New personalized cellular therapy approved for use in the European Union

The European Commission (EC) has approved a personalized cellular therapy developed at the University of Pennsylvania's Abramson Cancer Center, making it the first chimeric antigen receptor (CAR) T cell therapy permitted for use in the European Union in two distinct indications. The EC granted the approval today to Novartis for Kymriah^® (tisagenlecleucel, formerly CTL019) for the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) in pediatric and young adult patients up to 25 years of age, as well as relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in patients over 18. The decision follows approval from the U.S. Food and Drug Administration for Kymriah in B-cell ALL and DLBCL in the United States.

"This is another milestone in the fight against cancer, allowing patients across the European Union to benefit from these potentially lifesaving therapies," said Carl June, MD, the Richard W. Vague Professor in Immunotherapy in the department of Pathology and Laboratory Medicine in the Perelman School of Medicine at the University of Pennsylvania and director of the Center for Cellular Immunotherapies in Penn's Abramson Cancer Center. "This approval demonstrates the global impact of the therapies we developed in Philadelphia, and the far-reaching potential of these therapies to change the way cancer is treated across the world."

Investigators at Penn's Perelman School of Medicine led research, development, and clinical trials of CAR T therapy in collaboration with Novartis and Children's Hospital of Philadelphia (CHOP). In August 2017, Kymriah became the first therapy based on gene transfer ever approved by the FDA when it was authorized for children and young adults with relapsed or refractory B-cell ALL. Approval for relapsed or refractory DLBCL followed in May 2018.

The treatment modifies patients' own immune T cells, which are collected and reprogrammed at the Novartis manufacturing facility to potentially seek and destroy the patients' cancer cells. Once they are infused back into patients' bodies, these newly built cells both multiply and attack, targeting cells that express a protein called CD19. Tests reveal the army of hunter cells can grow to more than 10,000 new cells for each single engineered cell patients receive – producing durable remission rates in refractory ALL and DLBCL – and can survive in the body for years.

The approval in the EU is the latest accomplishment in the alliance between Penn and Novartis, which entered into a global collaboration in 2012 to further research, develop, and commercialize Kymriah and other CAR T-cell therapies for the treatment of cancers. Specifically, the action of the European Commission is based on two global CAR T cell trials.

The first global trial, known as ELIANA, evaluated patients in 25 centers in the US, Canada, Australia, Japan, and in Europe in Austria, Belgium, France, Germany, Italy, Norway and Spain. The trial involved 75 children and young adults with relapsed or refractory B-cell ALL and showed 81 percent of patients achieved a complete remission at three months follow up, with 80 percent of responders still in remission at six months. Overall survival at six months was 90 percent.

The second trial, called JULIET, is the largest study examining CAR T therapy in DLBCL, enrolling patients from 27 sites in 10 countries across the US, Canada, Australia, Japan, and Europe in Austria, France, Germany, Italy, Norway and the Netherlands. The trial showed an overall response of 52 percent, with 40 percent of patients achieving a complete response, among the 93 infused patients with three or more months of follow-up or earlier discontinuation.

Many patients in both trials experienced a side effect called cytokine release syndrome (CRS). CRS is a toxicity associated with CAR T therapy, which includes varying degrees of flu-like symptoms, with fevers, nausea, and muscle pain, and can require ICU-level care. In the ELIANA trial, 47 percent of patients experienced grade 3 or grade 4 CRS. In the JULIET trial, the number was 22 percent, using a CRS grading scale developed at the University of Pennsylvania. Patients with severe CRS required treatment with tocilizumab, a therapy initially implemented at Penn and CHOP, and now FDA-approved for CAR T cell-induced severe or life-threatening CRS, or corticosteroids. All of those patients recovered from their CRS. Other toxicities included infections, cytopenias or low blood count, neurologic events such as confusion, febrile neutropenia, and a metabolic abnormality called tumor lysis syndrome. All of those issues resolved on their own or with treatment, and there were no treatment-related deaths.

Novartis is working to create a registry to follow patients for 15 years after being treated to monitor their progress and any potential, future side effects.

The Novartis-Penn Center for Advanced Cellular Therapeutics (CACT) opened in 2016 and hosted Vice President Joe Biden at the launch of his Cancer Moonshot initiative, cementing Penn's role as international innovator in the development and manufacturing of personalized cellular therapies.

Patients who are interested in T-cell therapies at Penn Medicine can call 215-316-5127 for more information.