ASH Annual Meeting and Exposition

ASH Annual Meeting and Exposition

Perspective from Gary M. Kupfer, MD
December 05, 2015
3 min read

Gene therapy shows promise for patients with chronic SCID-X1

Perspective from Gary M. Kupfer, MD
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ORLANDO, Fla. — Lentiviral hematopoietic stem cell gene therapy with reduced-intensity conditioning produced pan-immunologic correction of T, B and natural killer cells in the bone marrow of older patients with X-linked severe combined immunodeficiency, according to study results presented at the ASH Annual Meeting and Exposition.

The gene therapy also appeared safe, results showed.

Suk See De Ravin

Suk See De Ravin

These data suggest that gene therapy may serve as salvage treatment for older patients with X-linked severe combined immunodeficiency, or SCID-X1 — also known as “Bubble Boy disease” —  who experience incomplete immune correction following allogeneic haploidentical hematopoietic stem cell transplantation (HSCT), according to the researchers.

HSCT can cure patients with SCID-X1; however, haploidentical parental HSCT without myeloconditioning often restores only T-cell immunity among infants lacking a matched sibling donor. These patients require life-long treatment with immune globulin and are at risk for chronic infections, warts, malnutrition, and progressive lung and gut diseases.

“These patients are alive, but many suffer the long-term consequences of the partial immune reconstitution and continue to face problems,” Suk See De Ravin, MD, PhD, staff clinician at the NIH’s Laboratory of Host Defenses, said during a press conference. “Lentiviral gene therapy can effectively rebuild the immune system.

Prior mouse retroviral vectors without conditioning successfully restored T-cell immunity in SCID-X1 infants, but similar approach failed to even correct T-cells in the older children with SCID-X1 who have persistent immune defects, suggesting there may be a barrier to engraftment in older patients.

Thus, De Ravin and colleagues sought to evaluate whether a combination of lentivector gene therapy — which involved inserting a normal form of the IL2RG gene into patients’ stem cells and using low-dose marrow conditioning to enhance engraftment of the patients’ gene-corrected stem cells — would restore B-cell immunity and antibody production in these patients.

The study included data from five patients aged older than 2 years (range, 7-24) who had worsening immune dysfunction and were dependent on immune globulin supplementation despite prior haploidentical HSCT.

The patients underwent granulocyte colony–stimulating factor- and plerixafor (Mobozil, Genzyme)-mobilized peripheral blood apheresis and CD34 isolation. The researchers prestimulated CD34-positive cells for 1 day and then exposed them to the vector for 6 to 8 hours on 2 consecutive days.

On the third day, researchers transduced the cells and infused them into the patients after they had received 6 mg/kg IV bulsulfan.  Researchers noted the busulfan conditioning appeared well tolerated in all patients, with no serious adverse events.

Researchers observed the patients for hematologic engraftment, immunological phenotype and functional profile, as well as gene marking in sorted immune cell lineages. The patients were followed for a range of 3 months to 3 years at time of reporting.

Among two older patients (aged 23 years and 24 years) with longer follow-up, the researchers observed stable engraftment of gamma chain-expressing cells, with an increasing proportion of immune cells with corrected genes, specifically for T (13% to 55%; 0.13-0.55 vector genome [vg]/cell), B (38%; 0.38 vg/cell) and natural killer (NK; 56% to 76%; 0.56-0.76 vg/cell) cells.

The gene marking in the myeloid lineages among these two patients stabilized by 1 year following treatment to 8% to 10% (0.1 VG/cell).

The researchers reported that early gene marking trend among the most recently treated three patients (aged 7-15 years) appears comparable if not better than the earlier-treated patients with longer follow-up.

Chimerism studies of T cells have shown increasing host cell contribution, reflecting a gradual replacement of the donor T-cell graft over time.

An increase in NK cells in one patient (aged 24 years) corresponded with an improvement in chronic warts. Further, both older patients produced immunoglobulin and antigen-specific responses with protective titer response to immunization, as well as clearance of chronic norovirus and resolution of protein-losing enteropathy.

Vector tracking has confirmed a diverse repertoire of gene insertion sites and the absence of oncogene-targeted clones observed in earlier murine gamma retrovirus gene therapy.

However, De Ravin noted that gene therapy appeared unable to reverse already-present organ damage in patients, as evidenced by a patient death following treatment.

“Despite an improvement in immune function, one patient unfortunately died of a right lung bronchiectatic bleed after 2 and a quarter years post-gene therapy,” De Ravin said. “This tells us that gene therapy cannot correct preexisting lung damage. This supports a need for early intervention to improve immunity before such damage occurs.” – by Cameron Kelsall


De Ravin SS, et al. Abstract 261. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.

Disclosure: The researchers report no relevant financial disclosures.