After decades of hype, dashed hopes, and setbacks, gene therapy has finally arrived and is poised to transform the treatment paradigm for many diseases, according to Cynthia E. Dunbar, MD, senior investigator at the Hematology Branch of the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health.

Hematologists can expect more developments that build on current successes with chimeric antigen receptor (CAR) T-cell therapy and gene therapy advances for hemophilia, as well as emerging advances in gene editing techniques including the CRISPR/Cas9 approach, Dr. Dunbar said in an interview.

“I think what is happening right now is sort of a critical mass of successes in studies with really unequivocally positive outcomes,” Dr. Dunbar said. “We’ve seen clinical improvements in some common cancers with CAR T cells, but also a range of rare diseases, such as immunodeficiencies and spinal muscular atrophy, as well as promise in diseases like sickle cell anemia.”

That’s on top of a small number of regulatory approvals in the United States and Europe, she said. “Along with that, there’s a lot of interest and now involvement from biotechnology companies and even large pharmaceutical companies. I think all those factors really have to come together to create this kind of acceleration, and I’ve never seen anything like this previously.”

Dr. Dunbar – a former editor in chief of the journal Blood – and her colleagues recently published a review of current developments and emerging gene therapy technologies in the journal Science (2018 Jan 12. doi: 10.1126/science.aan4672).

“We really felt it was the right time to write the article,” she said.


A new approach to cancer treatment was ushered in on Aug. 30, 2017, with the Food and Drug Administration approval of tisagenlecleucel, the first-ever gene therapy available in the United States. The CD19-directed CAR T-cell therapy is indicated for treatment of certain pediatric or young adult patients with B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse.

Soon afterward, FDA approved another CD19-directed CAR T-cell therapy, axicabtagene ciloleucel, for adult patients with large B-cell lymphoma after two or more lines of systemic therapy.

“It’s a very interesting time for immunotherapies in general,” Dr. Dunbar said. “There’s a huge number of options in terms of PD-1 inhibitors and other pharmacologics or antibodies that allow the patient’s own immune system to attack tumors. CAR T-cell therapy is an obvious step beyond that, in terms of arming your own T cells to very specifically target tumor cells.”

But randomized trials or meta-analyses may be necessary to determine the place of CAR T-cell therapy in the treatment armamentarium for acute lymphoblastic leukemia and large B-cell lymphoma given their cost and the availability of other therapeutic options, Dr. Dunbar suggested.

“Gene therapies have a large upfront cost, but if they’re truly curative and a one-time treatment, then they may in the long run be much cheaper than doing failed multiple transplants or needing monoclonal antibody infusion every 2 weeks for the rest of your life,” she said.

Another major success story still in the works, according to Dr. Dunbar, is the treatment of hemophilia A and B with gene therapy approaches. The positive data include a recent report showing that transgene-derived factor IX coagulant activity allowed for the termination of baseline prophylaxis, and the near elimination of bleeding and factor use, in patients with hemophilia B ( N Engl J Med. 2017 Dec 7;377[23]:2215-27 ).

While gene therapy for hemophilia A has been more challenging, another recent report nevertheless demonstrated sustained normalization of factor VIII activity level with a single intravenous infusion of adeno-associated virus serotype 5 vector encoding a B-domain–deleted human factor VIII ( N Engl J Med. 2017 Dec 28;377[26]:2519-30 ).

“The proof-of-principle was already there in hemophilia B,” Dr. Dunbar said. “It really was just a question of figuring out a way to package and deliver a Factor VIII that would work in the constraints of an AAV [adeno-associated virus] vector.”

Meanwhile, myeloma trials of CAR T-cell therapy seem very promising so far, but the challenge in that disease could be finding a place for gene therapy in a “much more diverse treatment landscape” that includes multiple effective regimens, according to Dr. Dunbar.

Future trends, challenges

Looking forward, gene editing with methods including the CRISPR/Cas9 approach have the potential to revolutionize treatment in HIV, b-thalassemia, and sickle cell disease, she said.

Notably, genome editing approaches to treat sickle cell anemia are likely to move forward in the near future, according to Dr. Dunbar, following reports validating an erythroid enhancer of human BCL11A as a target for reinduction of fetal hemoglobin ( Nature. 2015 Nov 12;527[7577]:192-7 ).

But all of this gene therapy development creates an educational challenge for frontline clinicians, even if the administration of CAR T-cell therapy and other advanced treatments is limited to highly specialized centers.

“There’s a lot of training that needs to go on with hematologists, oncologists, and other doctors about how to care for these patients after these treatments, in terms of what to look for and how to intervene early to prevent, for instance, severe toxicity from cytokine release syndrome,” Dr. Dunbar said.

Dr. Dunbar reported having no relevant financial disclosures.