Automated production of specific T cells for treatment of refractory viral infections after allogeneic stem cell transplantation.

Therapy-resistant viral reactivations contribute significantly to mortality after hematopoietic stem cell transplantation. Adoptive cellular therapy with virus-specific T cells (VST) has shown efficacy in various single-center trials. However, the scalability of this therapy is hampered by laborious production methods. In this study we describe the in-house production of VST in a closed system (CliniMACS Prodigy® system, Miltenyi Biotec). In addition, we report the efficacy in 26 patients with viral disease following hematopoietic stem cell transplantation in a retrospective analysis (adenovirus, n=7; cytomegalovirus, n=8; Epstein-Barr virus, n=4; multi-viral, n=7). The production of VST was successful in 100% of cases. The safety profile of VST therapy was favorable (n=2 grade 3 and n=1 grade 4 adverse events; all three were reversible). A response was seen in 20 of 26 patients (77%). Responding patients had a significantly better overall survival than patients who did not respond (P<0.001). Virus-specific symptoms were reduced or resolved in 47% of patients. The overall survival of the whole cohort was 28% after 6 months. This study shows the feasibility of automated VST production and safety of application. The scalability of the CliniMACS Prodigy® device increases the accessibility of VST treatment.

Correction to: Allogeneic hematopoietic stem cell transplantation in two brothers with DNA ligase IV deficiency: a case report and review of the literature.

After publication of the original article (1), it was brought to our attention that references 24 and 31 are inappropriately cited in the article.

Allogeneic hematopoietic stem cell transplantation in two brothers with DNA ligase IV deficiency: a case report and review of the literature.

BACKGROUND: DNA ligase IV deficiency is a rare autosomal recessive disorder caused by hypomorphic mutations in the DNA ligase IV (LIG4) gene. DNA ligase IV is an essential protein for the development of a healthy immune system as well as for the protection of genomic integrity. Apart from typical stigmata, patients with DNA ligase IV deficiency are characterized by progressive bone marrow failure and a predisposition to malignancy. To our knowledge this reported case is the first description of two brothers with ligase IV deficiency who are treated with different hematopoietic stem cell transplantation (HSCT) regimens resulting in vastly divergent outcomes. CASE PRESENTATION: The cases of two brothers suffering from severe recurrent infections and growth retardation are described. The laboratory findings showed pancytopenia with significant lymphopenia. The two boys were diagnosed with DNA ligase IV deficiency, associated with severe combined immunodeficiency (SCID). Both patients received HSCT from two different matched unrelated donors (MUD) at the age of 33 and 18 months. The older brother succumbed post-transplant due to fatal side-effects 143 days after allogeneic HSCT. The younger brother - conditioned with a different regimen - received a T cell depleted graft 4 months later. No severe side-effects occurred, neither post-transplant nor in the following years. Ten years after HSCT the patient is well off, living a normal life and attending a regular high school. His immune system is fully reconstituted, resulting in a maximum of T cell receptor (TCR) diversity, which is a prerequisite for immune competence. However, he still suffers from microcephaly, dwarfism and dystrophy. CONCLUSIONS: This case report gives an example of a successful HSCT as a treatment option in a genetic disorder such as ligase IV deficiency, using a rather mild conditioning regimen. Further studies are required to determine the viability and efficacy of this treatment option.

Mesenchymal stromal cells for treatment of steroid-refractory GvHD: a review of the literature and two pediatric cases.

Severe acute graft versus host disease (GvHD) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation. Human mesenchymal stromal cells (MSCs) play an important role in endogenous tissue repair and possess strong immune-modulatory properties making them a promising tool for the treatment of steroid-refractory GvHD. To date, a few reports exist on the use of MSCs in treatment of GvHD in children indicating that children tend to respond better than adults, albeit with heterogeneous results.We here present a review of the literature and the clinical course of two instructive pediatric patients with acute steroid-refractory GvHD after haploidentical stem cell transplantation, which exemplify the beneficial effects of third-party transplanted MSCs in treatment of acute steroid-refractory GvHD. Moreover, we provide a meta-analysis of clinical studies addressing the outcome of patients with steroid-refractory GvHD and treatment with MSCs in adults and in children (n = 183; 122 adults, 61 children). Our meta-analysis demonstrates that the overall response-rate is high (73.8%) and confirms, for the first time, that children indeed respond better to treatment of GvHD with MSCs than adults (complete response 57.4% vs. 45.1%, respectively).These data emphasize the significance of this therapeutic approach especially in children and indicate that future prospective studies are needed to assess the reasons for the observed differential response-rates in pediatric and adult patients.