There are many types of gene therapy, but all of them involve adding to or modifying the genetic program in a person – his or her DNA blueprint that provides instructions for building and operating the body. Gene therapy technology has been developed over several decades and has been successfully used to correct rare blood and immune disorders in children. It is also being used in cancer treatment.
One form of gene therapy involves adding functional copies of genes to replace ones that are missing or mutated – that is, their script is altered so that they malfunction or cause disease – in certain cells of patients. Another strategy is to change the regulation of genes that are over- or under-active, in an effort to treat certain pathological conditions or diseases.
Gene Therapy for Pediatric Patients
Led by Alessandra Biffi, MD, scientists at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center are treating young patients from more than 15 countries in gene therapy clinical trials for six different life-threatening medical conditions. The trials include sickle cell disease, cerebral adrenoleukodystrophy (CALD), X-linked severe combined immunodeficiency (SCID-X1) or “bubble boy” disease, Wiskott-Aldrich syndrome, and chronic granulomatous disease. In the sickle cell disease trial, patients receive an infusion of their own genetically modified blood stem cells that will reactivate the production of healthy fetal hemoglobin, suppressing the expression of the adult, abnormal hemoglobin in sickle-shaped red blood cells.
In October 2017, the program’s scientists, led by David Williams, MD, a pioneer in the field who began his studies on gene therapy in 1982, published results from its trial of gene therapy for cerebral adrenoleukodystrophy (CALD), a rapidly fatal neurological condition of children. The study found that the progression of the disease was halted in 88 percent of patients.
In late 2017, the Food and Drug Administration (FDA) approved the first gene therapy for an inherited disease. Called Luxturna, the therapy treats a form of blindness resulting from the body’s failure to make a protein needed by the light-sensitive retina at the back of the eye. Luxturna injects a modified virus into the retina, carrying a corrective gene so the cells can make the missing protein causing the disease. Patients reported they could for the first time see loved ones’ faces.
Leveraging the Immune System
Importantly, gene therapy can also be used to improve the immune system’s ability to recognize cancer cells, so that the immune system can attack those cancer cells in turn. In the fall of 2017, the FDA approved two forms of chimeric antigen receptor (CAR) T-cell therapy for blood cancers. One of them, known as Kymriah, is intended for pediatric and young adult patients with relapsed and refractory acute lymphoblastic leukemia (ALL).
The other one, known as Yescarta, was approved to treat adults with refractory aggressive B-cell non-Hodgkin lymphoma in adults.
Genetic modification of the patient’s immune T-cells is an essential part of CAR T-cell therapy. After collecting blood from the patient, T-cells are separated out and engineered to express a special type of receptor molecule, called a chimeric antigen receptor, or CAR, on their surface. The CARs enable the T-cells to recognize and bind tumor-specific cell proteins, called antigens, and to mount a very effective attack on the tumor cells. The CAR T-cells are grown in a laboratory to create a tailor-made fighting force against the patient’s tumor, and are then infused into the patient to combat the cancer. This therapy is like putting a turbocharger on an engine and then putting the accelerator of the car to the floorboard.
So far, CAR T-cell therapy has achieved some dramatic outcomes and high response rates in forms of lymphoma and leukemia, but it has to be used with caution because of potentially severe side effects.
Researchers hope to extend its benefits to other blood cancers, such as multiple myeloma, adult leukemia and other forms of lymphoma. Although CAR T-cell therapy hasn’t yet proven highly effective in solid cancers, there is significant ongoing research in this area.