Cell Therapy Clinical Trials in 2008 – part I

by Alexey Bersenev on November 17, 2008 · 0 comments

in clinical trials and cases

What have cell therapy clinical trials brought us this year? How stem cell research was translated to clinics? Positive or negative data?

I decided to overview results of the most important clinical trials published in 2008 based on my opinion. Some of them are still ongoing and we are waiting final conclusions.

tolerance induction in transplantation:

HLA-Mismatched Renal Transplantation without Maintenance Immunosuppression

Five patients with end-stage renal disease received combined bone marrow and kidney transplants from HLA single-haplotype mismatched living related donors, with the use of a nonmyeloablative preparative regimen. Transient chimerism and reversible capillary leak syndrome developed in all recipients. Irreversible humoral rejection occurred in one patient. In the other four recipients, it was possible to discontinue all immunosuppressive therapy 9 to 14 months after the transplantation, and renal function has remained stable for 2.0 to 5.3 years since transplantation. The T cells from these four recipients, tested in vitro, showed donor-specific unresponsiveness and in specimens from allograft biopsies, obtained after withdrawal of immunosuppressive therapy…

read more in Thomas Starzl commentary

leukemia – engraftment:

Direct intrabone transplant of unrelated cord-blood cells in acute leukaemia: a phase I/II study

Cord-blood transplants are associated with delayed or failed engraftment in about 20% of adult patients. The aim of this phase I/II study was to establish the safety and efficacy of a new administration route (intrabone) for cord-blood cells, measured by the donor-derived neutrophil and platelet engraftment.
Our preliminary data suggest that direct intrabone cord-blood transplantation overcomes the problem of graft failure even when low numbers of HLA-mismatched cord-blood cells are transplanted, thus leading to the possibility of use of this technique in a large number of adult patients.

read more in my commentary

leukemia – HSC expansion:

Transplantation of ex vivo expanded cord blood cells using the copper chelator tetraethylenepentamine: a phase I/II clinical trial

The copper chelator tetraethylenepentamine (TEPA; StemEx) was shown to attenuate the differentiation of ex vivo cultured hematopoietic cells resulting in preferential expansion of early progenitors. A phase I/II trial was performed to test the feasibility and safety of transplantation of CD133+ cord blood (CB) hematopoietic progenitors cultured in media containing stem cell factor, FLT-3 ligand, interleukin-6, thrombopoietin and TEPA. Ten patients with advanced hematological malignancies were transplanted with a CB unit originally frozen in two fractions. The smaller fraction was cultured ex vivo for 21 days and transplanted 24 h after infusion of the larger unmanipulated fraction. All but two units contained <2 times 107 total nucleated cells (TNCs) per kilogram pre-expansion. All donor–recipient pairs were mismatched for one or two HLA loci. The average TNCs fold expansion was 219 (range, 2–620). Mean increase of CD34+ cell count was 6 (over the CD34+ cell content in the entire unit). Despite the low TNCs per kilogram infused (median=1.8 times 107/kg), nine patients engrafted.
There were no cases of grades 3–4 acute graft-versus-host disease (GVHD) and 100-day survival was 90% . This strategy is feasible.

leukemia – GVHD & mesenchymal progenitors (MSC):

The correlation between cotransplantation of mesenchymal stem cells and higher recurrence rate in hematologic malignancy patients: outcome of a pilot clinical study

They found that only 1 out of 10 patients in the group receiving MSC developed grade II acute GVHD as compared to 8 out of 15 patients in the non-MSC group. Strikingly, the relapse rate of MSC group was significantly higher than that of non-MSC group (60 versus 20%).
The study published in this issue of Leukemia by Ning et al. is significant in that it shows in a randomized clinical trial that MSC transplantation, although beneficial, comes at a high price, as the prevention of GVHD is associated with a higher incidence of leukemia relapse. For those active in the field of HSC transplantation, these data are like a deja vu, when in the eighties we learnt that prevention of GVHD was associated with loss of GVL.

read more in my commentary
and one more trial

neuro – ALS:

Hematopoietic stem cell transplantation in patients with sporadic amyotrophic lateral sclerosis

Allogeneic hematopoietic stem cell transplantation (HSCT) was performed in patients with sporadic ALS to suppress neuroinflammation and improve clinical outcomes after CNS engraftment.
Six patients with definite ALS received total body irradiation followed by peripheral blood HSCT infusion from human leukocyte antigen identically matched sibling donors.
No clinical benefits were evident. Four patients were 100% engrafted; postmortem tissue examination in two of the 100% engrafted patients demonstrated 16% to 38% donor-derived DNA at sites with motoneuron pathology…
Conclusions: This study demonstrates that peripheral cells derived from donor hematopoietic stem cells can enter the human CNS primarily at sites of motoneuron pathology and engraft as immunomodulatory cells. Although unmodified hematopoietic stem cells did not benefit these sporadic amyotrophic lateral sclerosis patients, such cells may provide a cellular vehicle for future CNS gene therapy.

neuro – spinal cord injury:

Treatment of chronic spinal cord injured patients with autologous bone marrow-derived hematopoietic stem cell transplantation: 1-year follow-up

Nine patients with chronic complete SCI with American Spinal Injury Association (ASIA) Impairment Scale (ASIA) grade A were included in this study. They were treated with autologous BM-derived hematopoietic progenitor stem cell transplantation without any serious complications. All patients completed the protocols successfully.
Three weeks after the operation all patients’ movements and sensations were improved. All patients had ASIA grade B or C after the operation.

To evaluate the patients we used neurologic impairment scales (ASIA scores), pre- and post-operative Somato Sensorial Evoked Potential (SSEP) assessments and pre- and post-operative Magnetic Resonance Imaging (MRI). All the data showed that BM-derived autologous stem cell therapy is effective and safe for the treatment of chronic SCI.

Autologous olfactory ensheathing cell transplantation in human paraplegia: a 3-year clinical trial

Olfactory ensheathing cells show promise in preclinical animal models as a cell transplantation therapy for repair of the injured spinal cord. This is a report of a clinical trial of autologous transplantation of olfactory ensheathing cells into the spinal cord in six patients with complete, thoracic paraplegia.
The magnetic resonance images (MRIs) at 3 years showed no change from preoperative MRIs or intervening MRIs at 1 and 2 years, with no evidence of any tumour of introduced cells and no development of post-traumatic syringomyelia or other adverse radiological findings. There were no significant functional changes in any patients and no neuropathic pain.
We conclude that transplantation of autologous olfactory ensheathing cells into the injured spinal cord is feasible and is safe up to 3 years of post-implantation, however, this conclusion should be considered preliminary because of the small number of trial patients.

coming up next: clinical trials 2008 – diabetes, liver diseases, cancer…

more clinical trials

picture credit: Bsip Boucharlat / Science Photo Library

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