T-cell trial and we signed a consent that same day,” recalled Whitehead. “They put an apheresis catheter in her neck and extracted her T cells the next day, and followed up with a round of chemotherapy which completely knocked out her immune system, so she had to stay in isolation in her hospital room for 6 weeks.” During that time, her cells were re-engineered and made into fighting, warrior cells aimed at her cancer.

Then the moment of truth came—and it was not immediately pretty. On April 17, 18, and 19, 2012, Emily's re-engineered CAR T cells were infused back into her body. Within days she experienced cytokine release syndrome (CRS)—a veritable cytokine storm of the greatest intensity. While it was not an entirely unexpected reaction, its intensity was.

“Within days, CRS almost took her life,” recalled her father. “She had a 105°F temperature for many days, breathing difficulty, blood pressure problems; doctors finally induced a coma in the pediatric intensive care unit. She was put on an oscillating ventilator and she stayed on it for 14 days. We were living there at the hospital. It was brutal. Her condition was so bad that doctors told us not to go away. One night, they told us she had a one in 1,000 chance of surviving the night. She swelled up until she was unrecognizable, and it looked like she couldn't come back. They said, ‘She could lose her life at any minute now.’ But Emily kept fighting. And so did the doctors.”

Grupp weighed in on the immensity of the event, saying, “This was the first pediatric patient we'd treated and only the fourth patient ever treated with this medication. If she had experienced fatal toxicity that would have been devastating to her parents, devastating to the clinical team, and might have ended the whole endeavor.”

Porter also recounted those tense hours and days. “When this happened, it was frightening on so many levels. You have a patient—a young child—desperate and dying of leukemia. You have a family in torment. That alone is awful and devastating and sad. But then you think, ‘We gave her these T cells. What did we unleash here? Are we contributing to this misery?’ That makes it even more frightening. This wasn't just nature taking its course through an awful cancer; this was something we initiated and we didn't exactly know what was causing it or what the outcome would be. It was very scary. Potentially devastating.”

But it is because Emily persisted through this terrifying watershed moment that so much more was learned. Grupp explained, “It was so clear that what was going on with her was not some other thing—it was a reaction to the cells. I had put those cells in her body with my own hands. So there was an enormous sense of responsibility and an incredible urgency to try to work something out. We had absolutely no inkling that what we ended up doing was something that one even could do in these circumstances.

“On a Wednesday afternoon, we got back results from a profile for cytokines. Emily had all sorts of abnormalities—multiple cytokines were through the roof. But one, interleukin-6 (IL-6), really stuck out. IL-6 is not made by T cells, so it shouldn't have been part of this mix at all. It was something that really caught our interest.” Though there are very few cytokines that have drugs that directly target them, IL-6 was one that did. And because IL-6 was the one that was most strikingly abnormal, the medical team decided to go after it.

“It was absolutely a Hail Mary,” Grupp admitted. “We were looking for something that didn't belong and that we thought we could fix. On that Wednesday afternoon, we got the info at 3 p.m., by 8 o'clock she had gotten the medication—a repurposed arthritis drug (tocilizumab).”

Porter, too, recalled, “Steve gave her the drug out of desperation. And then there was another staggering revelation. It worked. Miraculously well.”

Grupp added, “The fact that we were able to sort out, on the fly, what was going on with Emily, find a treatment for her—and a treatment available for all the other patients who were receiving any kind of cell therapy, not just our patient—was an extraordinary moment.”

In an hour, Emily's fever was gone. Whitehead proudly recalled, “In a few days she had turned around so fast that the doctors said they'd never seen a patient that they thought would die recover as fast as her. She woke up on May 2, 2012, her seventh birthday—lucky seven!—and we took her home on June 1. She was back in school—on time—in August. I knew she would get better. I always told the doctors that.

“I remember Dr. June saying he had felt for sure it was past the point where she could come back and recover. He said if she didn't turn around, this whole immunotherapy revolution would be over. I can tell you that later Dr. June told me, ‘I personally don't pray that much, I'm a science guy. But you made half a dozen decisions that resulted in Emily being our first patient for CAR T cells and if you had changed any one of those decisions along the way, Emily would not be with us. And twice you went against the doctors when they were giving you the best medical advice possible. I now believe in miracles.’ I believe Emily turned around for a reason,” her father added, “because now this medical revolution is changing the world.”

Facing Forward

Emily is now 12 years old, and pursues the activities of a healthy pre-teen. She likes to make YouTube videos, paint, have sleepovers, and play with her dog, Lucy. “She likes to make homemade slime. And she is obsessed with cows,” revealed her dad.

But unlike most kids, Emily has just travelled to Switzerland with her parents to appear at a pharmaceutical conference to discuss her experience. Emily and her parents do a lot of such travelling and speaking engagements. “It has changed our lives,” said her father, now speaking from an airport as the family was about to board a plane for Europe. “I feel I have a new path now to inspire people and spread the word about the treatment [all the while he continues to be employed as a power company lineman]. Emily travels, too, with the full consent of her school. One principal told me, ‘By travelling, you are giving her an education that we couldn't begin to.’”

One very special, but not-too-distant trip, was at the request of former Vice President Joe Biden. He invited Emily and her family to the launch of the “moonshot” to cure cancer, at Penn. “He cried when he met Emily,” recalled Whitehead.

And the future of CAR T-cell therapy? In a word: optimistic. Tisagenlecleucel is now FDA-approved, following treatment in 63 more pediatric and young adult patients. The use of the CAR T-cell therapy has resulted in remission within 3 months in 83 percent of those patients, all of whom had failed to respond to standard treatments or had suffered relapses. Globally, testing of CAR T cells is just as vigorous. Researchers have built on the experience in pediatric ALL and manufactured CAR T cells for over 250 patients from 11 countries across various indications.

Porter also stressed that, while the recent FDA approval has—most importantly—made the treatment accessible to more patients, “Approval gives it validity, credibility, and makes it clear that it has been reviewed in meticulous detail. It elevates CAR T-cell therapy in the eyes of many people, whether patients or physicians or drug companies.”

The next frontier is testing CAR T-cell therapy in solid tumors. Porter informed, “Solid tumors present different challenges, because it is harder to identify the target on solid tumors. However, Penn has had trials on lung, ovarian, pancreatic and breast cancers, and glioblastoma. I am quite optimistic that with enough research and enough study this will someday be a therapy for solid tumors as well.”

Grupp said he hopes those in the field of oncology grasp two primary, overarching realities wrought by early CAR T-cell therapy success. “First, this is a brand-new way of treating cancer, so it truly is the tip of the iceberg—the first in what I hope is a large class of therapies for cancer. The second thing is we've made this work in a variety of blood cancers, not just leukemia. So the next real challenge is to make this work in more common adult solid tumors like breast or pancreas or lung. That is the work of the next 5 years. I personally am extremely optimistic that we will be able to do that.

“But until it happens,” he said cautiously, “we simply have to work hard. Right now it is just hope. But there is nothing wrong with hope.”

Valerie Neff Newitt is a contributing writer.

A Continued Quest to End Childhood Cancer

The Emily Whitehead Foundation is a non-profit that raises awareness and funds for childhood cancer research. The foundation aims to provide funding to researchers to develop innovative and less-toxic treatments, such as immunotherapy, for pediatric cancer patients. Emily Whitehead is a three-time cancer survivor who is alive today because of T-cell therapy. Emily was the first child in the world to receive T-cell therapy. The foundation shares Emily's story to inspire others to take action in the fight against pediatric cancer. You can learn more about the organization's activities by visiting http://emilywhiteheadfoundation.org/.

Wolters Kluwer Health, Inc. All rights reserved.
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