Emily Whitehead:

Emily Whitehead

Warriors come in all shapes and sizes. Take for example Emily Whitehead, as fresh-faced a 16-year-old as has ever graced the planet. Her eyes nearly sparkle with intellectual curiosity and dreams for a fulfilling future. But Emily is not a typical teen. She is the first pediatric patient in the world to receive CAR T-cell therapy for relapsed/refractory acute lymphoblastic leukemia (ALL). She is a singular figure in the annals of medicine. She is a soldier on the front lines of the war on cancer. And like the shot heard round the world, her personal medical assault sparked a revolution in cancer care that continues to power forward.

It has been 10 years since the only child of Thomas and Kari Whitehead of Philipsburg, PA, received an infusion of CAR T cells at the hands of a collaborative medical team from the Children's Hospital of Philadelphia (CHOP) and the Hospital of the University of Pennsylvania. That team included, among others, luminary CAR T-cell therapy pioneer, Carl June, MD, the Richard W. Vague Professor in Immunotherapy in the Department of Pathology and Laboratory Medicine and Director of the Center for Cellular Immunotherapies at Penn's Perelman School of Medicine; as well as Stephan Grupp, MD, PhD, Professor of Pediatrics at the Perelman School of Medicine (at that time, Director of the Cancer Immunotherapy Program at CHOP) and now Section Chief for Cell Therapy and Transplant at the hospital. He had been working with June on cell therapies since 2000.

Tremendous progress has flowedgushedfrom the effort to save Emily Whitehead; many more lives have been saved around the globe since that fatefulyet nearly fatalundertaking. While all the progress that has come from this story must be our ultimate theme, it cannot be fully appreciated without knowing how it came to be.

In 2010, Emily, then 5 years old, went from a being a healthy youngster one day, to a child diagnosed with ALL. Chemotherapy typically works well in pediatric ALL patients; Emily was one of the exceptions. After 2 years of intermittent chemotherapy, she continued to relapse. And when a bone marrow transplant seemed the only hope left, her disease was out of control and the treatment just wasn't possible. The Whiteheads were told by her medical team in Hershey, PA, nothing more could be done. They were instructed to take Emily home where she could die peacefully, surrounded by family.

But peaceful surrender didn't interest the Whiteheads; they rejected any version of giving up. It ran contrary to Tom Whitehead's vision of her recovery, something he said was revealed to him in the whispers. He saw, in a prophetic whispering dream, that Emily would be treated in Philadelphia. More importantly, he saw she would survive. It is as if it happened yesterday, said Tom, remembering how unrelentingly he called doctors at CHOP and said, We're coming there, no matter what you can or cannot do. We're not letting it end like this.

Since we treated Emily, we have treated more than 420 patients with CAR T cells at CHOP. She launched a whole group to be treated with this therapy; thousands have been treated around the world.Stephan Grupp, MD, PhD

A combination of persistence and perfect timing provided the magic bullet. It was just the day before that CHOP received approval to treat their first pediatric relapsed/refractory ALL patient with CAR T cells in a trial. And standing right there, on the threshold of history, was that deathly sick little girl named Emily.

At that time, only a scant few terminal adult patients had ever received the treatment, which is now FDA-approved as tisagenlecleucel and developed in cooperation with CHOP and the University of Pennsylvania. When three adults were treated, two experienced quick and complete remission of their cancers. Could CAR T-cell therapy perform a miracle for Emily? A lot would ride on the answer.

On March 1, 2012, Emily was transferred to CHOP and a few days later an apheresis catheter was placed in her neck; her T cells were extracted and sent to a lab. Emily received more chemotherapy, which knocked out her existing immune system, and she was kept in isolation for 6 weeks. Waiting.

Finally, over 3 days in April, Emily's re-engineered T cells, weaponized with chimeric antigen receptors, were infused back into her weakening body. But Emily did not rise like a Phoenix from the ashes of ALL. Instead, she sunk into the feverish fire of cytokine release syndrome (CRS), and experienced a worse-than-anticipated reaction. The hope for a swift victory seemed to be disappearing.

I can still see Emily's blood pressure dropping down to 53/29, her fever going up to 105F, her body swelling beyond recognition, her struggle to breathe, said Tom, of the most nightmarish period of his life. Doctors induced a coma, and Emily was put on a ventilator. For 14 days, her death seemed imminent. Doctors told us Emily had a one in a thousand chance of surviving, said Tom. They said she could die at any moment. But she didn't.

Medical team members who fought alongside the young patient are unwavering heroes in Emily's story. But at the time of her massive struggle, they too were exhausted and battle-scarred, descending into the quicksand of what could have been a failing trial, grasping for some life-saving branch of stability. They knew if CRS could be overcome, the CAR T cells might work a miracle as they had done for those earlier adult patients. But the CRS was severe. There was no obvious antidote; time was running out.

I recall Dr. June saying he believed Emily was past the point where she could come back and recover, said her father. And he said if she didn't turn around, this whole immunotherapy revolution would be over.

The Whiteheads enjoy Penn State football games not far from their hometown. The family has often taken part in Penn State's THON, a 48-hour dance marathon that raises funds for childhood cancer.

June confirmed to Oncology Times that he and Grupp believed Emily would not survive the night. It was mentioned to the Whiteheads that perhaps they should just concentrate on comfort care measures and stop all the ICU interventions, he recalled. I believed she was going to die on the trial due to all the toxicity. I even drafted a letter to our provost to give a heads up.

When the first patient in a trial dies, that's called a Grade 5 toxicity, June noted. That closes the trial as well. It goes right into the trash bin and you have to start all over again. But fortunately, that letter never left my outbox. We decided to continue one more day, and an amazing event happened.

Grupp, offering context to the mysterious amazing event, said it was clear that Emily's extreme CRS was caused by the infusion of cells that he himself had placed in her fragile body. He said he felt an enormous sense of responsibility and incredible urgency as he watched the child struggle to live.

It was not until the CHOP/Penn team received results from a test profiling cytokines in Emily's body that a new flicker of hope sparked. Though Emily had many cytokine abnormalities, the one most strikingly abnormal, interleukin-6 (IL-6), caught the team's attention. It is not made by T cells, and should not have been part of the critical mix. Though there were very few cytokines that had drugs to target them individually, IL-6 was one that did. So the doctors decided to repurpose tocilizumab, an arthritis drug, as a last-ditch effort at saving their young patient.

We treated Emily with tocilizumab out of desperation, June admitted. Steve [Grupp] has told me that when he went to the ICU with tocilizumab as a rescue attempt for CRS, the ICU docs called him a cowboy. The ICU docs had given up hope for Emily. But she turned aroundunbelievably rapidly. Today, tocilizumab is the standard of care for CRS, and the only drug approved by the FDA for that complication. Emily's recovery was huge for the entire field.

Grupp reflected on the immensity of the moment. If things had gone differently, if Emily had experienced fatal toxicity, it would have been devastating to her family and to the medical team. And it might have ended the whole research endeavor. It would have set us back years and years. The impact that Emily and her family had on the field is nothing short of transformational, he declared.

Since we treated Emily, we have treated more than 420 patients with CAR T cells at CHOP. She launched a whole group to be treated with this therapy; thousands have been treated around the world, Grupp noted. And, if not for Emily, we wouldn't be in the position we are in todaywith five FDA-approved [CAR T-cell] products: four for adults and one for kids. And I think it also important to point out that the very first CAR-T approval, thanks to Emily, was in pediatric ALL.

June noted that between 2010 and the time of Emily's treatment in 2012, My work was running like a shoestring operation. I had to fire people because I couldn't get grants to support the infrastructure of the research. It was thought there was no way beyond an academic enterprise to actually make customized T cells, then mail and deliver them worldwide, he recalled.

But then everything changed. We experienced that initial success; it was totally exciting. It was a career-defining moment and the culmination of decades of research. It led to a lot of recognition, both for my contribution and for the team here at the University of Pennsylvania and at CHOP.

Today, hundreds of pharmaceutical and biotech companies are developing innovations. Hundreds of labs are making next-generation approaches to improve in this area, June noted. Today, I'm a kid in a candy shop because all kinds of things are happening. We have funding thanks to the amazing momentum from Emily. She literally changed the landscape of modern cancer therapy.

Grupp said the continuing CAR T-cell program at CHOP offers evidence of success in a broad perspective. There are two things to look at, he offered. The first is how well patients do with their therapy in terms of getting into remission. A month after getting their cells, are they in remission or not? A study with just CHOP patients showed that more than 90 percent met that bar (N Engl J Med 2014; doi: 10.1056/NEJMoa1407222). Worldwide, the numbers appear to be in the 80 percent range (N Engl J Med 2018; doi: 10.1056/NEJMoa1709866). So, I would say it is a highly successful therapy.

We now have trials using different cell types, like natural killer cells, monocytes, and stem cells, noted Carl June, MD, at Penn's Perelman School of Medicine. An entirely new field has opened because of our initial success. This is going to continue for a long time, making more potent cells that cover all kinds of cancer.

The other big question, Grupp noted: How long does remission last? We are probably looking at about 50 percent of patients remaining in remission long-term, which is to say years after the infusion. The farther out we go, the fewer patients there are to look at because it just started with Emily in 2012, reminded Grupp. We have Emily now 10 years out, and other patients who are at 5, 6, 7, 8 years out, but most were treated more recently than that. We need to follow them longer.

June said registries of patients treated with CAR T-cell therapy are being kept worldwide by various groups, including the FDA. CAR T-cell therapy happened fastest in the U.S., but it's gained traction in Japan, Europe, Australia, and they all have databases. The U.S. database for CAR T cells will probably be the best that exists, because the FDA requires people treated continue follow-up for at least 15 years, he explained.

This will provide important information about any long-term complications, and the relapse rate. If patients do get cancer again, will it be a new one or related to the first one we treated? We will follow the outcomes, he noted. Clinicians are teaching us a lot about how to use the informationat what stage of the disease the therapy is best used, and which patients are most likely to respond. This can move us forward.

June mentioned that Grupp is collaborating with the Children's Oncology Group ALL Committee led by Mignon Loh, MD, at the University of California in San Francisco.

They are conducting a national trial to explore using CAR T cells as a frontline therapy in newly diagnosed patients, he detailed. Emily was treated when she had pounds and pounds of leukemia in her body; ideally we don't want to wait so long. There are a lot of reasons to believe it would work as a frontline therapy and spare patients all the complications of previous chemotherapy and/or radiation. The good news is that the clinical trial is under way, and I suspect we may know the answer within 2 years.

The only true measure of success in Emily's case is the state of her health. When asked if she is considered cured, June said, All we can do is a lot of prognostication. We know with other therapies in leukemia, the most similar being bone marrow transplants, if you go 5 years without relapsing, basically you are considered cured. We don't know with CAR T cells because Emily is the first one. We have no other history. But she's at a decade now, and in lab data we cannot find any leukemia in her. So by all of the evidence we haveand by looking in the magic eight ballI believe Emily is cured.

One might think that going through such a battle for life would be enough for any one person, any one family. But for Emily and her parents, her survival was just the beginning of a larger assault. All of them saw the experience as a way to provide interest in continuing research, education for patients as well as physicians, and an extension of hope to other patients about to succumb to a cancerous enemy.

Tom thought back to one particular occasion, all those years ago, when Emily finally slept peacefully through the night in her hospital bed. I should have felt nothing but relief, but I heard a mother crying in the hallway. Her child, who has been in the room next door, had died that morning, he recalled. I am constantly reminded of how fortunate we are. There are so many parents fighting for their children who do not have a good outcome.

As soon as Emily regained her strength and resumed normal childhood activities, the family began travelling with members of the medical team, joining in presentations at meetings and conferences throughout the world. They wanted to give a human face to the potential of CAR T-cell therapy, and as such they willingly became a powerful tool to raise understanding and essential research dollars. In 2016, the Whiteheads founded the Emily Whitehead Foundation (www.emilywhiteheadfoundation.org) ...to help fund research for new, less toxic pediatric treatments, and to give other families hope.

We decided to hold what we called the Believe Ball in 2017. We asked lots of companies to sponsor a child who had received CAR T-cell treatment to come with their family to the ball at no cost to them. Each company's representative would be seated with the child and family they sponsored, and would meet the doctors and scientists involved in the research, as well as members of industry and pharma, to see exactly where research dollars are going. We implored these companies to move the cancer revolution forward with sponsorship. When it all shook out, we had around 35 CAR T-cell families together for the first time, said Tom.

He noted proudly that since the foundation's debut, donations have been consistent and now have totaled an impressive $1.5 million.

When the Emily Whitehead Foundation had a virtual gala recently, it awarded a $50,000 grantthe Nicole Gularte Fight for Cures Ambassador Awardto a young researcher working to get another trial started. The award is named for a woman who found her way to CAR T-cell trials at Penn through the Whitehead Foundation. The treatment extended her life by 5 years during which time Gularte became an advocate for other cancer patients, travelled with the Whiteheads, and made personal appearances whenever she thought she could be of help or inspiration. Eventually, she would relapse and succumb, but she assured Tom Whitehead, These were 5 of the best years of my life. I think my time here on Earth was meant to help cancer research move forward.'

While raising funds for progress is important, the Whiteheads' work is not just about bringing in money. It's also about education.

We want to send a message to all oncologists; they need to be more informed about these emerging treatments when their patients ask for help, Tom noted. In the beginning of CAR T-cell therapy, a lot of doctors were against it. It's hard to believe, but some still are, though not as much. We need more education so that oncologists give patients a chance to get to big research hospitals for cutting-edge treatments before everything else has failed.

June said he regularly interacts with patients Tom or the foundation refer to him. Such unawareness happens with all new therapies, he noted. The people most familiar with them are at academic medical centers. But only about 10 percent of patients actually go to academic centers, the rest are in community centers where newer therapies take much longer to roll out, he explained.

So much of Emily's life has been chronicled through the eyes of observers. But since her watershed medical intervention, she has grown into a well-travelled, articulate young woman who talks easily about her life. I used to let my father do all the talking, but I am finding my own voice now, she said, having granted an interview to Oncology Times.

I'm currently 16 years old and I'm a junior at high school. Just like when I was younger, cows are my favorite animals, she offered with a laugh. I still love playing with our chihuahua, Luna. In school, I love my young adult literature class because I really like reading. Besides that, I like art and film. And I'm in really good health today.

She mentioned her health casually, almost as an afterthought. I really don't have any memory of my treatment at this point, she revealed, but, the experiences that I've had since then have really shaped who I am. Traveling is a huge part of my life now and something I look forward to. We've been to conferences at a lot of distant places. I'm so grateful that I get to travel with my family and make these memories that I will have forever, while still being able to advocate for less toxic treatment options and raising money for cancer research. All of that is really important to me.

Reminded that she has already obtained fame as pediatric patient No. 1 for CAR T-cell therapy, Emily considered her status for a moment then commented, I don't really like to base the progress of the therapy on my story and what I went through. Instead, I like to take my experience and use it to advocate for all patients so that what happened to me does not have to be repeated and endured by another family. My hope is that CAR T-cell therapy will become a frontline treatment option and be readily available, so pediatric patients can get back to a normal life as soon as possible. I want to tell people if conventional treatments do not work, other options do exist. Overall, I am grateful that I can encourage others to keep fighting. That's the main thing; I am grateful.

After a brief pause, Emily continued, I always tell oncologists and scientists that the work they are doing is truly saving children's lives. It allows these kids to grow up, be with their friends and families, take vacations, play with their dogs, and someday go to college, just like me. They are not only saving patients' lives, they are saving families. The work they do does not go unnoticed or unappreciated. Again, I am really so grateful.

Appreciation is a two-way street, and June said he and his team appreciate and draw inspiration from Emily on a daily basis. Her picture hangs on the wall of our manufacturing center, June stated. Some of the technicians who were in high school when Emily was infused are now manufacturing CAR T cells. They learned so much from Emily's experience; she continues to be a big motivator. She's helped my team galvanize and see that the work can really benefit people.

Grupp said the success that is embodied in Emily Whitehead has spurred additional successes, and new inroads in CAR T-cell therapy. There are more applications now, especially in other blood cancerslymphoma and myeloma, in addition to leukemia. We've seen a lot of expansion there.

He noted a national trial is under way for an FDA-approved therapy called idecabtagene vicleucel, which can benefit multiple myeloma patients. All other CAR Ts target the same target, CD19. But this goes after an entirely different target, BCMA. The fact that we now have approval in something that isn't aimed at CD19 is very exciting. And there are others coming right behind it.

The field also has seen further expansion ...into adults being treated safely, because initially there was concern that these drug therapies were too powerful for safe treatment in older adults, detailed Grupp. Now we know that is clearly not the case, and that is great news, particularly because multiple myeloma most often occurs in people over 60.

The use of CAR T cells in solid tumors continues to be challenging, although Grupp noted, We have certainly seen hints of patients with solid tumors having major responses and going into remission with CAR T cells. It is still a small handful of patients, so we haven't perfected the recipe for solid tumors yet. But I am absolutely confident we will have the answers in a very short numberperhaps 2-4of years.

June said, since Emily's infusion, CAR T cells have matured and gotten better. There are many ways that has happened, he informed. We have different kinds of CAR designs to improve and increase the response rates, to decrease the CRS, or to target other kinds of bone marrow cancers. One that is not curable with a lot of therapies is acute myeloid leukemia (AML), so we have a huge group at Penn and CHOP working on AML specifically. And there is the whole field of solid cancer; we have teams working on pancreatic, prostate, breast, brain, and lung cancer now.

In addition to targeting different types of cancer, June said contemporary research is also exploring the use of different types of cells. Our initial CAR T trial used T cells, and that is what all the FDA-approved CARs are. But we now have trials using different cell types, like natural killer cells, monocytes, and stem cells. An entirely new field has opened because of our initial success. This is going to continue for a long time, making more potent cells that cover all kinds of cancer, not just leukemia and lymphoma.

Is this the beginning of the end of cancer? Is this that Holy Grail called a cure to cancer? It's a question June has pondered.

Some people do think that, he answered. They believe the immune system is the solution. And that's a huge statement. President Biden has made a big investment in this work, with the Cancer Moonshot. He's accelerated this research at the federal level. But we just don't know how long it is going to take. Fortunately, a lot of good minds are working hard to make an end to cancer a reality.

As the battle grinds on, June said he applies something he's learned over time, with reinforcement from Tom and Kari Whitehead. They were bulldogs. When it came to getting treatment for Emily, they just wouldn't take no for an answer. They demonstrated the importance of never giving up. That's what happened; they would not surrender. I think that is why Emily is alive today.

Valerie Neff Newitt is a contributing writer.

The Emily Whitehead Foundation and the Whitehead family take extraordinary advantage of a variety of media to reach patients and physicians and optimize educational opportunities.

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The Incredible Story of Emily Whitehead & CAR T-Cell Therapy : Oncology Times - LWW Journals