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Gene therapy demonstrates clinical benefit for children with Wiskott-Aldrich syndrome
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ORLANDO, Fla. — Lentiviral gene therapy appeared well tolerated and produced a sustained clinical benefit in patients with Wiskott-Aldrich syndrome, according to study results presented at the ASH Annual Meeting and Exposition.
Further, the high level of gene transfer obtained with LV-WAS lentiviral vector encoding for WAS gene under the control of its own physiological promoter resulted in robust engraftment of transduced hematopoietic stem cells, even when combined with reduced-intensity conditioning, according to the researchers.
Allogeneic hematopoietic stem cell transplantation (HSCT) is a recognized curative treatment for Wiskott-Aldrich syndrome; however, this procedure is still associated with transplant-related complications and long-term morbidity, particularly among patients without fully matched donors and in older patients.
“Without an available donor for transplant, patients with Wiskott-Aldrich syndrome do not have any curative options,” Francesca Ferrua, MD, of the San Raffaele Telethon Institute for Gene Therapy at San Raffaele Scientific Institute in Milan, told HemOnc Today. “You can give them supportive treatment, but they will have a very poor quality of life. Without any curative intervention, classic WAS results in premature death, often during childhood”.
Ferrua and colleagues reported on eight pediatric patients (median age, 2.2 years; range, 1.1-12.4) treated in a phase 1/2 trial of hematopoietic stem cell gene therapy for Wiskott-Aldrich syndrome.
The treatment consisted of autologous CD34-positive hematopoietic stem cells engineered with a lentiviral vector encoding for Wiskott-Aldrich syndrome cDNA under the control of a 1.6 kb human Wiskott-Aldrich syndrome promoter. The product was infused after a reduced-intensity conditioning with an anti-CD20 monoclonal antibody, busulfan and fludarabine.
CD34-positive cell sources included bone marrow (n = 5), mobilized peripheral blood (n = 2) or both (n = 1). The median dose ranged between 7 and 16.8 x 106 CD34+/kg and contained between 88% and 100% transduced clonogenic progenitors.
As of November 2015 — after a median follow-up of 3.4 years (range, 0.2-5.5) — all patients remained alive.
The researchers did not observe any adverse reactions after the initial infusion. Further, the reduced-intensity conditioning appeared well tolerated.
The median duration of severe neutropenia was 18 days. One patient received granulocyte colony–stimulating factor.
In the first six children treated with longer than 2 years of follow-up, the researchers observed robust and persistent engraftment of gene-corrected cells. Transduced bone marrow progenitors ranged between 20.7% and 59.7%, with lentiviral vector-transduced cells detected in multiple lineages, including peripheral blood granulocytes (vector copy number range, 0.34-0.93) and lymphocytes (vector copy number range, 1.18-2.73).
Researchers detected Wiskott-Aldrich syndrome protein expression in the majority of peripheral blood platelets (mean ± standard deviation [SD], 71.4 ± 14%), monocytes (mean ± SD, 63.3 ± 18.5%) and lymphocytes (mean ± SD, 78.9 ± 14.9%).
Most patients had normal lymphocyte subset counts, and all patients had a normal range of proliferative response to anti-CD3 monoclonal antibodies.
The researchers observed a marked reduction in the annual estimated rate of severe infections following immune reconstruction. All patients with more than 1-year follow-up discontinued anti-infection prophylaxis and no longer required a protective environment.
Further, five out of seven patients with follow-up longer than 1 year ceased immunoglobulin supplementation, and those who completed vaccination schedule showed specific antibodies production.
Eczema resolved in six patients and remained mild in one. The researchers observed no clinical manifestations of autoimmunity at more than 1 year after gene therapy, in accordance with improved B-cell development and decreased autoantibody production.
All patients became platelet transfusion independent at a median of 3 months following gene therapy (range, 0.5-8.7).
Mean platelet counts progressively increased, from 13.4 ± 7.8 x109/l prior to therapy to 57 ± 18.7 x109/l up to 42 months after treatment in the first 6 patients treated with follow up longer than 2 years.
The frequency and severity of bleeding events decreased after the first year of follow-up, with no severe bleedings reported after treatment. Further, patients’ quality of life improved in the entire cohort, with a reduction in the number of hospitalizations for severe infections and no hospitalizations due to bleeding after treatment.
The researchers noted that the seventh and eighth treated patients — who received mobilized peripheral blood cells only — showed a faster platelet recovery.
No serious adverse events were related to gene therapy, with 85% of serious adverse events related to infections. Most occurred within the first year of follow-up.
No evidence of abnormal clonal proliferations emerged after gene therapy. The lentiviral vector integration profile showed a polyclonal pattern, with no skewing for proto-oncogenes.
“Providing a therapeutic option to these patients served an unmet medical need,” Ferrua said. “Our findings will influence future research, in terms of giving evidence that lentiviral stem cell gene therapy can be corrective for inherited diseases. Of course every disease is different and needs specific preclinical development, but there may be other diseases that will benefit from this approach. Every disease we can cure with this approach is a milestone on which we can build new knowledge.” – by Cameron Kelsall
Reference:
Ferrua F, et al. Abstract 259. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.
For more information:
Francesca Ferrua, MD, can be reached at San Raffaele Scientific Institute, Ospedale San Raffaele - Milano, via Olgettina 60, 20132, Milan, Italy; email: ferrua.francesca@hsr.it.
Disclosure: Ferrua reports no relevant financial disclosures. Please see the abstract for a list of all other researchers’ relevant financial disclosures.