Wearing a purple and white ensemble complete with cape, 7-year-old Emily Whitehead surveyed a line winding around the table. College students volunteering with Penn State’s IFC/Panhellenic Dance Marathon wore brightly colored T-shirts and waited their turn to get their faces painted.
Emily, who loves art, was more than happy to oblige.
She missed last year’s Thon Family Carnival, held each year to support children like Emily who are fighting cancer.
Emily couldn’t wait to walk through the human tunnel and to see her friend, Angela, a senior at Penn State.
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Emily’s parents, Tom and Kari Whitehead, were just excited to see their daughter happy and healthy.
While the line progressed, adults and children alike ran around the gym, dressed up as superheroes for the day.
But, to many people, including a team of doctors and researchers in Philadelphia, Emily is a hero every day.
Beating the odds
While second-grader Emily has returned to her home in Philipsburg, researchers from the University of Pennsylvania and Children’s Hospital of Philadelphia spent this past weekend sharing her story at the American Society of Hematology’s annual meeting in Atlanta.
Diagnosed in May 2010, Emily has had a recurring battle with acute lymphoblastic leukemia, or ALL, the most common form of pediatric cancer.
Chemotherapy failed and she could not remain in remission long enough to receive a bone-marrow transplant. That’s when the Whiteheads turned to experts at Penn and CHOP for help.
In April, Emily became the first child to have her own T cells — infection-fighting white blood cells in her immune system — genetically engineered to recognize and attack the cancer cells in her body. The doctors removed her T cells through a process similar to blood donation, programmed them to attack her cancer, then grew them and injected them back into her body.
A few days later, Emily spiked a fever. A week later, she was on a ventilator in the pediatric intensive care unit, unable to breathe on her own.
On the night of April 24, Emily became gravely ill. The Whiteheads were told their daughter had a 1 in 1,000 chance of surviving the night.
But with the help of doctors working around the clock to save their little girl, the Whiteheads beat those odds.
A week later, the cancerous B cells were absent from her blood work, and on May 13, the Minimal Residual Disease report, which can look for one leukemia cell in 10,000 to 100,000 cells or more, came back negative for cancer.
On June 1, Emily got to go home.
Since then, the doctors and researchers have been using what they learned from Emily’s case to treat other cancer patients who have run out of conventional options.
Their aim is to eventually replace bone-marrow treatments with the new T cell therapy.
“We are basically trying to treat cancer a whole new way,” said Dr. Stephen Grupp, the pediatric oncologist treating Emily at CHOP.
Training T cells
T cells are “immune cells in the body that are actually very good at getting rid of cells that don’t belong,” Grupp said, but “unfortunately, cancer is really good at dodging T cells.”
Researchers have been working for years to develop a way to “train” these fighter cells to multiply and attack cancer, similar to a vaccine.
But “all those efforts have been essentially unsuccessful because once you get a big tumor in your body, it’s very hard to marshal up the immune system,” said Michael Kalos, director of the Translational and Correlative Studies Laboratory in Penn’s Perelman School of Medicine.
So, under the leadership of Dr. Carl June, researchers decided to attempt to grow the T cells outside the body so there would be plenty to fight off a tumor. This process is known as adoptive T cell transfer, or adoptive immunotherapy.
“So instead of trying to stimulate or trigger a rare cell in somebody’s body by a vaccine, you give them the end product of that, which is a billion cells that are engineered to recognize what you want them to recognize,” Kalos said.
Emily’s form of cancer is leukemia of the B cells, which are another type of white blood cell.
Researchers are “putting in a new gene using a virus. That gene gets incorporated into the actual DNA of the cell … and that gene produces a new protein that doesn’t exist in nature,” Grupp said.
The two innovations that make the treatment possible are creating the new protein, and then getting it onto the T cell’s surface.
That protein is called a chimeric antigen receptor, or CAR, and it forces a T cell to go after and bind with a target on a cancer cell.
In Emily’s case, that target is another protein, called CD19, which is only present on the surface of B cells.
The whole procedure is referred to as the CART-19 process.
“You could call that the ‘guided missile rationale,’ ” said Bruce Levine, director of the Clinical Cell and Vaccine Production Facility, because the T cells only kill the B cells. That is different from traditional chemotherapy, which doesn’t have a specific target.
The research team used a gutted HIV virus, called a lentivirus, to introduce the chimeric antigen receptors into the T cells. The infectious part of the virus is removed, leaving “just the carcass” behind for this process, so there is no risk of viral infection, Kalos said.
Once the T cells are grown and testing is complete, a process that takes at least three weeks, they are given back to the patients to start fighting the disease.
The idea is similar to that of an immunization. The difference is that with immunizations, the T cells learn how to attack a disease by themselves.
“We’re not letting the immune system figure it out by itself,” Grupp said. “We’re forcing it to attack by using this genetic engineering approach.”
Grupp said the advantage to using T cells instead of traditional cancer treatments is that successfully introduced T cells grow in the body and will potentially be there for a long time to keep looking for cancer cells.
Penn researchers first reported on this type of successful T cell treatment last year. Three adults were treated and two had complete remission. Their cases were detailed in the New England Journal of Medicine and Science Translational Medicine in August 2011.
Two years after treatment, the two adults still have no evidence of disease — they also still have the engineered T cells present in their bodies, a major scientific breakthrough, researchers said.
“The problem is that lots of people have figured out how to engineer T cells, lots of people figured out how to grow T cells in a lab, but nobody figured out how to make the cells actually grow in the patient,” Grupp said.
That is, until now.
This weekend, researchers shared new data showing that nine of 12 patients with advanced leukemia in the clinical trial, including Emily and another child after her, responded to treatment.
“When we first treated our first three adults ... the results came back over a period of six weeks, and at that point I knew that my life was forever changed,” said June, the Richard W. Vague professor in immunotherapy in the department of pathology and laboratory medicine and director of translational research in Penn’s Abramson Cancer Center.
“We were worried that there was a small number of patients but what we’ve seen has never been seen before. And now ... two years later, the results have held up and we have more patients. ... I was always worried that this is a fluke of small numbers ... but now we know that it wasn’t just a fluke. In April, when Emily got treated, it both confirmed it and then showed that it works in a different kind of cancer.”
June hopes that genetically engineered T cells will one day replace more invasive procedures.
“It is possible that in the future, this approach may reduce or replace the need for bone-marrow transplantation,” June said in a news release.
Not without risk
While the study has shown “dramatic evidence that things work,” Kalos said, it’s not without risk.
After the T cell infusion, each of the patients became ill — marked by fever, nausea, hypoxia and low blood pressure — from the rapid release of cytokines, or cell-signaling proteins, from the T cells once they began fighting the cancer.
“The T cells get so revved up and there’s so much tumor that patients get quite sick,” Kalos said. “And (Emily) was probably an extreme example of that.”
And out of Emily’s struggles have come great discoveries.
“In retrospect, this is all 100 percent clear, but I can tell you in the moment (it) wasn’t as clear,” Grupp said.
“At the time, we were going back and forth asking if this is an infection or is it the T cells, and then over the next few days it became very clear that this was pretty much due to her T cells” because they started appearing in her blood work in large numbers, he said.
The researchers saw that the T cells were producing inflammatory proteins, which cause some of the side effects, including fever.
On her worst day, Emily was given the medication tocilizumab to target an inflammatory protein that was particularly high in her system. The medication is normally used to treat rheumatoid arthritis, but it had a dramatic effect on Emily.
“We think (it) is really sort of the keystone ... of the toxicity effect of the T cells,” Grupp said. “This is the astonishing thing. It’s not like we invented this drug. It was sitting on the shelf in a pharmacy.”
Emily began getting better in a matter of hours, something researchers attribute, in part, to the medication.
“We didn’t think it would make her sicker, (but) we had no idea it would make her better,” Grupp said. “No one’s ever used this drug for that purpose before.”
Ever since Emily’s experience, all T cell patients have been given tocilizumab when needed.
One known long-term side effect of the treatment is the permanent loss of non-cancerous B cells for Emily in addition to the cancerous ones, which means she’ll need to take an antibody replacement.
“Not having B cells is something that is not that uncommon,” Grupp said. “We know that the innocent bystander in this therapy is normal B cells, and that is tolerable.”
‘Showed us the way’
“Even if this had not been a good outcome in (Emily’s) case, I think we learned so much from her to be able to treat the next children and adults,” Levine said.
From Emily, researchers learned “that these cells can work very well. They can not only put a person into remission, but do it for a long period time,” Grupp said.
Emily was not only the first child, but also the first person with acute lymphoblastic leukemia to be treated this way. All the adults who were treated had a different type of cancer called chronic lymphocytic leukemia, or CLL.
“It was huge to know that a childhood cancer could respond in the same way as the adults,” Grupp said.
And there is the T cell response treatment.
“You can get quite sick with this treatment and ... there actually is a potential way to manage that and still not interfere with the way the T cells work,” Grupp said.
He said Emily “was the patient who showed us the way for that.”
And the difference between this study and other studies before it that have been less successful?
“The simple answer is the way we make the T cells,” Grupp said. “This is really a night-and-day difference between the old manufacturing approaches and this manufacturing approach.”
While one reason can’t be pinpointed, Grupp said, the use of the HIV lentivirus to insert a gene into the T cells; the complex details of how researchers put the protein pieces together; and the actual growth process, developed by June and Levine, where you start out with a small number of T cells and grow a large number of T cells, all contributed to the study’s success.
“That growth process, in my personal medical opinion, is probably one of the keys to preserving the longevity of these T cells,” Grupp said.
Using immunotherapy to target cancer cells is a different way of thinking for many doctors, said Dr. Susan Rheingold, the medical director of the oncology outpatient clinic. She was the first doctor at CHOP to speak with the Whiteheads earlier this year.
The process is “what I would consider kind of a paradigm shift to what oncologists are used to,” Rheingold said. “It takes a lot of orchestration. … It’s not something I could give to you tomorrow.”
Because T cells that have been weakened by traditional cancer treatments such as chemotherapy are less likely to grow and become cancer-fighting cells, doctors at CHOP are beginning to identify high-risk patients early and storing their T cells before other treatment is given.
“That’s kind of a weird concept for patients to buy into,” Rheingold said. “Before we wipe everything out with chemo, we need to do this three-day thing.”
“That was a key thing that we learned from (Emily) and our subsequent patients,” Grupp said. “That we had to collect her T cells before we gave her the intensive chemotherapy, even though the intensive chemotherapy didn’t do anything for her. That’s why she ended up getting CART-19.”
Levine said researchers are working on ways to improve the T cell culture so that more T cells that have been through chemotherapy can be “rescued” down the road.
Levine said the idea is also a shift for pharmaceutical companies, since each version only treats one individual.
It’s “a drug that’s one-lot-treats-one-patient,” he said. It’s “complex to test and to make this drug, but if you look at what we call the therapeutic index, so the magnitude of the effect, then I think it’s worth it.”
While the T cell treatment is promising, researchers aren’t looking to replace standard treatments at this time. Of the children who are diagnosed with ALL, 85 percent are successfully treated with chemotherapy, Grupp said.
“The place for this treatment is when standard treatments like chemotherapy and radiation don’t work,” he said. “The kids who need these cells are the kids whose leukemia comes back.”
Grupp, who has been practicing bone-marrow transplantation for 20 years, says his “vision for this in the next short number of years is to see whether this treatment could actually be a substitute for bone-marrow transplant, which is very hard and very risky.”
Grupp said: “When I talk about how hard transplant is, I say, ‘If there were another way to do it, we would do it that way and not this way.’ If we could actually take transplant off the table and find a more tolerable substitute and a more effective substitute using these cells, that would be fantastic.”
Levine agrees that a replacement for bone-marrow transplants is on the horizon.
“I think that we have turned that from a dream into a goal. A dream is something you wish will happen, and a goal is something that you’re going to work to make happen,” he said.
“I think we have demonstrated through 16 years of clinical trials starting in 1996 that we have the technology developed to the point, and now we have the resources available to take it to that level to be able to offer it to more patients and to be able to submit it to the FDA.”
The Penn research team is working to expand the study soon with more pediatric and adult patients.
While Emily has stayed in remission for more than six months, the second child also had complete remission, but has not been able to sustain it.
“Our goal is to treat another dozen patients in the next nine to 12 months,” Grupp said. “We’re very excited about the results. Clearly we need more experience with this to see how we do in a broader group.”
The team is also looking to expand the T cell study to different types of leukemia over the next year and to other kinds of cancers.
“In theory, there is no reason why we can’t expand this,” Grupp said. “And we are actively working on expanding this into other cancers. No questions about that.”
In August, the university made a research and licensing agreement with pharmaceutical giant Novartis, which has opened doors for the researchers.
“We are rapidly ramping up our ability to manufacture more cells,” Grupp said.
And a big part of that is due to the company’s investment in this therapy, he said.
“The next two to three years are going to be incredibly busy for us at Penn and at CHOP,” Kalos said. And seeing Emily’s outcome has “put wind under all of our sails here.”
The next steps are larger trials and then eventually FDA approval.
But right now, the doctors and researchers are enjoying the moment.
“The definition of research is you have to re-search, which means that you spend most of your career (where) your job description is failure,” Kalos said. “So most scientists, researchers, clinicians spend the entirety of their careers trying to develop something and not succeeding. …
“We have small advances, but not really doing something profound, but it’s the dream of all of us that do this. To actually be part of something that succeeded at the level that this succeeded is extraordinary.”
‘Rolling with it’
While Emily was being treated, the Whiteheads updated family and friends on her progress through aFacebook
Today, that page has more than 17,600 followers, and her celebrity is expected to grow.
“It seems like everywhere we go someone recognizes Emily,” Tom Whitehead said.
But they’re just taking it in stride. Their goal is to let everyone possible — especially other families with children facing cancer — about the T cell study.
“We’re really trying to do as much as we can,” he said. “Parents whose kids are having leukemia relapses and they don’t know what to do need to know about it.”
Emily appeared on billboards in Philadelphia and Atlantic City to promote a CHOP fundraiser in September, and has been fielding interviews with national media organizations in preparation for the T cell study’s release.
And she thinks it’s “pretty cool” that she’ll be a subject in a short film called, “Fire with Fire,” being produced by Oscar-winning director Ross Kauffman. The three-minute documentary will be premiered at the Dubai International Film Festival this week. Kauffman would also like to take the film to the Sundance Film Festival in January where he hopes to gain enough interest to make a full documentary, Tom Whitehead said.
The film will be available to watch Thursday on Emily’s Facebook page and at emilywhitehead.com.
As for Emily?
“She’s just kind of rolling with it,” he said.
‘Dream come true’
Grupp and the rest of the team at CHOP and Penn will continue to monitor Emily’s progress with testing and a bone-marrow check every three months. She’s had a few complications, such as a bout of salmonella, but she’s back in school and excelling.
While the T cells have gone down in number since they’re not actively fighting cancer cells, they still remain present in her body, just like the adults who underwent successful treatment before her.
“We do not use the C-word. We cannot say that (Emily) is cured for a long, long time, but things are looking very good so far,” Kalos said. “We still see T cells in her blood. We still see no evidence of disease. All green lights for (Emily) so far.”
After her recovery, Levine gave the Whiteheads a tour of the lab where Emily’s T cells were grown and stored. Upon learning that Emily got a kick out of the naming system of the freezers — each one has been named after a character from the TV show “The Simpsons” — Levine made Emily a card with her freezer’s assigned animated character that reads: “Krusty says T cells kill cancer.”
A picture of Emily and her sign sits in a frame on his desk, Levine said, to remind him and his staff why they do their jobs.
“I’ve shown (Emily’s) picture when I’ve given talks internally at Penn and a couple times when I’ve given talks outside ... and every time I show that slide, I have a hard time getting through without choking up,” he said.
“That’s the dream when you start out, and you think some day we’re going to be able to do this, and now we’ve done it and we’ve done it in a small number of very lucky patients. But now the next step is to be able to take it several levels above.”
Grupp echoed that sentiment.
“It’s a once-in-a-career, once-in-a-lifetime dream come true,” he said. “No doubt about it.”