Miracles Large and Small: Penn and CHOP Partnerships that Lead the Way

Philadelphia can claim both the first medical school in Amer­ica and the nation’s first hospital devoted exclusively to the care of children. When the University of Pennsylvania moved to West Philadelphia in 1872, it was a bold step that allowed for greater and more thoughtful expansion. Two years later, Medical Hall opened. Formal affiliation between the medical school and the Children’s Hospital of Philadelphia came in 1930. Then, in 1974, the hospital also came west to its present location, next to Penn’s campus. CHOP physicians are mem­bers of the Perelman School of Medicine’s faculty, but the col­laborations between the two institutions go far beyond a sin­gle department. 

In the past decade, these joint efforts have produced re­markable advances as both eminent institutions have grown and developed new interdisciplinary centers and programs. CHOP’s Main Building abuts the Ravdin Building of the Hos­pital of the University of Pennsylvania on 34th Street. But ad­jacent newer buildings serve as a metaphor for the constant growth of both institutions and their shared mission to pro­mote health for people of all ages. Penn Med’s Clinical Re­search Building (emblazoned with a giant Penn shield) and Biomedical Research Building II/III look across Osler Circle at CHOP’s Abramson Pediatric Research Center and Wood Pe­diatric Ambulatory Care Center. And on Civic Center Boule­vard, the newest of the new – and less traditional – edifices have risen: CHOP’s Colket Translational Research Building and the Buerger Center for Advanced Pediatric Care can nod to the Perelman Center for Advanced Medicine, the Smilow Center for Translational Research, the Roberts Proton Ther­apy Center, and the Jordan Center for Medical Education. Collaboration is only a few footsteps away.

The many joint programs housed in these and other build­ings on the two campuses span just about every bodily system and collection of conditions, including the Penn-CHOP Tran­sition Center for Digestive, Liver, and Pancreatic Medicine, with two directors, one from each organization. The group’s work seeks to ensure a safe and smooth transition from pedi­atric to adult care, which can be wrenching when young pa­tients leave behind the well-established regimens they’ve grown accustomed to. A similar program, the Philadelphia Adult Congenital Heart Center, also helps young adults with congenital heart conditions, who are living well into adulthood after de­cades of advances in treating their conditions. One of the principal goals of Penn Med’s Institute for Transla­tional Medicine and Therapeutics is to bridge the pediatric-to-adult divide in the understanding of physiology and disease. The recently established PennCHOP Microbiome Program fo­cuses on the rapidly expanding field that studies the vast number of mi­crobes that colonize our bodies and influence our long-term health. Another complex that wel­comes both adults and children is the Center for the Treat­ment and Study of Anxiety. A newer addition in the area of psychiatric care is the Penn Center for Youth and Family Trauma Response and Recovery, recently profiled in Penn Medicine). 

Among the recent successful collaborations between Penn and CHOP are two in the field of gene therapy – going very far in reviving an area of medicine that had long suffered false starts and serious setbacks – and one that resulted in the first bilateral hand transplant of a child. Each of these advances has an almost science-fiction-like quality that has aroused new public interest in medical conditions once thought to be untreatable.

Mending Broken Genes

For ophthalmologists, making the blind see would be the greatest achievement. Jean Bennett, M.D., Ph.D., the F. M. Kirby Professor of Ophthalmology, and Albert Maguire, M.D., a professor of Ophthalmology, have developed a therapy to treat a retinal disease caused by mutations in the eye’s RPE65 genes. Without treatment, individuals with Leber congenital amaurosis (LCA) – an inherited disease that affects the reti­na’s ability to respond to light – eventually lose their sight. But developing the therapy took a lot of patience, perseverance, hard work, and collaboration, at a time when gene therapy was little more than a distant hope because genetic mutations were just being discovered.

Bennett and Maguire began their collaboration – and life together – long before they came to Penn. They met as first-year medical students at Harvard. Both developed an interest in vision and, it turned out, in each other – they married a couple of years later. Early on, Bennett knew she wanted to develop gene-based treatments. Maguire was studying ophthalmology.

After medical school, as Bennett tells it, Maguire was building his clinical career. “In one of our conver­sations, he asked, ‘do you think gene therapy could be used to treat retinal disease?’ That was in 1985.” Back then, none of the genes that caused eye disease had even been identified, so all the reagents used in creating a gene therapy had yet to be studied and devel­oped. This is when Bennett and Maguire began collaborating to find a way to LCA. Both were recruited to Penn’s Depart­ment of Ophthalmology in 1992. 

Bennett continued her basic research, while Maguire spent most of his time in the clinic. Whenever he had free time, she points out, he came to the lab and used his skills, including his surgical skills. They spent a good part of the 1990s build­ing the infrastructure for future clinical trials. That included developing the means to transport the necessary genes and the surgical procedures to inject the gene therapy – healthy RPE65 genes – into an eye. In 1996, they had success in tests transferring genes in mice with retinitis pigmentosa. “The first time this worked in a large animal was a dog in 2000,” Bennett says. They had successfully transferred healthy genes into eyes of dogs that had a genetic mutation causing LCA. A single in­jection of healthy RPE65 genes was restoring the dog’s vision. The next step would be human clinical trials.

But that would not be easy, because human testing in the entire gene therapy field came to a stop following the death of 18-year-old Jesse Gelsinger. He died in 1999 after participat­ing in a clinical trial at the University of Pennsylvania. Al­though Bennett’s and Maguire’s meticulous work in animal models provided the evidence that their gene therapy ap­proach might help humans vision improve, they were faced with fresh challenges to meet the new stricter regulatory and ethical requirements for conducting human tests. 

Enter Katherine High, M.D., then the William H. Bennett Professor of Pediatrics in the Perelman School and an investi­gator of the Howard Hughes Medical Institute. As the direc­tor of CHOP’s Center for Cellular and Molecular Therapeutics, she was able to offer vast and expert resources for launching a clinical trial. High’s team developed the vector – that is, the vehicle – that would carry the new gene to the cells in the eye.

This Penn Med-CHOP team still had to convince the U.S. Food and Drug Administration, the National Institutes of Health, and two institutional review boards, as well as other committees, that this clinical trial should proceed. Even though they were studying an eye disease that begins in child­hood, the team was asked to conduct the first experiments in adults because there was concern about what the trial would do to the patients’ eyes. Before research is conducted in chil­dren, there must be either adequate safety and efficacy infor­mation from trials conducted in adult participants (given that adults are more capable of weighing the risks and benefits of study participation and making an informed decision) or suf­ficient justification for why adult studies cannot be conducted before conducting the research in children. In addition, the children must stand either to benefit individually from re­search participation or there must be a sufficient argument that, while direct benefit for each participant may not occur, the information gained from the conduct of the research would contribute to generalizable knowledge in a condition that is found only in children. 

In 2007, they were ready. The first three patients to be in­jected by Maguire with healthy versions of the RPE65 gene de­veloped by Bennett were young adults. The results were en­couraging – the patients weren’t cured and were still legally blind. But their improvements in seeing light better were good enough and the safety of the therapy meant that the trial would continue. There were five children in the initial safety trial. One of them was Corey Haas, then eight years old. Already le­gally blind because he was missing the functioning RPE65 gene, he was on the way to total blindness. At CHOP, Maguire injected the gene therapy with a healthy version of the gene into Corey’s worse eye. By the time he was nine, Corey was able to do many of the things healthy children his age could do – see colors better, read print (albeit large-sized, but no longer braille), ride a bike, and play baseball. Today, he’s no longer le­gally blind and so far his improved vision has been sustained.

Another boy who went through the LCA trial is Christian Guardino. He received his injections in 2013 and had his two-year follow-up last summer. Now a 10th-grader on Long Is­land, N.Y., Christian made the news in January when he sang at the New York Stock Exchange as part of a celebration of the Apollo Theater’s birthday 82nd birthday. Christian won the 2014 Grand Prize in the theater’s amateur “Apollo Stars of To­morrow” category.

The subsequent trials progressed well. Last October, phase 3 results of the clinical trial were published, indicating that patients who received the gene therapy met the primary end­point of functional vision compared to the control groups. The trial is now run by Spark Therapeutics, a company launched in 2013 with a $50 million investment from CHOP, [and the company licensed the treatment]. Buoyed by these encouraging results, the company expects to file for FDA ap­proval this year. If approved, it would be the first gene therapy treatment to reach that point. At the same time, Penn’s in­volvement with Spark has continued to expand, and High has left Penn and CHOP to become president and chief scientific officer of the company.

 “We did it, thanks to the interactions between CHOP and Penn,” Bennett says. “All the progress has involved a huge team of people with huge complementary expertise.” 

In addition, this successful Penn-CHOP collaboration led Penn Medicine to launch the Penn Center for Advanced Reti­nal and Ocular Therapeutics (CAROT) in 2014. Bennett and Maguire serve as co-directors. The center functions as a knowledge base to provide interested investigators with guid­ance on constructing vector gene therapy, designing clinical trials, and identifying and enrolling patients.

Bennett is already working on treating another slowly pro­gressing inherited eye disease that leads to blindness: choroi­deremia. The disease is caused by a genetic defect of the X-chromosome, which means that typically only males suffer the full effects. The research is in early-phase clinical trials now, she says, and “early results are promising.” With a num­ber of other targets in the laboratory, Bennett’s enthusiasm for her work never wanes. “It’s a very exciting time for the devel­opment of all these technologies.”

T Cells to the Rescue

It’s not the typical thing on the to-do list of a 10-year-old, but in January, 2016, Emily Whitehead and her family donated $100,000 to the Children’s Hospital of Philadelphia. The money, raised by by the Emily Whitehead Foundation, was earmarked to support research by her physician, Stephan A. Grupp, M.D., Ph.D., a professor of Pediatrics in the Perelman School who heads the Cancer Immunotherapy Frontier Pro­gram and translational research for CHOP’s Center for Child­hood Cancer Research. The hope is that the funds will help propel further progress in the field that made Emily a talis­man for the many researchers and physicians who have de­voted their careers to the pursuit of an effective cellular ther­apy for cancer.

^{Emily Whitehead became the first child to fight cancer using Penn’s personalized cellular therapy.}

Her checkup that day also revealed that three and a half years after she became the first child to receive an experimen­tal, personalized treatment that taught her immune system to fight her cancer, she was still free of the disease.

Emily’s success and survival is the result of a lot of hard work over a long period of time. “It’s been a great collabora­tion,” says Carl H. June, M.D., a professor of Pathology and Laboratory Medicine and director of translational research in the Abramson Cancer Center. He leads the Penn Medicine and CHOP research team that developed the treatment that saved the lives of Emily and dozens of other patients with sev­eral types of advanced blood cancers. Surveying the immense change in Emily’s life since she was near death at the time she entered the clinical trial in 2012, he observes, “To see a pa­tient and the family come back and now be contributing to the treatment of other children – it can’t get better than that.”

Emily was just five years old when she was diagnosed with acute lymphoblastic leukemia (ALL), which has an 85-to-90 percent cure rate with standard chemotherapy. But Emily re­lapsed in 2011, and her chances of survival dropped to 30 per­cent. Even with further therapy, she relapsed again the follow­ing year. Each time, her prognosis worsened.

Later that year, as Emily got sicker and sicker and was run­ning out of options, her mother found information about a clinical trial that had started at Penn Medicine. But Emily couldn’t participate in the trial yet – it was approved only for adults, with a different type of cancer. Again, FDA rules guided the strict process that would pave the way to testing the therapy in children. The timing wasn’t right – yet.

At the time, only a small number of adults, all of whom had chronic lymphocytic leukemia (CLL) that had persisted de­spite multiple conventional treatments, had received the ex­perimental therapy. The treatment used so-called CAR T cells. Carl June, who had been recruited to Penn a decade ear­lier, led the research.

David L. Porter, M.D., a professor of hematology-oncology and director of Blood and Marrow Transplantation in Penn’s Abramson Cancer Center, was in charge of the clinical trial in adults. Grupp was poised to lead the pediatric trial. They, too, had moved in similar orbits even before arriving at Penn. “Da­vid and I crossed paths before we came to Penn because he was at Brigham and Women’s Hospital and I was at Children’s Hospital in Boston,” says Grupp, who conducted some of the preclinical work that was neces­sary to bring the CAR T cell therapy into human trials. 

“I believe the best thing I did was to walk into Carl June’s office about 2000,” Grupp says. “It started a collab­oration that was absolutely incredible and has gone on for 15 years.” He adds that June has been extremely committed to facilitating the pe­diatric work and making sure that what his group was devel­oping in adults would apply to children as well.

T cells are the body’s natural-born cancer-cell killers. The problem is, cancer cells often have cloaking devices that make them invisible to T cells. June and his team developed a way to help a patient’s immune system see the cancer cells and kill them. The process begins with removal of some of each pa­tient’s T cells, through a procedure similar to dialysis. Inside HUP’s Clinical Cell and Vaccine Production Facility, led by Bruce L. Levine, Ph.D., a professor of Pathology and Labora­tory Medicine, those cells are modified into so-called chime­ric antigen receptors (CAR) cells. This engineering allows the new T cells to recognize a specific protein or antigen called CD19, which is expressed on the surface of cancerous B cells found in the blood cancers ALL and CLL. Once infused back into the patient, the reengineered cells hunt for cancer cells and attach to them like Velcro. A signaling domain built into each CAR T cell also prompts them to multiply and grow into 10,000 or more genetically modified cells in the body, expand­ing into a cancer-fighting army in the body as it does its work hunting for sick cells.

Doug Olson, a patient in his 60s, was one of the first three adults to volunteer to try this new therapy in 2010. He be­came a pivotal part of a clinical experiment that would quickly expand to help patients two generations younger.

^{Doug Olson was one of the first patients in the CAR T trial.}

He had been one of Porter’s patients and, for more than a decade, a series of drugs had kept his CLL in check. But the cancer was beginning to win. Porter believed he would be a good candidate for the clinical trial of the T cell therapy now known as CTL019. Olson en­tered the clinical trial at his sickest, without any FDA-approved options left. Entering the clinical trial, he says, was his last shot: “Quite honestly, I wasn’t thinking about moving science forward.” Instead, he was thinking about ways to live long enough until there was a cure for his disease. It’s something he firmly believes every cancer patient should be focused on – what’s right for me.

The treatment indeed worked, and Olson, a retired scientist himself, remains very grateful to be alive. “I’m five years past treatment. I still have these CART-19 cells, and there’s no sign of cancer.” 

But would the treatment work for Emily? By early 2012, she was so sick and her cancer was growing so fast, she didn’t even qualify for a risky bone-marrow transplant. Her father, Tom Whitehead, says she was within days of kidney failure and was offered hospice at the Hershey Medical Center, which had been treating her cancer. The family called CHOP again to see if there was anything they could do. This time around, the timing was perfect: a pediatric clinical trial had opened just the day before. CHOP’s institutional review board had ap­proved the trial based on the strong early results seen in Olson and the other two participants in the adult clinical trial.

So in April 2012, Emily became the first child to fight cancer using Penn’s personalized cellular therapy. The treatment was successful, but while her body was fighting her cancer, Em­ily got very sick with a condition known as cytokine release syndrome. She spent weeks in the ICU. Further studies have shown that this side effect occurs in about a third of the patients, says Grupp, but at the time the researchers were not sure what was happening. Grupp, Porter, and June, along with other members of the team from CHOP and Penn, were in constant communication, trying to figure out how to treat her. In the end, Emily pulled through, after receiving a combination of drugs that have be­come standard therapy to treat patients who suffer severe side effects as the cancer-killing modified cells attack their tumors. The T cell therapy worked, and she has been in remission without further treatment for four years. 

Emily and her family started their foundation to help other children have access to groundbreaking treatments. Since her pioneering experience, the research team has reported results from 59 children – and 55 went into remission.

According to Grupp, 79 percent of patients treated so far survived a year after treatment. Of those who remain in re­mission for a year, not a single patient has seen the cancer re­turn. About twenty children are in this category. In addition to Olson, the first adult patient to receive the therapy, Bill Ludwig, a retired correctional officer, also remains healthy more than five and a half years after participating in the trial. According to the researchers, that is a tempting sign that the therapy may have real potential to last.

Since Penn launched the CART-19 clinical trial (now CTL019), other institutions are conducting similar trials. Grupp notes, however, that there is a big difference. The patients elsewhere are often seeing the engineered T cells go away after about two months, or they receive the therapy as a bridge to un­dergo bone marrow transplants. Although it’s too early to say if these cancer-fighting cells will persist in patients forever, Doug Olson and Bill Ludwig still have them, and Emily Whitehead still has them. 

June is looking to the future when these CAR T cells will help fight other cancers. He expects that his team will make real progress in pancreatic and brain cancers over the next decade – “all because of this leukemia research.” 

Groundbreaking research can take a long time to reach the finish line, which June understands. He’s very optimistic about the future. In fact, he believes many more innovations will de­but in Philly. The foresight and talent that has built upon the long-term collaboration between Penn and CHOP will con­tinue to fuel innovative research. June calls it “CELLacon Val­ley,” a playful nod to Stanford University’s influence that led to Silicon Valley. One piece of evidence is Penn’s recent alliance with Novartis to construct the Center for Advanced Cellular Therapeutics on the Penn Medicine campus. The center, which is dedicated to the development, testing, and manufac­turing of new types of CAR therapies, opened in February, funded in part through a $20 million investment from Novar­tis. Penn’s cell-therapy research has even caught the attention of Vice-President Joe Biden, who kicked off his cancer “moon­shot” fact-finding tour at the Abramson Cancer Center earlier this year.

Giving the Gift of Hands

In the fall of 2011, two months after a Penn Medicine surgi­cal team had successfully completed its first bilateral hand transplant, many of the experts involved gathered on campus to meet the local press. At one point, Abraham Shaked, M.D., Ph.D., direc­tor of the Penn Transplant Institute, was asked how he responded when L. Scott Levin, M.D., Penn’s chair of the Department of Orthopaedic Surgery, first suggested the incredibly intricate procedure. “I thought he was a little crazy,” Shaked said. But when he met the candidate for the first time, she gave him a hug, without arms. He felt very moved. “You start to think about life in a different way,” he said.

Levin, a native Philadelphian, came home to the city in 2009, after 27 years of experience in plastic and orthopaedic surgery at Duke University Medical Center. “From day one, I began working with CHOP,” he says. The process to trans­plant hands involves multiple tissues, including blood vessels, bone, nerves, muscles, tendons, and skin, and calls for spe­cialized expertise from many types of surgeons. Levin began work right away with Shaked, and both were aware that hand transplants were not without controversy. They are not life-saving procedures, although they fundamentally improve quality of life. Nor are the procedures risk-free: just as in the case among patients who undergo organ transplants, the re­cipients of hand transplants must take immune-suppressing drugs for the rest of their lives to prevent rejection of their new hands. The risks of infection, diabetes, tumors, and pre­mature death all rise.

In 2010, the Penn Hand Transplant Program was launched. The new program – a collaboration between the Penn Trans­plant Institute, the Department of Orthopaedic Surgery, and HUP’s Division of Plastic Surgery – would perform only bilat­eral hand transplants. Levin and Shaked became the co-direc­tors. In 2011, the transplant team was prepared. They already had a patient: Lindsay Ess, who followed Levin from Duke. She was the first patient to meet all the medical and psycho­logical criteria for a hand transplant. At age 24, she developed a life-threatening infection that led to the amputation of her hands and feet. Once donor hands were located by The Gift of Life Program, the non-profit tissue and organ procurement program serving the Delaware Valley region, Levin and his team quickly set the operation in motion.

The surgery, lasting more than 11 hours and involving 30 specialists, was a success. Levin and Benjamin Chang, M.D., an associate professor of clinical surgery at Penn, each headed a team that attached one of the donor hands. Lindsay Ess under­went an intensive, months-long regimen of physical therapy to train her to use her new hands. It was six months before she could control her fingers and thumbs, but important step al­lowed her to eat by herself. These days, she has mastered CrossFit, the strength and conditioning program (the version for people with disabili­ties), and is even lifting bar bells. 

If performing a bilateral hand trans­plant on a young adult might strike some people as a little crazy, imagine how they must feel about operating on a child! But according to Levin, Lind­say’s remarkable progress “gave us a foundation to adapt the intricate tech­niques and coordinated plans required to perform this type of complex procedure on a child.” Once again, he teamed with Chang, co-director of CHOP’s Hand Transplantation Program. Levin says the pediatric transplant world is not a large one, and eight-year-old Zion Harvey was referred to him by Scott Kozin, M.D., chief of staff at the Phila­delphis Shriner’s Hospital for Children. The experience gained from Lindsay’s transplants taught Levin and Shaked – and all the other orthopaedic and plastic surgeons, nurses, psycholo­gists, anesthesiologists, therapists, and social workers involved – valuable lessons in preparation for Zion’s surgery four short years later. 

Putting an adult on immune-suppressing drugs for a surgical procedure not meant to save a life was an ethical concern and a medical risk; with a child, it was an even more serious consid­eration. At the age of two, Zion had to have both hands and both legs below his knees amputated after developing a life-threatening infection. Just two years later, the sepsis dam­aged his kidneys to such an extent that he needed a kidney transplant, with an organ donated by his mother. That trans­plant, it turned out, helped pave the way for the first double hand transplant in a child. Because Zion was already taking im­mune-suppressing drugs after his kidney transplant, this ethical concern was moot, which helped convince the institutions to move ahead with the surgery. Another hurdle: Would this young boy have the psychological fortitude to cope with risk of the surgery, painful long hours of post-surgery physical therapy, and waking up every morning knowing he had another child’s hands? In his meetings with Zion, Levin was impressed by his maturity and by the obstacles he had already overcome.

Zion Harvey was 8 years old when he underwent the world’s first pediatric bilateral hand transplant.

 

The Penn-CHOP team was ready; Zion was prepared. But when the operation could proceed depended on when donor hands might become available. That was contingent on the decisions of families in the midst of tragic losses – the death of a child. Levin notes that the donor pool is very limited; each year in the United States, only about 15 children become eligible. But the Gift of Life program and its counterparts across the nation find ways to approach prospective donor families at the worst times of their lives and guide them through the delicate process that allows their children to be­come organ and tissue donors. “The donor families – they are the real heroes,” Levin says.

Last July, while visiting a friend in Montana, Levin got the call that donor hands had been found. He flew back immedi­ately. That same night, he, Chang, Kozin, and about 40 other members of their team assembled at CHOP and began the operation that would give Zion new hands. It was a medical first: the world’s first pediatric bilateral hand transplant.

For what is an already very delicate procedure, Zion’s team had to adjust tools and techniques to account for his smaller bones, blood vessels, and tissues – a critical component of the CHOP teams’ expertise. In the weeks following the procedure, the CHOP physical and occupational therapy team, along with Levin, noticed that Zion’s recovery was not advancing as they had hoped. The cause? His smaller brain. Unlike Lindsay, who lost her hands later in life, Zion’s brain had never fully developed the sensation or power to control his hand mus­cles. Penn Medicine and CHOP clinicians assembled a team of neuroscientists to begin brain imaging and analysis to help with Zion’s mental and physical rehabilitation, adding yet an­other level of integration between the two programs. 

About Zion, Levin says, “I never heard a whimper from him,” even through six to eight hours of therapy each day. By six months after the groundbreaking surgery, Zion could hold a fork and write a letter to Santa, even arm wrestle with his surgeon and friend Dr. Levin. 

Aside from the transplant surgeries, Levin has fostered con­nections between Penn Med and CHOP in other ways. An at­tending surgeon at both CHOP and Penn, he has established a basic research program housed at both hospitals; fellows in hand surgery go back and forth between CHOP and Penn; and Levin has launched national and international education programs.

The public got to meet Zion in the weeks following his story, as his case made news headlines around the world. Be­hind the little boy and his family is a belief and commitment to the power of possibility by the transplant team. It is, Levin says, “an exemplary program that has no boundaries and is fully integrated for a medical cause.”