I continue to collect and digest most interesting in my opinion clinical trials and cases in cell therapy field, published in peer-reviewed journals. Beginning of the year was very eventful.
hematology – intra-bone BMT / engraftment
The time to neutrophil engraftment for adult patients after myeloablative double unit umbilical cord blood (UCB) transplantation is 23 days when the two units are given i.v. We hypothesized that the intra-BM injection (IBMI) of one of the two UCB units would reduce systemic loss of hematopoietic progenitors and shorten time to neutrophil recovery after myeloablation. Ten patients with a median age of 35 years were transplanted.
In all, 9 of 10 patients engrafted, 5 with the i.v. unit and 4 with the IBMI unit; 7 of 8 evaluable patients developed acute GVHD and 5 of 10 patients died from treatment-related causes. Survival was 47% at 1 year. Despite safety of administration, IBMI of one of two UCB units did not shorten the time to neutrophil engraftment and offers no advantage over conventional double unit transplantation.
gene therapy – HIV
Phase 2 gene therapy trial of an anti-HIV ribozyme in autologous CD34+ cells  (International)
Gene transfer has potential as a once-only treatment that reduces viral load, preserves the immune system and avoids lifetime highly active antiretroviral therapy. This study, which is to our knowledge the first randomized, double-blind, placebo-controlled, phase 2 cell-delivered gene transfer clinical trial, was conducted in 74 HIV-1–infected adults who received a tat-vpr–specific anti-HIV ribozyme (OZ1) or placebo delivered in autologous CD34+ hematopoietic progenitor cells.
This study indicates that cell-delivered gene transfer is safe and biologically active in individuals with HIV and can be developed as a conventional therapeutic product.
gene therapy – SCID
Gene therapy for immunodeficiency due to adenosine deaminase deficiency  (International)
We infused autologous CD34+ bone marrow cells transduced with a retroviral vector containing the ADA gene into 10 children with SCID due to ADA deficiency who lacked an HLA-identical sibling donor, after nonmyeloablative conditioning with busulfan. Enzyme-replacement therapy was not given after infusion of the cells.
Eight patients do not require enzyme-replacement therapy, their blood cells continue to express ADA, and they have no signs of defective detoxification of purine metabolites. Nine patients had immune reconstitution with increases in T-cell counts (median count at 3 years, 1.07×109 per liter) and normalization of T-cell function. In the five patients in whom intravenous immune globulin replacement was discontinued, antigen-specific antibody responses were elicited after exposure to vaccines or viral antigens.
neurology – MS
Autologous non-myeloablative haemopoietic stem cell transplantation is a method to deliver intense immune suppression. We evaluated the safety and clinical outcome of autologous non-myeloablative haemopoietic stem cell transplantation in patients with relapsing-remitting multiple sclerosis (MS) who had not responded to treatment with interferon beta.
Between January, 2003, and February, 2005, 21 patients were treated.
Non-myeloablative autologous haemopoietic stem cell transplantation in patients with relapsing-remitting MS reverses neurological deficits, but these results need to be confirmed in a randomised trial.
neurology – ALS
CD133+ stem cells are known to have the capacity to differentiate into neural lineages. Stem cells may provide an alternative treatment for ALS and other neurodegenerative diseases.
Five men and five women (aged 38-62 years) with confirmed ALS were included in this study.
Bone marrow was stimulated with 300 µg filgrastim subcutaneously daily for 3 days. The isolated cells (2.5-7.5times105) were resuspended in 300 µL of the patient’s cerebrospinal fluid, and implanted in motor cortexes using a Hamilton syringe. Ten patients with confirmed ALS without transplantation were used as a control group. Patients were followed up for a period of 1 year.
The autologous transplantation of CD133+ stem cells into the frontal motor cortex is a safe and well-tolerated procedure in ALS patients. The survival of treated patients was statistically higher (P=0.01) than untreated control patients. Stem-cell transplantation in the motor cortex delays ALS progression and improves quality of life.
cardiology – myocardial infarction
Intracoronary infusion of bone marrow-derived selected CD34+CXCR4+ cells and non-selected mononuclear cells in patients with acute STEMI and reduced left ventricular ejection fraction: results of randomized, multicentre Myocardial Regeneration by Intracoronary Infusion of Selected Population of Stem Cells in Acute Myocardial Infarction (REGENT) Trial (Poland)
Comparison of intracoronary infusion of bone marrow (BM)-derived unselected mononuclear cells (UNSEL) and selected CD34+CXCR4+ cells (SEL) in patients with acute myocardial infarction (AMI) and reduced <40% left ventricular ejection fraction (LVEF).
Two hundred patients were randomized to intracoronary infusion of UNSEL (n = 80) or SEL (n = 80) BM cells or to the control (CTRL) group without BM cell treatment.
In patients with AMI and impaired LVEF, treatment with BM cells does not lead to a significant improvement of LVEF or volumes. There was however a trend in favour of cell therapy in patients with most severely impaired LVEF and longer delay between the symptoms and revascularization.
rheumatology – juvenile idiopathic arthritis
As part of collaborative multi-centre study started in 2000, 7 children in the UK fulfilled the inclusion criteria for treatment with autologous T cell depleted (TCD) haematopoietic stem cell transplantation (HSCT) for severe juvenile idiopathic arthritis (JIA). Here we report on the outcome and transplant-related complications.
The initial, often dramatic clinical response in all patients was followed in 4 with sustained benefit, including the withdrawal of immunosuppressive and anti-inflammatory treatment, significant catch-up growth and immense improvement of the quality of life during 5–8 years long follow-up. Two patients relapsed within 1–12 months, and one died 4 months post transplant.
Autologous TCD HSCT for children with severe JIA results in two-phase response. The initial remission seen in all patients is due to immunosuppressive conditioning. This is followed by sustained drug-free remission in over 50% of patients, which is due to ‘immunomodulatory’ effects of TCD HSCT. The procedure carries a significant morbidity and mortality risk. However, this risk should be balanced against the risks of life-threatening infections occurring in this very selective group of patients on long-term and combined immunosuppressive and anti-inflammatory therapies.
picture credit: Julie Cotton