Gene therapy as salvage

The success of gene therapy in most severe combined immunodeficiency (SCID) infants treated in recent years was contrasted by a report of ineffectiveness in older (ie, teenage) SCID patients.¹  The decline in thymic function that occurs even with normal adolescence may limit the capacity for older patients to produce T lymphocytes de novo from transduced HSCs.

The cohort of preteens with X-linked SCID (XSCID) reported by Chinen and colleagues was unique in that each had undergone haploidentical, T-cell–depleted bone marrow transplantation without cytoreductive conditioning during infancy.²  Despite this, they were chronically ill for a decade or longer, due to minimally corrected immune function and, possibly, chronic graft-versus-host disease (GVHD). There were no further conventional allogeneic HSC transplantation (HSCT) options to restore immunity, and thus they underwent gene therapy, weighing potential benefits from immune restoration with the risks of a T-lymphoproliferative disorder seen to date in 4 XSCID infants.³  A retroviral vector carrying a normal human γC cDNA was used to transduce their bone marrow CD34⁺ cells from autologous bone marrow, an approach similar to that used in the gene therapy trials for the XSCID infants.

One of the 3 patients had evidence of some immunologic improvement, with increased production of T lymphocytes (approximately 2-fold increase in the absolute number of T cells and increased levels of naive T cells). Because SCID patients failing to achieve immune reconstitution after HSCT are in a desperate clinical situation, even this modest level of benefit may be relevant. However, the other 2 patients did not show any significant effects from the procedure and remained immune-deficient. Reconstitution of T lymphopoiesis may be primarily limited by poor thymic function in these older, chronically ill children, especially if they have prior maternal or transplant-related GVHD that can cause thymic damage.⁴  Gene therapy may prove to be better in this setting than additional attempts at haploidentical or matched unrelated allogeneic HSCT, if only in that there should be no risk of GVHD being caused or worsened by reinfusion of autologous HSCs.

As gene therapy continues to improve in efficacy and safety, it may used up front as primary therapy for most SCID patients lacking matched sibling donors. If so, the emergence of further cohorts of patients who have not responded to allogeneic HSCT could be avoided. In the meantime, gene therapy may be a beneficial option for these unique patients as a salvage therapy.