Gene Therapy EU Approval, Long-Term CAR T-cell Effectiveness, 10 Years of CAR, AHA Conference, CAR T-cell Resistance

The end of the year inevitably arrives with a handful of things to celebrate, from memorable moments to astounding achievements to milestones made. With less than three weeks left in 2018, our list of celebratory moments at Children’s Hospital of Philadelphia Research Institute continues to grow, as this edition of our biweekly research news roundup shows. Read on to learn about two gene therapies pioneered at CHOP and the University of Pennsylvania that recently reached important milestones, a novel discovery from our scientists that could help to improve cancer immunotherapies, the 10-year anniversary of our Center for Autism Research, and more.

CHOP Celebrates European Commission Approval of Gene Therapy for Inherited Blindness

The European Commission (EC) has approved voretigene neparvovec-rzyl, the first and only gene therapy for patients with an inherited retinal disease, in all 28 member states of the European Union (EU) as well as Iceland, Lichtenstein, and Norway. The approval arrives one year after the Food and Drug Administration approved the therapy in the U.S. and after more than a decade of research studies led by scientists at Children’s Hospital of Philadelphia, the University of Pennsylvania, and Spark Therapeutics, a biotech company created by CHOP in 2013. The EU approved the gene therapy for treatment of vision loss due to inherited retinal dystrophy caused by confirmed biallelic RPE65 mutations in pediatric and adult patients. Individuals with RPE65 mutations suffer from severe visual impairment at infancy or early childhood and become blind by mid-life; previously, they had no pharmacologic treatment options.

Initial research for the gene therapy began in 2000 by Jean Bennett, MD, PhD, F.M. Kirby professor of Ophthalmology at the Perelman School of Medicine at the University of Pennsylvania’s Scheie Eye Institute, and Albert M. Maguire, MD, a professor of Ophthalmology at Penn’s Perelman School of Medicine and an attending physician at CHOP. Drs. Bennett and Maguire then joined forces with Katherine High, MD, a gene therapy pioneer who is now Spark Therapeutics’ president and head of research and development.
Read more in the press release and learn more about voretigene neparvovec-rzyl’s development on Cornerstone.

Happy 10^th Anniversary to Our Center for Autism Research

The Center for Autism Research (CAR) at CHOP is celebrating an exciting decade of innovative research into autism spectrum disorder (ASD) with a special 10^th Anniversary Report. Placing a spotlight on the past, present, and future discoveries at CAR, the report highlights the Center’s ongoing efforts to understand the causes of ASD, in order to develop more effective therapies while also supporting individuals living with ASD and their families.

Born in 2008 in response to the increasing awareness and prevalence of children being diagnosed with ASD, CAR’s earliest discoveries focused almost exclusively on the basic science of ASD. Since then, their fundamental findings about the genetics of ASD and differences in brain structure and function have laid the foundation for more basic research discoveries and increasingly informed clinical guidance for patients at CHOP and beyond. We invite you to learn about some of the many milestones CAR has achieved over the past 10 years – and get a glimpse of the future – on Cornerstone.

You can also read more in a CAR blog post about the 10^th anniversary report.

Updated ELIANA Data Provides Key Validation for CAR T-cell Therapies

At the 60th American Society of Hematology (ASH) Annual Meeting earlier this month, Stephan Grupp, MD, PhD, director of the Cancer Immunotherapy Program at CHOP, presented important data regarding the long-term effectiveness of tisagenlecleucel (formerly CTL019), the breakthrough cancer immunotherapy pioneered at CHOP alongside Novartis and Penn Medicine. At the ASH meeting, Dr. Grupp introduced updated analysis from the ELIANA trial, a global study evaluating tisagenlecleucel’s safety and efficacy, which showed young patients with relapsed or refractory acute lymphoblastic leukemia – who had exhausted all traditional therapies – can achieve durable remissions with the personalized gene therapy.

“These are patients who weren’t eligible for transplant, or who had relapsed after transplant; none were in remission, and no other treatments were available at the time they entered the trial,” said Dr. Grupp in a press release. “We’ve shown that not only can we get these patients into remission, but they’re also going into remission with durable responses with CAR-T alone – the majority of patients without any subsequent therapies, and with no minimal residual disease when we tested for evidence of leukemia.”
Learn more in the press release and read about tisagenlecleucel on Cornerstone.

CHOP Scientists Report Possible Mechanisms Behind Resistance to CAR T-cell Therapy

While researchers continue to gather data validating the effectiveness of chimeric antigen receptor (CAR) T-cell therapies in clinical trials, basic scientists at CHOP are simultaneously learning more about the biological mechanisms behind why some cancer cells develop resistance to the treatment. In a recently published paper in Molecular and Cell Biology, Andrei Thomas-Tikhonenko, PhD, chief of the Division of Cancer Pathobiology, and his colleagues described how leukemia cells may thwart the efforts of the personalized immunotherapy.

In CAR T-cell therapy, a patient’s T-cells are bioengineered to hunt and destroy ALL cells – a treatment that has significantly improved survival in patients who relapsed or never responded to initial chemotherapy. However, 20 to 30 percent of ALL patients who receive CAR T-cell treatment don’t respond or develop resistance to the therapy within a few weeks. In the current study, the research team built on their previous findings that showed mutations in leukemia cells could hamper CD19 antigen, a protein that is essential for CAR T-cell therapy’s success. Furthering this research, the team found that insertional mutations can cause the CD19 antigen to “misfold” within the cell so that it cannot be carried to the leukemia cell’s surface in tact – and thus cannot be recognized and destroyed by CAR T-cells.

Learn more about this research, including the team’s discovery of clues to a possible method to overcome the cancer’s resistance, in this CHOP News Brief and read the study abstract.

CHOP Researchers Share New Findings at 2018 AHA Conference

Clinician-scientists from the Cardiac Center at CHOP presented a handful of new research findings at November’s American Heart Association (AHA) 2018 Scientific Sessions. The studies covered a range of subjects related to cardiovascular disease in children, including factors that can influence a patient’s survival and success after treatment such as defibrillator use, CPR education, and the benefits of prenatal ultrasound and echocardiography to detect congenital heart disease.

Two presentations were finalists for the Outstanding Research Award in Pediatric Cardiology. David J. Goldberg, MD, an attending cardiologist at CHOP, presented his team’s investigation of impaired exercise capacity in patients who had undergone a Fontan procedure with fellow colleagues from the NIH/NHLBI’s Pediatric Heart Network. Meanwhile, Maryam Y. Naim, MD, a pediatric intensive care physician in our Division of Cardiac Critical Care, presented her team’s study of the benefits of performing conventional bystander CPR compared to compression-only BCPR for children who experience cardiac arrest outside of a hospital.

Another CHOP presentation was a finalist in the CVDY Early Career Young Investigator Competition: Michael L. O’Byrne, MD, MSCE, an attending interventional cardiologist at CHOP, shared findings from his team’s research into measuring quality of care for pediatric and congenital cardiac catheterization programs using failure to rescue (FTR) as an outcome metric in addition to the standard metric of risk-adjusted adverse event.

Read about these and more AHA Scientific Sessions presentations in the press release.

ICYMI

Catch up on our headlines from our Nov. 30 In the News:

• Crib-Sleeping for Toddlers
• Lower Blood Pressure Associated With Smoke-Free Policies
• CHOP Doc Receives ‘Be My Sugar’ Award for Medical Excellence
• CHOP Researcher Discovers Genetic Mutation in a Pediatric Mitochondrial Disease
• Healthcare Heroes Award Honors Phillip B. Storm, MD

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