On Wednesday, an advisory panel convened by the US Food and Drug Administration (FDA) voted 10 to 0 to recommend the approval of CAR T-cell therapy for treatment of children and young adults with late-stage leukemia. Novartis’s CTL019 is a gene-altering treatment directed against the protein CD19 found on the leukemic B-cells. Wednesday’s unanimous endorsement paves the way for the first gene therapy to win FDA approval, which is expected in September.

CAR stands for “chimeric antigen receptor.” The word “chimera” comes from Greek mythology and means an animal that is a mixture, or hybrid, of more than one animal, such as a lion and a goat. In CAR T-cell therapy, a patient’s T-cells are taken from the bloodstream and genetically re-programmed using a disabled form of HIV virus to attack the cancer cells— in this case, CD19-positive leukemia B-cells. Treatment is customized for each patient.

A breakthrough approach

The gene-altering therapy, developed by the University of Pennsylvania and Novartis, has produced dramatic results in leukemia. In the pivotal trial, 83 percent of patients went into remission and more than 60 percent were still in remission after one year. So, a pretty impressive, sustained benefit for patients with devastating relapse!

However, questions and concerns that were expressed leading up to and during Wednesday’s FDA hearing  focused on the treatment’s logistics, safety, and costs.

• Logistics are complex for this individually-tailored treatment. The cells are grown in a large batch and securely shipped to and from the Novartis facility, where they are re-engineered and then shipped back to the institution where the patient is receiving treatment by intravenous infusion.
• Key safety concerns are brain toxicity (linked to a cytokine or hormone-like “storm” reaction that can occur), viral infections, and the development of second cancers due to the severe depression of the normal B-cell immune response. The engineered T-cells are hybrids and are therefore “foreign” to the patient. The longer-term implications of this therapy are unknown. The panel acknowledged that these safety issues should not prevent access to a lifesaving therapy. Nonetheless, very close monitoring and follow-up were recommended.
• The potential costs are quite staggering. Estimates are in the $300,000 to $600,000 range for a single therapy, which does not include initial and ongoing supportive care costs. The financial calculations are quite complex, since the approval will be for the small number of leukemia patients failing with other therapies.

A treatment option for myeloma?

Wednesday’s unanimous recommendation prompts several important questions. What is the broader application of this technology? Is it sufficiently effective and safe to use in all patients and/or earlier in the disease? Can such therapy be the basis for achieving long-term cure?

In myeloma, CAR T-cell therapy directed against BCMA (B-cell maturation antigen) may produce dramatic results for myeloma patients. Fewer than 100 patients have been treated so far (across eight trials). While the trial results offer much hope, I am concerned that the over-promotion of the early results has produced too much hype before the trial results are in! It is too soon to know the longer-term value.

Stunning results, but serious risks

I am especially concerned about the lack of true “myeloma specificity” of the current CAR T-cell approaches in myeloma. In the disease, the normal immune system is severely compromised, leaving patients open to viral, fungal, and other infections, as well as the risk of second cancers. Thus, the current versions are great as salvage therapies but are not safe enough for earlier use until we have longer follow-up and can assess the true risk-benefit ratio.

Yesterday was an exciting research landmark, representing the potential approval of a whole new type of cellular genetic therapy. We sincerely hope that important, broader applications for the treatment of myeloma will emerge.  

Dr. Brian G.M. Durie serves as Chairman of the International Myeloma Foundation and serves on its Scientific Advisory Board. Additionally, he is Chairman of the IMF's International Myeloma Working Group, a consortium of nearly 200 myeloma experts from around the world. Dr. Durie also leads the IMF’s Black Swan Research Initiative®.