Kymriah (tisagenlecleucel, CTL-019, Novartis AG) and other chimeric antigen receptor (CAR) T cells have been making their way through clinical trials as cell therapies. So the FDA’s Aug. 30 announcement that its approval of Kymriah was “a historic action today making the first gene therapy available in the United States” initially led to some head-scratching.
Why a gene therapy?
The most obvious possible goal of gene therapy is to replace a missing gene, or correct a defective one. Two of the gene therapies that have been approved by the European Commission, Glybera (alipogene tiparvovec, Uniqure BV), approved for the treatment of lipase deficiency (LPL) by in 2012, and Strimvelis (GSK-2696273, Glaxosmithkline plc.), approved in 2016 for treatment of patients with the rare immune disorder ADA-SCID, have the goal of replacing faulty genes.
But in the FDA’s 1998 “Guidance for Human Somatic Cell Therapy and Gene Therapy,” gene therapy is defined more broadly, and depends on the process a cell has undergone before it is administered to a patient rather than on its therapeutic goal.
According to the guidance document, “gene therapy is a medical intervention based on modification of the genetic material of living cells. Cells may be modified ex vivo for subsequent administration to humans, or may be altered in vivo by gene therapy given directly to the subject. When the genetic manipulation is performed ex vivo on cells which are then administered to the patient, this is also a form of somatic cell therapy.”
By that definition, Kymriah is both a cell therapy – just not the first – and a gene therapy – just not one that replaces a missing gene.
Why the first?
There is another genetically manipulated therapy on the market – Imlygic (talimogene laherparepvec, Amgen Inc.), an oncolytic virus that was approved in 2015 for the treatment of melanoma lesions in the skin and lymph nodes.
Imlygic is also conditionally approved in the European Union, and there, it is considered a gene therapy.
On its website, the European Medicines Agency describes Imlygic, like Glybera and Strimvelis, as “a type of advanced therapy medicine called a ‘gene therapy product’. This is a type of medicine that works by delivering genes into the cells of the body.” Imlygic works both by replicating inside the melanoma cells, and by delivering the gene for GM-CSF, which stimulates the immune system to recognize the tumor cells.
The FDA, however, does not consider Imlygic a gene therapy because “although Imlygic has been genetically modified, Imlygic’s primary biological activity is attributable to the oncolytic virus, not the genetic modification,” an FDA spokesperson told BioWorld. In contrast, “the function of the CAR T-cell product depends on the genetic material transferred to the patient’s cells. Therefore, the agency considers CAR T cells to be a type of cell-based gene therapy.”