Novartis' CAR-T Therapy for Pediatric Leukemia to Face FDA Advisory Panel

Novartis’ chimeric antigen receptor T-cell (CAR-T) therapy for treating pediatric leukemia is on the cusp of being the first FDA-approved gene therapy, which will lead to new developments and utilizations of CAR-T therapy for treating other advanced blood cancers.

Customizable CAR-T therapies are developed through harvesting a patients’ white blood cells, which are then genetically modified to target and attack cancer cells. Novartis’ therapy, tisagenlecleucel or CTL019, is specifically intended for treating children and young adults (3 to 25 years old) with relapsed or refractory B-cell acute lymphoblastic leukemia. CTL019 was originally developed at the University of Pennsylvania, and in 2012, the University partnered with Novartis in a global collaboration to continue research with efforts to advance and commercialize CAR-T therapies.

The ELIANA study demonstrated the efficacy of CTL019 and initiated the potential FDA approval. In the phase 2 study, 41 of 50 (82%) patients reached complete remission or complete remission with incomplete blood count recovery at 3 months following CTL019 treatment, according to Novartis. The phase 2 JULIET study was the second global CAR-T trial, following ELIANA, and focused on investigating the efficacy and safety of CTL019 in adult patients with relapsed or refractory diffuse large B-cell lymphoma.

“Even if a patient has difficult-to-treat relapsed/refractory leukemia, we have seen treatment with CTL019 in clinical trials put cancer into remission,” said Grupp, director of the Cancer Immunotherapy Frontier Program and director of Translational Research for the Center for Childhood Cancer Research at the Children’s Hospital of Philadelphia, in a press release following the study.

Results from the ELIANA and JULIET studies led the FDA to accept Novartis’ application for approval.

The FDA has few doubts regarding the efficacy of the therapy; however, the long-term effects are unknown, as seen in the FDA’s briefing documents from a treatment hearing. The FDA questions if the benefits of the treatment are worth the risk of the unknown and potentially harmful effects.

“The FDA seeks the opinion of the Committee regarding 1) post-marketing considerations for risk mitigation for short-term toxicities, particularly cytokine release syndrome, and 2) long-term follow-up for anticipated safety concerns related to the potential for insertional mutagenesis and secondary malignancies 3) whether the benefits justify the risks for a marketing approval of tisagenlecleucel for the proposed indication,” the FDA wrote.

A common side effect of the CAR-T treatment is cytokine release syndrome. This causes dangerously high fevers and flu-like symptoms among patients and often requires intensive care. Neurotoxicity is also a concern, as it can result in temporary confusion or potentially fatal brain swelling. Novartis has not observed this type of brain swelling in their trials; however, Juno Therapeutics was forced to end a trial because of 5 patient deaths due to brain swelling.

Typically, a product is distributed as quickly and widely as possible; however, Novartis is using an alternative method to maximize patient safety. Novartis plans to designate 30 to 35 medical centers as treatment administrators that have participated in clinical trials and have experienced thorough training for administering the treatment. A prospective registry and follow-up study to assess and investigate long-term effects have also been proposed by Novartis to maintain patient safety.

Researchers are already exploring the expansion of CAR-T cell therapy use for more diseases. Kite Pharma, for example, has applied for the therapy to be used for aggressive non-Hodgkin lymphoma, and Novartis is also researching the treatment for the same indication. CAR-T therapy is also being tapped into for the treatment of multiple myeloma and chronic lymphocytic leukemia. Doctors and researchers also look to expand the utilization of the therapy to eventually be able to treat solid tumors in the lungs or brain.

“We’re saving patients who three or four years ago we were at our wit’s end trying to keep alive,” stated Stephen Schuster, MD, director, Lymphoma Translational Research, Abramson Cancer Center of the University of Pennsylvania, who is leading a Novartis lymphoma study.

Schuster’s study, in addition to results from a trial conducted by Kite Pharma, have demonstrated the ability of CAR-T therapy to bring one-third of adults with advanced diseases into remission. However, at an estimated one-time price ranging between $300,000 to $600,000, wide spread use of this treatment may be difficult.

The FDA’s committee meeting on Wednesday, July 12, will include discussion on the need, efficacy, and safety of CTL019 for treating pediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia. The meeting will conclude with a vote by a panel of independent experts on whether they recommend the approval of Novartis’ CAR-T therapy.