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Transplantation of allogeneic hematopoietic stem cells represents an established treatment for children with high-risk leukemia. However, steroid-refractory chronic graft-versus-host disease (SR-cGvHD) represents a severe life-threatening complication, for which there is no standard therapy. After failing several lines of immunosuppressive and biological treatment, we applied an immunoablative therapy with re-transplantation of purified CD34+ donor stem cells to reset the aberrant immune system. Two pediatric patients, who had been transplanted for high-risk acute lymphoblastic leukemia, underwent the procedure. Interestingly, enough stem cells could be mobilized, harvested, and purified to be used as grafts more than one year after allogeneic transplantation under intensive immunosuppressive therapy and ongoing SR-cGvHD. With a follow-up of 8 and 22 months, respectively, both patients are without immunosuppressive therapy and do not show signs of active disease. Regeneration of skin manifestations started promptly, other damaged organs did not progress and continue to show recovery from severe fibrotic transformation. Bone marrow function is robust and T cell receptor repertoires showed polyclonal immune reconstitution. In conclusion, stem cell harvest and re-transplantation of human CD34+-selected allogeneic stem cells is possible and represents a new therapeutic option in SR-cGvHD by resetting a profoundly disturbed immune network. [ABSTRACT FROM AUTHOR]

The majority of children undergoing Hematopoietic Stem cell Transplantation (HSCT) require conditioning therapy to make space and prevent rejection of the donor stem cells. The exception is certain children with Severe Combined immune deficiency, who have limited or no ability to reject the donor graft. Transplant conditioning is associated with significant morbidity and mortality from both direct toxic effects of chemotherapy as well as opportunistic infections associated with profound immunosuppression. The ultimate goal of transplant practice is to achieve sufficient engraftment of donor cells to correct the underlying disease with minimal short- and long-term toxicity to the recipient. Traditional combinations, such as busulfan and cyclophosphamide, achieve a high rate of full donor engraftment, but are associated with significant acute transplant-related-mortality and late effects such as infertility. Less “intensive” approaches, such as combinations of treosulfan or melphalan with fludarabine, are less toxic, but may be associated with rejection or low level chimerism requiring the need for re-transplantation. The major benefit of these novel approaches, however, which we hope will be realized in the decades to come, may be the preservation of fertility. Future approaches look to replace chemotherapy with non-toxic antibody conditioning. The lessons learnt in refining conditioning for HSCT are likely to be equally applicable to gene therapy protocols for the same diseases.

Multiple sclerosis (MS) is thought to be an autoimmune disease targeting the central nervous system leading to demyelination, and axonal and neuronal damage, resulting in progressive disability. More intensive therapies such as immunodepletion with hematopoietic stem-cell rescue are being used at a time prior to patients becoming irreversibly disabled. Over the last 15 years, there has been a shift away from using autologous hematopoietic stem-cell transplants (aHSCT) to treat patients with progressive MS, towards treating those with active inflammation and relapses. There is an increasing body of evidence that aHSCT improves all measured MS outcomes, including burden of disease on MRI, clinical relapses, accumulation of disability, and quality of life of patients with active MS not controlled with standard therapy. Importantly, the progression-free survival curves of these patients plateau after the first few years demonstrating the impact that aHSCT has in changing the natural history of MS, potentially freeing patients from the relentless accumulation of disability. Concurrently there has been a reduction in procedure-related mortality. The results of randomized trials will likely spur further development of this field. [ABSTRACT FROM AUTHOR]

Introduction: Current treatments for multiple sclerosis (MS) remain partially successful, with certain patients remaining treatment resistant. A recent treatment, known as 'immunoablation' has been used in severe cases of adult MS with promising results. However, due to its high risk and reservation for severe or refractory cases, its full potential remains unknown. Methods: We report the case of MM, a 14-year-old boy diagnosed with MS and a concurrent diagnosis of Hodgkin's lymphoma. Results: After receiving aggressive chemotherapy (immunoablation) for Hodgkin's lymphoma, MM's MS symptoms appear to have remitted, and he has remained progression- and disease activity-free for over six years. Discussion: This case study will focus on MM's cognitive and behavioural development over this time, but will also discuss treatment implications raised by this rare case. [ABSTRACT FROM AUTHOR]

Expression of the transmembrane NG2 chondroitin sulphate proteoglycan ( CSPG) defines a distinct population of NG2-glia. NG2-glia serve as a regenerative pool of oligodendrocyte progenitor cells in the adult central nervous system ( CNS), which is important for demyelinating diseases such as multiple sclerosis, and are a major component of the glial scar that inhibits axon regeneration after CNS injury. In addition, NG2-glia form unique neuron-glial synapses with unresolved functions. However, to date it has proven difficult to study the importance of NG2-glia in any of these functions using conventional transgenic NG2 'knockout' mice. To overcome this, we aimed to determine whether NG2-glia can be targeted using an immunotoxin approach. We demonstrate that incubation in primary anti- NG2 antibody in combination with secondary saporin-conjugated antibody selectively kills NG2-expressing cells in vitro. In addition, we provide evidence that the same protocol induces the loss of NG2-glia without affecting astrocyte or neuronal numbers in cerebellar brain slices from postnatal mice. This study shows that targeting the NG2 CSPG with immunotoxins is an effective and selective means for killing NG2-glia, which has important implications for studying the functions of these enigmatic cells both in the normal CNS, and in demyelination and degeneration. [ABSTRACT FROM AUTHOR]

Abstract: Background: Individuals with MS undergoing immunoablative therapy and hematopoietic stem cell transplantation (HSCT) show substantial decrease in brain volume over 2.4 months, presumably from chemotoxic effects, although other mechanisms have also been postulated. Objective: We examined whether volume loss was accompanied by a concomitant decrease in cognition. White and gray matter volumes, and the effect of stem cell dosage were considered. Methods: Seven individuals with rapidly progressing MS and poor prognosis underwent high dose immunosuppression and autologous HSCT. Neuropsychological testing and MRI scans were performed at baseline, 2 and 24 months post-procedure. Results: Cognitive impairment was noted at all times in most participants. Median decline of 1.39% in total brain volume was noted 2 months post-HSCT. By 24 months a further decline of 1.65% was noted. At 2 months significant decline was observed for areas of executive functioning. At 24 months almost no significant declines were noted. No significant correlations were found between cognitive decline and change in imaging variables or stem cell dosage. Conclusions: Cognition changed in the early period following treatment but with little apparent relationship to volume changes. With temporal distance from the HSCT procedure, cognition returned to baseline levels. With the caution of a very small sample, preliminary results suggest that immunoablation and HSCT may have no lasting deleterious effects on cognition. [Copyright &y& Elsevier]

Background: The Autologous Stem Cell Transplantation International Crohn's Disease (ASTIC) trial is a randomised controlled evaluation of the proposition that immunoablation and haemopoietic stem cell transplantation improves the course of Crohn's disease. Recruitment of all 48 patients in the trial will be completed in early 2012 and the results to date are descriptively presented here. Methods: Patients with an impaired quality of life due to active Crohn's disease, despite the administration of at least 3 immunosuppressive agents, all received mobilisation treatment (cyclophosphamide 4 g/m2 over 2 days followed by recombinant human granulocyte colony stimulating factor (filgrastim) 10 μg/kg daily before randomisation to immediate (after 1 month) or delayed (after 1 year) immunoablation and stem cell transplantation. The conditioning regime was cyclophosphamide 50 mg/kg/day for 4 days, anti-thymocyte globulin 2.5 mg/kg/day and methylprednisolone 1 mg/kg on days 3-5. The bone marrow was reconstituted by the infusion of an unselected graft of 3-8 × 106/kg CD34-positive stem cells. Results were compared 1 year after mobilisation alone or after transplantation. Results: Twelve months after stem cell transplantation (early or delayed) the Crohn's Disease Activity Index (CDAI) fell from 324 (median, interquartile range 229-411) to 161 (85-257, n = 17) compared to 351 (287-443) to 272 (214-331) following mobilisation alone (n = 11). Six patients had a normal CDAI after transplantation versus 1 after mobilisation. C-reactive protein fell from 16.6 (6.7-32.0) to 6.5 (3.5-12.5) mg/l versus 14 (8.0-27.0) to 9.0 (2.0-23.4) mg/l following mobilisation alone. The Crohn's Disease Endoscopic Index of Severity (CDEIS) (aggregate for upper and lower endoscopy) fell from 18 (10-25) to 5 (1-11) following transplantation versus 14 (12-16) to 9 (4-22) following mobilisation. Three patients achieved the goal of a normal CDAI, no drug therapy and normal upper and lower endoscopy 1 year after transplantation, but so did 1 patient following mobilisation alone. Serious adverse events were common (n = 100 to date) with 42 infective episodes requiring or prolonging hospitalisation, following both mobilisation and conditioning and transplantation. There were 7 episodes of viral (re)activation. Temporary flare of Crohn's disease activity or a need for surgery occurred in 8 patients. Conclusions: Immunoablation and haemopoietic stem cell transplantation appear to be an effective treatment for some patients with Crohn's disease, although full results will be required for a firm conclusion. The risks are significant, making it potentially suitable for only a limited number of patients. Data from the whole trial will be needed to judge whether mobilisation alone has any benefits. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: The Autologous Stem Cell Transplantation International Crohn's Disease (ASTIC) trial is a randomised controlled evaluation of the proposition that immunoablation and haemopoietic stem cell transplantation improves the course of Crohn's disease. Recruitment of all 48 patients in the trial will be completed in early 2012 and the results to date are descriptively presented here. Methods: Patients with an impaired quality of life due to active Crohn's disease, despite the administration of at least 3 immunosuppressive agents, all received mobilisation treatment (cyclophospha-2 mide 4 g/m³ over 2 days followed by recombinant human granulocyte colony stimulating factor (filgrastim) 10 &#181g/kg daily before randomisation to immediate (after I month) or delayed (after I year) immunoablation and stem cell transplantation. The conditioning regime was cyclophosphamide 50 mg/kg/day for 4 days, anti-thymocyte globulin 2.5 mg/ kg/day and methylprednisolone 1 mg/kg on days 3-5. The bone marrow was reconstituted by the infusion of an unselected graft of 3-8 x 106/kg CD34-positive stem cells. Results were compared 1 year after mobilisation alone or after transplantation. Results: Twelve months after stem cell transplantation (early or delayed) the Crohn's Disease Activity Index (CDAI) fell from 324 (median, interquartile range 229-411) to 161 (85-257, n = 17) compared to 351 (287-443) to 272 (214-331) following mobilisation alone (n = 11). Six patients had a normal CDAI after transplantation versus I after mobilisation. C-reactive protein fell from 16.6 (6.7-32.0) to 6.5 (3.5-12.5) mg/1 versus 14 (8.0-27.0) to 9.0 (2.0-23.4) mgll following mobilisation alone. The Crohn's Disease Endoscopic Index of Severity (CDEIS) (aggregate for upper and lower endoscopy) fell from 18 (10-25) to 5 (1-11) following transplantation versus 14 (12-16) to 9 (4-22) following mobilisation.Three patients achieved the goal of a normal CDAI, no drug therapy and normal upper and lower endoscopy I year after transplantation, but so did I patient following mobilisation alone. Serious adverse events were common (n = 100 to date) with 42 infective episodes requiring or prolonging hospitalisation, following both mobilisation and conditioning and transplantation. There were 7 episodes of viral (re)activation. Temporary flare of Crohn's disease activity or a need for surgery occurred in 8 patients. Conclusions: Immunoablation and haemopoietic stem cell transplantation appear to be an effective treatment for some patients with Crohn's disease, although full results will be required for a firm conclusion. The risks are significant, making it potentially suitable for only a limited number of patients. Data from the whole trial will be needed to judge whether mobilisation alone has any benefits. [ABSTRACT FROM AUTHOR]

There are multiple sclerosis patients who suffer from an aggressive course of the disease with severe relapses and rapid accumulation of disability despite adequate treatment. In such cases high-dose immunoablation with autologous haematopoietic stem cell transplantation (ASCT) may be considered. Our objective was to report our experience with 26 multiple sclerosis patients treated with ASCT within the years 1998-2008. Twenty-six patients (Expanded Disability Status Scale 2.5-7.5 (median 6.0), multiple sclerosis duration 2-19 years (median 7)) with aggressive multiple sclerosis underwent autologous haematopoietic stem cell transplantation. Stem cells were mobilized by high-dose cyclophosphamide and granulocyte colony-stimulating factor, BEAM (carmustine, etoposide, cytarabine, melphalan) was used for immunoablation. Patients were evaluated at baseline and every six months post ASCT for adverse events and clinical outcome. Follow-up period was 11-132 months (median 66). Progression-free survival was calculated using the Kaplan-Meier method. At 3 and 6 years of follow-up 70.8% and 29.2% of patients respectively were free of rogression. Patients with relapsing multiple sclerosis course, disease duration <5 years and age <35 years had a more favourable outcome. There was no death within 100 days after ASCT. We conclude that ASCT represents a viable and effective treatment option for aggressive multiple sclerosis. [ABSTRACT FROM AUTHOR]

Conventional drugs, including disease-modifying drugs, various cytostatic regimens and steroids, are unable to control disease activity in a small group of patients with “malignant” multiple sclerosis (MS). This group of patients could be offered aggressive therapies, such as high-dose immunosuppression followed by haematopoietic stem cell transplant (HSCT). Bone marrow or peripheral blood HSCT has been proposed for the treatment of autoimmune diseases because of its immunosuppressive and immunomodulatory effects, and recapitulation of lymphocyte ontogeny may stabilise or improve the course of MS in some patients. There have been a few small studies conducted using high-dose immunoablation and HSCT. A recent clinical trial of 85 patients treated by HSCT revealed that more than 60% of patients may benefit from this procedure. Due to the perceived risks associated with HSCT, only patients with malignant MS who no longer benefit from more conventional therapies were enrolled. HSCT is thus a justified and feasible treatment in certain patient groups, although transplant-related mortality must be reduced. [ABSTRACT FROM AUTHOR]

The majority of children undergoing Hematopoietic Stem cell Transplantation (HSCT) require conditioning therapy to make space and prevent rejection of the donor stem cells. The exception is certain children with Severe Combined immune deficiency, who have limited or no ability to reject the donor graft. Transplant conditioning is associated with significant morbidity and mortality from both direct toxic effects of chemotherapy as well as opportunistic infections associated with profound immunosuppression. The ultimate goal of transplant practice is to achieve sufficient engraftment of donor cells to correct the underlying disease with minimal short- and long-term toxicity to the recipient. Traditional combinations, such as busulfan and cyclophosphamide, achieve a high rate of full donor engraftment, but are associated with significant acute transplant-related-mortality and late effects such as infertility. Less "intensive" approaches, such as combinations of treosulfan or melphalan with fludarabine, are less toxic, but may be associated with rejection or low level chimerism requiring the need for re-transplantation. The major benefit of these novel approaches, however, which we hope will be realized in the decades to come, may be the preservation of fertility. Future approaches look to replace chemotherapy with non-toxic antibody conditioning. The lessons learnt in refining conditioning for HSCT are likely to be equally applicable to gene therapy protocols for the same diseases., (Copyright © 2019 Shaw, Shizuru, Hoenig and Veys.)

Background: Effective treatments for glioblastoma multiforme (GBM) are lacking due, in part, to cellular heterogeneity. Consequently, single-target therapeutic strategies are unlikely to succeed. Simultaneous targeting of different neoplastic cell populations within the same tumour may, therefore, prove of value. Neuron-glia 2 (NG2), a transmembrane chondroitin sulphate proteoglycan, present on developing glial cells, and GD3(A), a ganglioside expressed on developing migratory glia, are re-expressed in GBM., Materials and Methods: The aims of this study were to conduct 'proof of concept' experiments in human GBM cell lines to show that proliferative high NG2-expressing cells and high GD3(A) -expressing migratory cells could be effectively ablated using a Mab-Zap saporin immunotoxin system., Results: The combinatorial ablation of both NG2 and GD3(A)-expressing cells resulted in significant reduction in GBM cell viability compared to single epitope targeting and controls (p<0.0001); non-neoplastic astrocytes were not affected., Conclusion: Multiple targeting of GBM sub-populations may, therefore, help inform novel therapeutic approaches., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)