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A novel gene therapy for severe combined immunodeficiency from adenosine deaminase deficiency (ADA-SCID) restored immune cell counts without death or need for enzyme replacement therapy, researchers reported.

Survival without needing to re-initiate pegylated ADA enzyme replacement therapy, or have a rescue allogeneic hematopoietic stem cell transplantation (AHCT), was 95% to 97% at last follow-up at 24 or 36 months across three studies pooled together by Donald B. Kohn, MD, of the University of California Los Angeles, and colleagues.

Those rates compare favorably with the current standard of care, AHCT, for which overall survival of 65% to 88% and event-free survival of 56% has been reported, they stated in the . The results will be presented at the virtual meeting.

While there were two cases of treatment failure due to lack of engraftment among the 50 children with ADA-SCID in the studies Kohn's group reported, median ADA enzyme activity in red cells in patients treated across the studies was at least as high as in healthy children at the last follow-up visit, and lymphocyte counts normalized or nearly so for most types of lymphocytes.

Most patients were also able to stop prophylactic antibiotics and immunoglobulin replacement therapy.

Another type of gene therapy for primary immunodeficiencies -- ex vivo autologous hematopoietic stem-cell gene therapy with a gamma-retroviral vector that is approved in Europe as Strimvelis -- has shown vector-related leukemia and myelodysplastic events caused by insertional oncogenesis.

Rather than a retrovirus, the gene therapy Kohn's group studied used a self-inactivating lentivirus for ex vivo genetic modification of autologous CD34+ hematopoietic stem and progenitor cells.

No clonal expansion or evidence of replication-competent lentivirus turned up with it through 24 or 36 months of follow-up.

This finding "adds to the growing evidence for the safety of lentiviral vectors that has been seen in other clinical studies, in which various genes have been introduced in patients with other disorders, with follow-up extending to more than 10 years for the first patients treated," they wrote.

'It Really Has to Be Zero'

While the findings highlight how robust gene therapy can be for these genetic immunodeficiencies, longer follow-up is needed, argued Stephen Gottschalk, MD, chair of the department of bone marrow transplantation & cellular therapy at St. Jude Children's Research Hospital in Memphis, Tennessee.

"It is very encouraging that everything is stable," he said referring to the gene correction. However, "in the original in Europe, everybody thought it was safe; but at 6.8 years after gene transfer, a patient developed ," he added.

Even just reducing this risk compared to the retroviral agent likely wouldn't be enough, he said in an interview monitored by St. Jude media relations. "It really has to be zero...Even if, say, after 10 years I develop a leukemia, I would say 'Let's do a transplant.'"

He speculated that risk of secondary malignancy is likely what has prevented such products from thus far being approved in the U.S. for primary immunodeficiency.

Stefano Rivella, PhD, scientific director of the Sickle Cell and Red Cell Disorders Curative Therapy Center at the Children's Hospital of Philadelphia, who made one of the first lentiviral vectors used in gene therapy, agreed that the results from Kohn's team looked "really promising ... but only numbers and time will tell."

What wasn't clear from the paper, he said, was the minimum vector copy number necessary to achieve engraftment and correct the disease.

"The big question is if you need a lot of integration to correct the patient," he told 番茄社区app. "Maybe the vector can be improved. When you can treat the same patient with less drug, it's always better."

Study Details

Kohn's group reported on pooled data from three nonrandomized studies: two parallel phase I/II clinical studies conducted in the U.S. and one in the U.K. with slight variations in design between them.

The U.S. studies encompassed 30 children, ages 1 month or older, with ADA-SCID who lacked an HLA-matched sibling or a related donor for stem cell transplant (SCT). Their median age was 10 months, with a range from 4 to 51 months. Ten of them received a cryopreserved rather than fresh formulation of the gene therapy. Efficacy appeared similar between the two formulations.

The U.K. study included 10 children with a confirmed diagnosis of ADA-SCID who were younger than age 5 years (or up to age 15 years if they had preserved thymic function) and had no matched, related donor for an SCT. Another 10 children received the gene therapy through a compassionate-use program. All got the fresh formulation of the gene therapy. Median age was 11.6 months (range 4 to 193 months).

The novel gene therapy was manufactured from the patient's own bone marrow or blood, followed by nonmyeloablative weight-adjusted busulfan conditioning after stem cell harvest. Pegylated ADA enzyme-replacement therapy was discontinued 30 days after treatment.

While all of the patients had adverse events (AEs), most were mild or moderate and considered related to conditioning.

Through 24 months of follow-up in the U.S. studies, grade 3 or 4 leukopenia and neutropenia led to the withdrawal of one patient who didn't have sustained engraftment. Serious AEs occurred in 12 patients, most frequently infections (27%) and gastrointestinal events (17%). The only one considered treatment related was a case of staphylococcal bacteremia due to contamination of the fresh product that resolved with antibiotics.

In the U.K. study, there was a case of serious case of staphylococcus in the harvested cells. That patient was clinically stable after getting IV antibiotics immediately after the gene therapy infusion. Overall, 55% of the U.K. patients had a serious AE, most commonly fever.

Gottschalk suggested that this incidence was unfortunate but not unexpected for this type of gene therapy.

Two patients in the U.S. studies and two patients in the U.K. study had serious AEs of immune reconstitution inflammatory syndrome (commonly with rash, fever, and elevated inflammatory markers), but these resolved with supportive glucocorticoids and weren't deemed related to the treatment.

Severe infection rates were "generally low" across the full post-treatment period in all the studies, the researchers noted.

This novel gene therapy "may be a robust and viable treatment option for patients with ADA-SCID, including older children for whom current treatments are not always suitable or effective and who may have reduced or absent thymic function," they concluded.

The researchers noted that there may be advantages to gene therapy like this over the standard approach of allogeneic transplant, for which 80% of patients can't find donors and those who do run the risk of graft-versus-host disease. Gene therapy also requires less conditioning, reducing toxicity, and allows patients to continue protective enzyme replacement therapy while the immune system reconstitutes.

Success in ADA-SCID, which is diagnosed in perhaps only 10 U.S. patients a year, has broader implications, Gottschalk suggested. It is proof of concept as one of the first examples of a monogenic condition that can be safely fixed with gene therapy, hopefully paving the way for success in more common conditions like sickle cell disease, where trials started later and are ongoing, he said.

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