Patient-Tailored Immunotherapy Receives Breakthrough Designation From FDA

A personalized immunotherapy called chimeric antigen receptor (CAR) therapy has been given the breakthrough therapy designation by the US Food and Drug Administration (FDA). The investigational therapy known as CTL019 is being developed for relapsed and refractory acute lymphoblastic leukemia (ALL) for both adult and pediatric patients.

This is the first patient-tailored cellular cancer therapy to receive this designation from the FDA.

The breakthrough designation requires substantial preliminary clinical evidence that shows a drug has the potential to have a significant clinical benefit for patients with the goal of facilitating an expedited drug development process to more quickly bring the therapy to patients.

The CTL019 therapy development is being led by Carl June, MD, professor of immunotherapy, at the University of Pennsylvania in Philadelphia.

While this FDA designation is specific for ALL, this CAR-based therapy is also being tested in relapsed and refractory non-Hodgkin lymphoma, myeloma, and chronic lymphocytic leukemia (CLL), as well as for patients with non-Hodgkin lymphoma and myeloma.

In early-stage, proof of principle trials, 89% of ALL patients (both adult and pediatric), at the Children’s Hospital of Philadelphia and the University of Pennsylvania, experienced remission after the immunotherapy treatment. These patients had not previously responded to standard of care ALL treatments. Results from these clinical trials were presented at the American Society of Hematology Annual Meeting in December of 2013.

The CAR therapy involves extracting a patient’s T-cells from a blood sample. Then, researchers reprogram these immune cells genetically to produce surface receptors called CAR, similar to antibodies, which facilitate the T-cells to recognize tumor-specific antigens. The patient’s CAR T-cell population is then expanded in the laboratory and infused back into patients as therapy. Once inside the patient, the CAR T-cells need to multiple and hone in to target and destroy cancer cells. The clinical trials also found that both CLL and ALL patients who had complete remissions also had CD19 protein expressing normal B-cells which are thought to be a marker of continued T-cell response.

Eight-six (19 of 22) pediatric ALL patients had complete remissions--one being an 8-year-old patient treated with CTL019 who was in remission for 20 months as of December 2013. Additionally, five of the first adult ALL patients treated with the immunotherapy had a complete remission and 47% (15 of 32) of adult CLL patients had a complete remission in an early phase clinical trial.  

Patients treated with CTL019 experience what is known as a "cytokine release syndrome" which, according to the researchers, is a sign that the engineered T-cells are dividing within the patient and attacking the tumor cells. This syndrome includes intense flu-like symptoms: nausea, high fever, muscle pain, shortness of breath, and low blood pressure. These symptoms can be partially controlled with an immunosuppressant drug, such as tocilizumab, which dampens the inflammatory cytokine, IL-6.

In 2012, The University of Pennsylvania partnered with the pharmaceutical company, Novartis, in a global research and licensing agreement to commercialize CTL019. The University of Pennsylvania granted Novartis exclusive rights to license the technologies used in clinical trials in patients with CLL and on other CAR therapies.

A phase II clinical trial of CTL019 is currently underway testing the immunotherapy in patients with CD19-positive lymphomas: non-Hodgkin, diffuse large B-cell, follicular, and mantle cell lymphomas.