Conference Coverage

Gene therapy regimen for XSCID shows rapid results in newly diagnosed infants



– A new approach to gene therapy produced rapid T cell reconstruction and normal markers of B-cell and natural killer (NK)-cell function in newly diagnosed infants with X-linked Severe Combined Immunodeficiency (XSCID), according to initial results from a phase 1/2 trial.

Researchers used a regimen of safety-modified lentiviral vector plus reduced-exposure busulfan conditioning in seven newly diagnosed infants and found that it was well tolerated in all patients and quickly improved T-cell immunity in five of seven patients.

Dr. Ewelina Mamcarz of St. Jude Children's National Medical Center in Memphis Mary Ellen Schneider/Frontline Medical News

Dr. Ewelina Mamcarz

“Stem cells are resistant to a genetic modification,” study author Ewelina K. Mamcarz, MD, of Children’s National Medical Center, Memphis, said at a press briefing at the annual meeting of the American Society of Hematology. “That has intrigued the field for almost 20 years.”

Initial gene therapy trials used a mouse vector without busulfan conditioning. These trials produced T-cell correction but were unable to restore B-cell function, NK-cell function, or myeloid-cell function. As a result, patients continued to experience viral infections and required monthly, life-long intravenous immunoglobulin infusions, Dr. Mamcarz said.

The phase 1/2 multicenter safety and efficacy study tested the gene therapy regimen for the first time in seven newly diagnosed infants. The regimen involved transducing purified bone marrow CD34+ cells with the lentiviral vector, which was generated by a stable producer cell line and then cryopreserved. The busulfan was given as two single daily doses, which were tailored based on patient age and weight.

In total, seven patients have been treated and all tolerated the low-dose busulfan chemotherapy well. Five patients had normal numbers of previously defective cells (T cells, B cells, and NK cells) and were taken off protective isolation and prophylactic medications. Those infants appear to have functioning immune systems, Dr. Mamcarz said. One infant has stopped monthly intravenous immunoglobulin infusions and has received normal pediatric vaccines, but responses have not yet been tested.

For the two infants who did not show responses, one is early in the trial and there is not yet adequate follow-up data to assess the immune system reconstitution, Dr. Mamcarz said.

The other infant had high levels of maternal T cell engraftment, severe neutropenia, and ongoing cytomegalovirus infection, resulting in delayed and partial T-cell reconstitution. The researchers sought to boost the patient’s immunity through an infusion of corrected cells – without busulfan – at 1 year after receiving the initial therapy. Three months after the second treatment, the infant has normal functioning of T cells and NK cells, but he is not yet engrafting B cells, Dr. Mamcarz said.

Overall, there was no evidence of vector-mediated effects on blood formation, Dr. Mamcarz reported.

The ultimate evaluation of the efficacy of the trial would be to assess vaccine responses in the infants treated with gene therapy, she said.

The study was supported by the Assisi Foundation of Memphis and the California Institute of Regenerative Medicine. Dr. Mamcarz reported having no relevant financial disclosures. Her coauthors reported financial relationships with InsightRX, UpToDate, Invitae, and Homology Medicines.

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SOURCE: Mamcarz E et al. Abstract 523.

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