Immune Reconstitution After Gene Therapy (GTx) for Adenosine Deaminase Deficient Severe Combined Immune Deficiency (ADA-SCID) (2009)

We report on immune reconstitution in 3 patients (pts) who received GTx for ADA-SCID. After conditioning with 75 mg/m2 busulfan, pts received 2–5 × 106 autologous CD34+ bone marrow cells/kg that had been exposed to two retroviral vectors, MND-ADA and GCsapM-ADA. Chemotherapy was well tolerated, although in two pts, return of neutrophil counts was delayed. Post-transplant, indices of immunity improved or normalized. At 18 months after treatment, pt 301N's absolute lymphocyte counts (ALC's) have been up to ∼600/μl (n.v. 2300–5400/μl). T-cell stimulation index (SI) to phytohemmaglutinin (PHA) and serum immunoglobulins and IgG subclass levels have normalized. In addition, the pt responded normally to tetanus, diphtheria, polio and haemophilus vaccines. Recently, he promptly recovered from a gram-negative central venous catheter infection. Pt 303N is 15 months after treatment and her ALC have been up to ∼250/μl. PHA-SI and serum IgA levels have normalized, although the pt remains on IVIG. Pt 304C has been followed for 9 months. IgA has normalized, but other indices of immunity remain low. She resumed ADA enzyme replacement therapy after an episode of pneumonia. Nevertheless, her mononuclear cell ADA activity and percent corrected cells continue to increase. In all three pts, ADA activity has risen from less than 2 units to more than 30 units (n.v. 58–128 units), and toxic adenosine metabolites have fallen to levels comparable to those seen in pts who have engrafted after allogeneic hematopoietic cell transplant. Retroviral vector-marked cells in the peripheral blood vary from ∼0.1% (301N) to 15% (303N) of the pts’ circulating mononuclear cells. A fourth patient was treated on October 2, 2008, and is not yet evaluable. In summary, after treatment with myelosuppressive chemotherapy and bone marrow GTx, all 3 evaluable pts have shown improvement in laboratory indices of ADA activity and of immunity. Of the two pts who have been observed for more than a year off of PEG-ADA, one has had no infections and the other has answered two immunologic challenges as well as one would expect of a normal child. The results are in line with those reported by researchers in Italy and UK and indicate that gene therapy for ADA-SCID can lead to measurable improvement of immune function. While the degree of reconstitution is only partial when assessed in the laboratory, clinical responses to immunologic challenges appear to be robust. We report on immune reconstitution in 3 patients (pts) who received GTx for ADA-SCID. After conditioning with 75 mg/m2 busulfan, pts received 2–5 × 106 autologous CD34+ bone marrow cells/kg that had been exposed to two retroviral vectors, MND-ADA and GCsapM-ADA. Chemotherapy was well tolerated, although in two pts, return of neutrophil counts was delayed. Post-transplant, indices of immunity improved or normalized. At 18 months after treatment, pt 301N's absolute lymphocyte counts (ALC's) have been up to ∼600/μl (n.v. 2300–5400/μl). T-cell stimulation index (SI) to phytohemmaglutinin (PHA) and serum immunoglobulins and IgG subclass levels have normalized. In addition, the pt responded normally to tetanus, diphtheria, polio and haemophilus vaccines. Recently, he promptly recovered from a gram-negative central venous catheter infection. Pt 303N is 15 months after treatment and her ALC have been up to ∼250/μl. PHA-SI and serum IgA levels have normalized, although the pt remains on IVIG. Pt 304C has been followed for 9 months. IgA has normalized, but other indices of immunity remain low. She resumed ADA enzyme replacement therapy after an episode of pneumonia. Nevertheless, her mononuclear cell ADA activity and percent corrected cells continue to increase. In all three pts, ADA activity has risen from less than 2 units to more than 30 units (n.v. 58–128 units), and toxic adenosine metabolites have fallen to levels comparable to those seen in pts who have engrafted after allogeneic hematopoietic cell transplant. Retroviral vector-marked cells in the peripheral blood vary from ∼0.1% (301N) to 15% (303N) of the pts’ circulating mononuclear cells. A fourth patient was treated on October 2, 2008, and is not yet evaluable. In summary, after treatment with myelosuppressive chemotherapy and bone marrow GTx, all 3 evaluable pts have shown improvement in laboratory indices of ADA activity and of immunity. Of the two pts who have been observed for more than a year off of PEG-ADA, one has had no infections and the other has answered two immunologic challenges as well as one would expect of a normal child. The results are in line with those reported by researchers in Italy and UK and indicate that gene therapy for ADA-SCID can lead to measurable improvement of immune function. While the degree of reconstitution is only partial when assessed in the laboratory, clinical responses to immunologic challenges appear to be robust.