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Cell therapy clinical trials 2009 – part IV

I continue to digest published results of the most important (in my opinion) clinical trials in cell therapy, gene therapy, tissue engineering and combined approaches.

Current trends:
1. More trials around the world, harder to pick the most important ones.
2. Gene therapy finally woke up!
3. Eye diseases!
4. No positive long-term outcome after autologous mononuclear bone marrow cells transplantation in post-infarct patients.

leukemia – GVHD
Haemopoietic stem-cell transplantation with antibody-based minimal-intensity conditioning: a phase 1/2 study [1] (International)

This trial is remarkable! It’s a proof-of-principal study showed that monoclonal antibody can be used for depletion host marrow hematopoietic cells, reduce toxicity and pretransplant comorbidity in non-malignant disease.

read more [2]

First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4+CD25+CD127− T regulatory cells [3] (Poland)

The therapy allowed for significant alleviation of the symptoms and reduction of pharmacologic immunosuppression in the case of chronic GvHD, while in the case of grade IV acute GvHD it only transiently improved the condition, for the longest time within all immunosuppressants used nonetheless.

Efficacy of bone marrow-derived mesenchymal stem cells in the treatment for sclerodermatous chronic graft-versus-host disease: A clinical report of four patients [4] (China)

Correspondingly, symptoms of all the four patients gradually improved. During the course of MSCs treatment, the life signs and laboratory results from the recipients remained normal. By the time of this report, there has been no recurrence of leukemia in the four patients. In conclusion, although this study alone cannot guarantee the application of MSCs in ScGVHD, the results are strongly in favor of the idea that the MSCs treatment for ScGVHD patients is therapeutically practical without any detectable side effects…

Generation of donor natural killer cells from CD34+ progenitor cells and subsequent infusion after HLA-mismatched allogeneic hematopoietic cell transplantation: a feasibility study [5] (South Korea)

These results showed that clinical-grade donor NK cell production from CD34+ cells is feasible.

Adoptive immunotherapy with liver allograft–derived lymphocytes induces anti-HCV activity after liver transplantation in humans and humanized mice [6] (Japan)

Here, we describe an adoptive immunotherapy approach, using lymphocytes extracted from liver allograft perfusate (termed herein liver allograft–derived lymphocytes), which includes an abundance of NK/NKT cells that mounted an anti-HCV response in HCV-infected liver transplantation recipients, despite the immunosuppressive environment.
During the first month after liver transplantation, the HCV RNA titers in the sera of recipients who received immunotherapy were markedly lower than those in the sera of recipients who did not receive immunotherapy.

eye diseases
Successful clinical implementation of corneal epithelial stem cell therapy for treatment of Unilateral Limbal Stem Cell Deficiency [7] (UK)

Treatment of limbal stem cell deficiency [LSCD] has been achieved with transplantation of ex vivo expanded LSCs taken from a small biopsy of limbus.
Eight eyes of 8 consecutive patients with unilateral total LSCD treated with ex vivo expanded on human amniotic membrane (HAM) autologous LSC transplant with a mean follow up of 19 (RANGE) months were included in the study. Postoperatively, satisfactory ocular surface reconstruction with a stable corneal epithelium was obtained in all eyes [100%].

Long term results after intracoronary injection of autologous mononuclear bone marrow cells in acute myocardial infarction. The ASTAMI randomized, controlled study [8] (Norway)

A small improvement in exercise time in the mBMC group was found, but no other effects of treatment could be identified 3 years after cell therapy.


A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction [9] (USA)

We performed a double-blind, placebo-controlled, dose-ranging (0.5, 1.6, and 5 million cells/kg) safety trial of intravenous allogeneic hMSCs (Prochymal, Osiris Therapeutics, Inc., Baltimore, Maryland) in reperfused MI patients (n = 53).
Intravenous allogeneic hMSCs are safe in patients after acute MI. This trial provides pivotal safety and provisional efficacy data for an allogeneic bone marrow-derived stem cell in post-infarction patients. NCT00114452 [10]

Clinical outcome 2 years after intracoronary administration of bone marrow-derived progenitor cells in acute myocardial infarction [11] (Germany)

Intracoronary administration of bone marrow – derived progenitor cells is associated with a significant reduction of the occurrence of major adverse cardiovascular events maintained for two years after acute myocardial infarction. Moreover, functional improvements following BMC therapy may persist for at least 2 years. Larger studies focusing on clinical event rates are warranted to confirm the effects of bone marrow-derived progenitor cell administration on mortality and progression of heart failure in patients with acute myocardial infarctions.

neurology – spinal cord injury
Ex vivo-expanded autologous bone marrow-derived mesenchymal stromal cells in human spinal cord injury/paraplegia: a pilot clinical study [12] (India)

The results indicate that our protocol is safe with no serious adverse events following transplantation in SCI patients. The number of patients recruited and the uncontrolled nature of the trial do not permit demonstration of the effectiveness of the treatment involved. However, the results encourage further trials with higher doses and different routes of administration in order to demonstrate the recovery/efficacy if any, in SCI patients.

neurology – inherited diseases
Clinical study of transplantation of neural stem cells in therapy of inherited cerebellar atrophy [13] (China)

The cells from human fetal cerebellum (8-10 weeks of gestation) were grown and expanded in vitro. The cultured neurospheres were then planted into the dentate nuclei of patients by stereo tactic operation.
After the operation, no rejection was detected. Follow up, the effective rates were 58.3% after 3 months, 75.0% after 6 months, and 66.7% for 12-24 months (mean 18 months).

therapeutic angiogenesis
Intramuscular transplantation of G-CSF-mobilized CD34+ cells in patients with critical limb ischemia: A phase I/IIa, multicenter, single-blinded, dose-escalation clinical trial [13] (Japan)

In conclusion, the outcomes of this prospective clinical study indicate the safety and feasibility of CD34+ cell therapy in patients with CLI. Favorable trends in efficacy parameters encourage a randomized and controlled trial in the future.

gene and molecular therapy
Gene therapy for Leber’s Congenital Amaurosis is safe and effective through 1.5 years after vector administration [14] (Italy-USA)

The persistence of functional amelioration suggests that AAV-mediated gene transfer to the human retina does not elicit immunological responses which cause significant loss of transduced cells. The persistence of physiologic effect supports the possibility that gene therapy may influence LCA2 disease progression. The safety of the intervention and the stability of the improvement in visual and retinal function in these subjects support the use of AAV-mediated gene augmentation therapy for treatment of inherited retinal diseases.

First-in-human mutation-targeted siRNA phase Ib trial of an inherited skin disorder [15] (USA)

This trial represents the first time that siRNA has been used in a clinical setting to target a mutant gene or a genetic disorder, and the first use of siRNA in human skin. The callus regression seen on the patient’s siRNA-treated foot appears sufficiently promising to warrant additional studies of siRNA in this and other dominant-negative skin diseases.

Clinical cases:
Successful Immunotherapy of HCMV Disease Using Virus-Specific T Cells Expanded from an Allogeneic Stem Cell Transplant Recipient [16] (Australia)

Here we demonstrate for the first time, the successful expansion of HCMV-specific T cells from a seropositive transplant recipient of a seronegative graft with active HCMV disease and the long-term reconstitution of protective antiviral immunity following their adoptive transfer back into the patient.

Autologous mesenchymal stem cell treatment increased T regulatory cells with no effect on disease activity in two systemic lupus erythematosus patients [16] (Chile)

gene therapy
Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy [17] (France)

Autologous CD34+ cells were removed from the patients, genetically corrected ex vivo with a lentiviral vector encoding wild-type ABCD1, and then re-infused into the patients after they had received myeloablative treatment.
Beginning 14 to 16 months after infusion of the genetically corrected cells, progressive cerebral demyelination in the two patients stopped, a clinical outcome comparable to that achieved by allogeneic HCT. Thus, lentiviral-mediated gene therapy of hematopoietic stem cells can provide clinical benefits in ALD.