Zosia Chustecka

December 17, 2015

ORLANDO, Florida ― The latest results with gene therapy in inherited blood disorders were met with great enthusiasm here at the American Society of Hematology (ASH) 57th Annual Meeting. The abstracts on gene therapy were selected for the "Best of ASH" and were featured in the presidential symposium.

"I am thrilled with these results. It seems like gene therapy is becoming a clinical reality," commented Marcela Maus, MD, PhD, director of cellular immunotherapy at the Massachusetts General Hospital Cancer Center and assistant professor of medicine at Harvard Medical School, Boston. There have been a lot of challenges in this field, but the new results are showing both efficacy and safety, she said.

Abstracts showing clinical benefit from gene therapy in patients with beta-thalassemia, in boys with Wiskott-Aldrich syndrome, and in older patients with X-linked severe combined immunodeficiency (SCID-X1) who had already received a stem cell transplant were highlighted at a press briefing.

These latest results are impressive, and they "show, simply put, that gene therapy works," commented moderator George Daley, MD, PhD, director of the Stem Cell Transplantation Program at Boston Children's Hospital. "What we are witnessing now are the results of 30 years of investment in translational research," he said.

There have been challenges along the way, many related to the viral vectors that are used to insert the gene, Dr Maus explained. Earlier studies used adenoviral vectors, but they caused inflammatory responses and were rejected. Then retroviral l vectors were used, but this work came to an abrupt halt when it was discovered that these retroviral vectors were being inserted into oncogene areas, which caused leukemia in these patients.

"Obviously, this risk was not known before the trials were done," she said, but it turned out that use of these retroviral vectors carried a 25% risk of causing leukemia.

The current gene therapies are using lentiviral vectors. They do not integrate into oncogenes and so appear to be much safer, Dr Maus commented, and the expression levels for the gene are higher, which increases the duration of the gene, potentially making it more efficacious, she said.

So these new gene therapies do seem to be an advance, and there have been no incidences of cancer to date that have been caused by these therapies, she added. However, the gene insertion is random, and there is always a risk that the random insertion may end up in an oncogene, which is why the US Food and Drug Administration now requires 15 years of follow-up to collect long-term outcomes, she added.

So for the new gene therapies, it's early days ― so far, the data for these new lentiviral vector gene therapies reflect only 5 years' follow-up.

With these rare inherited disorders, the current standard of care is a stem cell transplant from a donor, with as close a match as possible, but this involves aggressive chemotherapy conditioning, which carries with it the risk for potentially life-threatening complications, such as graft-vs-host disease, Dr Maus explained.

With gene therapy, the patient's own stem cells are used. This approach is potentially safer, because it requires a milder conditioning regimen, she noted. The stem cells are removed, manipulated in the laboratory with the insertion of a corrected form of the defective gene, and then transfused back to the patient. The results that have been reported at the ASH meeting suggest that the gene therapies are working and that the corrected gene appears in all types of blood cells, she commented.

Results in Wiskott-Aldrich Syndrome

One of the diseases being treated by gene therapy, Wiskott-Aldrich syndrome, is a rare disease caused by mutations in the WAS gene, which is located on the X-chromosome and so only affects males. The malfunctioning WAS gene stops blood cells from developing properly. The condition is characterized by low platelet counts, recurrent infections, easy bruising, bleeding, eczema, autoimmune disorders, and high susceptibility to cancer.

Data on eight children were presented (abstract 259) by Francesca Ferrua, MD, San Raffaele Telethon Institute for Gene Therapy, Milan, Italy. No adverse reactions to gene therapy were observed after infusion. "Importantly, no evidence of abnormal clonal proliferations emerged after gene therapy, and the lentiviral integration profile shows a polyclonal pattern, with no skewing for proto-oncogenes," she said.

All patients were alive after a median follow-up of 3.3 years after treatment (range, 0.1 - 5.4 years), she reported.

Notably, six patients with a follow-up of more than 2 years experienced a marked reduction in the rate of severe infections and bleeding events after treatment, as compared with the rate of such events before gene therapy, she said. These six patients have discontinued anti-infective prophylaxis and no longer require a protected environment. Four patients no longer receive immunoglobulin supplementation, and of these, two have developed specific antibodies after vaccination. Eczema resolved in four patients and remains mild in two patients.

These six patients have shown a "robust and persistent engraftment of gene-corrected cells," and WAS protein expression, measured by flow cytometry, was detected in the majority of platelets (mean ± standard deviation, 71.4 ± 14.0%), monocytes (63.3 ± 18.5%), and lymphocytes (78.9 ± 14.9%). Lymphocyte subset counts were normal in most patients, and proliferative response to anti-CD3 mAb was in the normal range in all six patients.

The seventh patient treated, who received MPB-derived CD34+ cells only, showed the fastest platelet recovery with the highest level of transduced myeloid cell engraftment. That patient is clinically well.

"While continued patient follow-up is needed to understand the long-term safety and efficacy of this treatment, this form of gene therapy appears to be well tolerated and may lead to sustained clinical benefit for these patients," Dr Ferrura said.

Data on WAS gene therapy from another four patients were reported (abstract 260) by Sung-Yun Pai, MD, from the Dana Farber/Boston Children's Cancer and Blood Disorders Center, on behalf of a team of investigators from the United States, Turkey, Japan, and Chile.

All four boys are alive and have improved during a period of 9 to 24 months following treatment. Since receiving the gene therapy, none have experienced bleeding events or severe infections, and two patients who needed drugs to stimulate platelet production no longer require this therapy.

However, the improvements in platelet count have been variable, Dr Pai noted, and it is not yet clear which factors are involved. "We suspect that infusing a few cells that each have two or three copies of the WAS gene may be better than infusing many cells with only one copy of the gene each," she commented. "But with the very small number of patients we've treated to date, our results are only suggestive."

Works Even After Transplant in SCID-X1

The new results for gene therapy in SCID-X1, also known as bubble boy disease, show that the treatment can work in older patients, and can even salvage failed stem cell transplants by rebuilding the immune system. These data were presented at the meeting (abstract 261) by Suk See De Ravin, MD, PhD, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.

In SCID-Xl, mutations occur in the IL2RG gene. Patients with these mutations have poorly functioning immune systems and are prone to life-threatening infections. The five patients in this study (aged 23, 24, 7, 16, and 10 years) had already received one or more transplants from a partially matched parental donor, which restores T-cells but not B-cells. They continue to have worsening immune systems and complex medical problems, Dr De Ravin noted. Many of these patients need life-long immunoglobulin supplementation, have serious and life-threatening infections, large numbers of warts that are quite disfiguring, malnutrition, as well as other symptoms, she said.

All five patients received IL2RG gene therapy with the lentiviral vectors. Follow-up ranges from 3 months to 3 years.

The two older patients with longest follow-up have an increasing percentage of immune cells with corrected genes, specifically, T-cells (13% to 55%), B-cells (38%), and NK cells (56% to 76%), demonstrating broad restoration of immunity that includes full restoration of antibody production, Dr De Ravin reported. They both show immunoglobulin production and normal reactions to vaccines, she added.

However, one of these patients subsequently died from pre-existing lung damage, despite having responded well to the gene therapy. "What this tells us is that gene therapy cannot correct pre- existing organ damage," she said, "which in turn supports early intervention in such patients, before damage occurs."

Gene Therapy in Beta-Thalassemia

The results of gene therapy in beta-thalassemia (abstract 201) were presented at the meeting by Mark C. Walters, MD, from the University of California, San Francisco, Benioff Children's Hospital, in Oakland.

This blood disorder is characterized by reduced production of hemoglobin, which is associated with life-threatening complications, such as severe anemia and organ damage. Patients with more severe forms of beta-thalassemia require frequent blood transfusions but face transfusion-related complications, such as iron overload, which can be deadly, he explained.

Dr Walters reported results from 13 transfusion-dependent patients with beta-thalassemia major who were treated with gene therapy using LentiGlobin BB305 to introduce a fully functioning hemoglobin gene into the patients' stem cells.

Of the nine patients who were treated more than 6 months ago, five remain transfusion free, including three who were treated longer than a year ago. These five patients all have HBB gene mutations that are associated with reduced, but not totally absent, production of functional haemoglobin, Dr Walters explained.

For the other four patients, the need for transfusion has been reduced (by at least 50%) but has not been entirely eliminated. These four patients have two copies of a specific type of HBB gene mutation known as beta 0 (β00), and for their need of transufions to be reliably eliminated, it appears that they need a higher level of corrected hemoglobin, Dr Walters commented.

Two serious adverse events, skin infection and veno-occlusive liver disease, have been reported during the study but were not related to the gene therapy, he said.

"These results indicate that gene therapy is a promising option for reducing or eliminating blood transfusions and limiting long-term complications in patients with beta-thalassemia," Dr Walters concluded.

American Society of Hematology (ASH) 57th Annual Meeting. Abstract 201, abstract 259, abstract 260, and abstract 261. Presented December 6, 2015.


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