PHILADELPHIA – Ninety percent of children and adults with acute lymphoblastic leukemia (ALL) who had relapsed multiple times or failed to respond to standard therapies went into remission after receiving an investigational personalized cellular therapy, CTL019, developed at the Perelman School of Medicine at the University of Pennsylvania. The results are published this week in The New England Journal of Medicine.

The new data, which builds on preliminary findings presented at the American Society of Hematology’s annual meeting in December 2013, include results from the first 25 children and young adults (ages 5 to 22) treated at the Children’s Hospital of Philadelphia and first five adults (ages 26 to 60) treated at the Hospital of the University of Pennsylvania. Twenty-seven of the 30 patients in the studies achieved a complete remission by a month after receiving an infusion of these engineered “hunter” cells, and 78 percent of the patients were alive six months after treatment.

“The patients who participated in these trials had relapsed as many as four times, including 60 percent whose cancers came back even after stem cell transplants. Their cancers were so aggressive they had no treatment options left,” said the study’s senior author, Stephan Grupp, MD, PhD, the Yetta Deitch Novotny Professor of Pediatrics in the Perelman School of Medicine and director of Translational Research in the Center for Childhood Cancer Research at the Children's Hospital of Philadelphia. “The durable responses we have observed with CTL019 therapy are unprecedented.”

Shannon Maude, MD, PhD, an assistant professor of Pediatrics and a pediatric oncologist at CHOP, and Noelle Frey, MD, MSCE, an assistant professor of Medicine and an oncologist at Penn’s Abramson’s Cancer Center, are co-first authors of the new study. The research team is led by Carl June, MD, the Richard W. Vague Professor in Immunotherapy in the department of Pathology and Laboratory Medicine and director of Translational Research in the Abramson Cancer Center, along with David Porter, MD, the Jodi Fisher Horowitz Professor in Leukemia Care Excellence and director of Blood and Marrow Transplantation in the Abramson Cancer Center.

CTL019 manufacturing begins with a patient’s own T cells, which are collected via an apheresis process similar to dialysis, then reprogrammed in Penn’s Clinical Cell and Vaccine Production Facility with a gene transfer technique that is designed with the intent to teach the T cells to target and kill tumor cells. The engineered cells contain an antibody-like protein known as a chimeric antigen receptor (CAR), which is designed to bind to a protein called CD19 found on the surface of B cells, including the cancerous B cells that characterize several types of leukemia. The modified “hunter” cells are then infused back into the patient's body, where they multiply and are believed to attack the cancer cells. A signaling domain built into the CAR promotes rapid multiplication of the modified cells that tests reveal can grow to more than 10,000 new cells for each single engineered cell patients receive.

Nineteen patients in the study remain in remission, 15 with this therapy alone, including a 9 year old who was the first ALL patient to receive the therapy more than two years ago. The follow-up periods reported in the study are more than six months for most patients, with a range from 1.4 to 24 months. Five patients went off-study for alternate therapy, three of whom proceeded to allogeneic stem cell transplants while in remission. Seven patients relapsed, between 6 weeks and 8.5 months after their infusions, including three whose cancers returned as CD19-negative leukemia that would not have been targeted by the modified cells.

All patients who received the CTL019 “hunter” cells experienced a cytokine release syndrome (CRS) within a few days after receiving their infusions – a key indicator that the engineered cells have begun proliferating and killing tumor cells in the body, but also a known potentially lethal type of toxicity. During this time, 22 of 30 patients experienced mild to moderate CRS, which included varying degrees of flu-like symptoms, with high fevers, nausea, and muscle pain. Eight patients developed severe CRS, which required treatment for low blood pressure and breathing difficulties. Nine patients were treated with tocilizumab, an immunosuppressant drug that blocks the effects of the inflammatory cytokine IL-6, which have been found to spike during the most robust phase of the engineered cells’ expansion in the body. Six patients also received short courses of steroids to combat CRS symptoms. No patients in this study died as a result of CRS. Tests of patients who experienced complete remissions also showed that their normal, non-cancerous B cells, which also express the CD19 protein, had been eliminated along with their tumors. The researchers note that persistent absence of normal B cells following CTL019 treatment indicates continued activity of the gene-modified T cells, which are believed to represent longer-term, vaccine-like activity, which hopefully will prevent tumor recurrence. Since B cells play a role in helping fight infection, patients typically receive immunoglobulin replacement to maintain healthy immune function.

“Our results support that CTL019 can produce long-lasting remissions for certain heavily pre-treated ALL patients without further therapy,” Frey said. “For our patients who have already relapsed after stem cell transplants, or don’t have any options for donors, this option has provided new hope.”

In July 2014, the U.S. Food and Drug Administration granted CTL019 its Breakthrough Therapy designation for the treatment of relapsed and refractory adult and pediatric ALL, a step which is intended to expedite the development and review of new medicines that treat serious or life-threatening conditions, if a therapy has demonstrated substantial advantages over available treatments. CTL019 is the first personalized cellular therapy to receive the designation. The first multicenter CTL019 trial has recently opened in the U.S., and plans are underway for additional multisite trials.

The study was supported by the National Institutes of Health (R01CA165206, R01CA102646 and R01CA116660), multi-year research funding under The Leukemia & Lymphoma Society’s Specialized Centers of Research grant program, and a Stand Up To Cancer-St. Baldrick’s Pediatric Dream Team Translational Research Grant.

Editor’s note: The University of Pennsylvania has licensed technologies involved in this trial to Novartis. Some of the scientists involved in these trials are inventors of these technologies, including Drs. June, Porter, Grupp, and Bruce Levine. As a result of the licensing relationship with Novartis, the University of Pennsylvania and the Children’s Hospital of Philadelphia receive significant financial benefit, and the inventors have benefitted financially and/or may benefit financially in the future.

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Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.



The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 17 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2013 fiscal year.



The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; Chester County Hospital; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.



Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2013, Penn Medicine provided $814 million to benefit our community.



About The Children's Hospital of Philadelphia: The Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program receives the highest amount of National Institutes of Health funding among all U.S. children's hospitals. In addition, its unique family-centered care and public service programs have brought the 535-bed hospital recognition as a leading advocate for children and adolescents.



The Children's Hospital of Philadelphia has one of the largest pediatric cancer programs in the United States, which has been top ranked by U.S.News & World Report and Parents Magazine. Its large basic and clinical research programs are particularly strong in pediatric neuro-oncology, neuroblastoma, leukemia and lymphoma, and sarcomas. Of all pediatric institutions, Children's Hospital enrolls the most patients in national clinical trials, working in close collaboration with national organizations such as the Children's Oncology Group. Physicians at Children's Hospital have had pioneering roles in developing international standards for diagnosing and treating neuroblastoma, and in developing programs for survivors of childhood cancer. For more information, visit http://www.chop.edu/cancer.