Successes in Gene Therapy: 2017

September 14, 1990.

Anaheim, California: The Seattle Mariners were playing the California Angels. In the first inning, Ken Griffey Sr. hits a home run to center. Next at bat, his son Ken Griffey Jr. hits a home run to left center, becoming the first father-son duo to hit back-to-back home runs in a major league game.

New York, New York: Madison Square Garden is packed as the Grateful Dead kick off the first of six shows in NYC as part of their tour. The set starts off with Feel Like a Stranger and ends with U.S. Blues.

Bethesda, Maryland: Four-year-old Ashanti DeSilva lies on a bed in the National Institutes of Health’s Clinical Center. Diagnosed with adenosine deaminase severe combined immunodeficiency (ADA-SCID), and no longer responding to PEG-ADA, Ashanti becomes the first patient treated with gene therapy.

Twenty-seven years have since passed, and while Ken Griffey is now retired and Grateful Dead is winding down as Dead and Company, gene therapy is on a remarkable upward trajectory. 2017 is clearly the year when decades of work are finally coming to fruition.

The Ernest Beutler Lecture and Prize was fittingly awarded at the 2017 ASH Annual Meeting to Luigi Naldini and Marina Cavazzana who have been pioneers in driving the field of gene therapy forward. Their lectures eloquently highlighted the long scientific and clinical pursuit that has led to the successes we are seeing today. Patients with ADA-SCID, X-SCID, metachromatic leukodystrophy, Wiskott-Aldrich syndrome, Beta-thalassemia, and other diseases have been treated because of the continued pursuit to advance gene therapies.

The first hematologic gene therapy approval took place in Europe in 2016 with Strimvelis for the treatment of ADA-SCID. In 2017, the first two patients were treated with the commercial product, a remarkable achievement for this year on its own. However, there have now been three gene therapies approved in the United States in 2017. Kymriah, a chimeric antigen receptor T cell (CAR-T) therapy for acute lymphoblastic leukemia; Yescarta, a CAR-T therapy for non-hodgkin’s lymphoma, and Luxturna, an adeno-associated virus (AAV) to correct RPE65 mutations that cause retinal dystrophy.

These clinical approvals pave the way for a wide variety of gene therapies that have made significant steps towards clinical use in the past year. At the 2017 ASH Annual Meeting, clinical data on other AAV products for hemophilia A^1,2  and hemophilia B³  were presented. New gene therapy approaches in X-SCID using self-inactivating virus and mild conditioning have shown promising results in generating multi-lineage chimerism.⁴  Advanced follow-up of patients treated with a lentiviral gene therapy for beta-thalassemia are showing evidence of transfusion independence in 2017,⁵  and advances in gene-modified cell delivery directly into the bones may increase the efficacy of gene therapy for beta-thalassemia⁶  and other diseases. As vector development and conditioning regimens continue to improve, gene therapy in sickle cell disease is also beginning to take shape in 2017.⁷  CAR-T therapies, which use gene therapy techniques to add the chimeric receptor, were so prominent in the 2017 meeting it is impractical to highlight them all here. Hematologists are also leading the way in using gene modified hematopoietic stem cells to treat non-hematologic disorders, such as the phase 2 to 3 data published this past year treating patients with cerebral leukodystrophy.⁸ 

As this 2018 edition of The Hematologist hits our readers’ mailboxes, these are the advances I am looking forward to this year. In hematopoietic stem cell therapies, integrating lentiviruses are leading the way, but I expect considerable advances at the pre-clinical or clinical stages of gene editing techniques using CRISPR-cas9 to be headliners at the 2018 meeting. More follow-up, and importantly, larger cohorts of patients across all the diseases discussed above will happen over the next year, and 2018 may be a time when “curative therapy” is attached to more of these strategies. Finally, this year will see a lot of talk about the cost of this new class of medicine – a lot of talk. Clinics providing these new therapies will struggle with costs, patients will have access issues, and ever-increasing ingenuity with reimbursement/payment/money-back guarantees will be constantly in the news. These are important issues, but my hope is that these issues do not distract us from what we are witnessing in our field. Dogged determination in the laboratory and the clinic are leading to incredible results for patients. The first gene therapy approval in the U.S., followed by two more in the same year, seems to be one for the record books, just like father and son back-to-back home runs.