I continue to overview published results of the most important (in my opinion) clinical trials in cell therapy, gene therapy, tissue engineering and combined approaches.
I’d start from one of the most important reports that came up a month ago and made us re-think the significance and our expectations of fetal tissue transplantation for treatment of neurodegenerative diseases.
neurology – Huntington’s disease
Two of 3 patients with HD reported here, who underwent neural transplantation containing striatal anlagen in the striatum a decade earlier, have demonstrated marginal and transient clinical benefits.
Here we report in patients with HD that (i) graft survival is attenuated long-term; (ii) grafts undergo disease-like neuronal degeneration with a preferential loss of projection neurons in comparison to interneurons; (iii) immunologically unrelated cells degenerate more rapidly than the patient’s neurons, particularly the projection neuron subtype…
These results, when combined, raise uncertainty about this potential therapeutic approach for the treatment of HD. However, these observations provide new opportunities to investigate the underlying mechanisms involved in HD, as well as to explore additional therapeutic paradigms.
Furthermore, Thomas Freeman indicated in his comment for Nature News :
It is unfortunate that this news report did not have space to compare the results seen in our Huntington’s disease transplant program to what we described in our transplanted patients with Parkinson’s disease. In the latter program, only 5-8% of the transplanted neurons developed Lewy bodies. Also, grafts still survived and functioned clinically for over a decade. The article and the responses seem to cast a haze over the entire field of stem cells in general, which is certainly not accurate. The magnitude and mechanisms of neural degeneration that we reported was specific to grafts in patients with Huntington’s disease. We are still enthusiastic about the potential of brain repair with stem cells for many different diseases.
neurology – ALS
Mesenchymal stem celltransplantation in amyotrophic lateral sclerosis: A phase I clinical trial  (Italy)
Our study is the first clinical trial with MSCs transplantation and the first surgical trial in ALS.
We have demonstrated that the concerns regarding possible additional lesions of the spinal cord, at least at the thoracic level, that might be caused by the surgical procedure or the severe complications after general anesthesia are, apparently, not legitimate.
In most patients we detected no significant changes of the progression of the disease in the posttransplantation period. Only in patients 1 and 2 did we find a trend toward a slower deterioration of FVC and upper limb MRC in the 12 months after transplant rather than in the 9 month pre-treatment period. However, these data are due to the younger age of these patients (Beghi E et al., 2006). These results are apparently different from those obtained in our previous study (Mazzini et al., 2003, 2 006, 2008) showing a trend toward a slowing down of the progression of the disease after transplantation and prolonged survival in 5\9 patients.
PS: This is extremely important trial. I had a lot of pleasure reading this manuscript. Very well done study and very nicely written. This is one of examples how cell therapy clinical trials should be done.
neurology – stroke
Purpose: Bone marrow stem cells (BMSC) were transplanted into the perilesional area in five patients bearing sequels of stroke, to evaluate the safety of the procedure and tolerance to the transplanted cells.
Methods: Cells were obtained from bone marrow samples taken from the same patient and stereotactically implanted into the targets, determined using a combination of images, and trans-operative recording of multiunit activity….
Results: No important adverse events derived from surgery or transplant were observed during the one year follow-up period, or detected using a combination of tests and functional measurements applied pre- and post-surgically. In contrast, some improvements were observed regarding the neurological condition of the patients, but the small number of patients in the study does not allow any conclusive statement.
neurology – demyelinating neuropathy
The role of PBSCT in CADP refractory to other treatment deserves further investigation but the serious adverse events and lack of sustained response in some patients emphasize the need for caution.
Clinical-grade manufacturing of autologous mature mRNA-electroporated dendritic cells and safety testing in acute myeloid leukemia patients in a phase I dose-escalation clinical trial . (Belgium – Netherlands)
A monocyte-to-mDC conversion factor of 25±10% was reached. All DC preparations exhibited high expression of mDC markers. Despite a decreased cell recovery of mDC after a combination of mRNA electroporation and cryopreservation, successful vaccine preparations were obtained in all AML patients. DC injections were well tolerated by all patients.
Our method yields a standardized, simplified and reproducible preparation of multiple doses of clinical-grade mRNA-transfected DC vaccines from a single apheresis with consistent mature phenotype, recovery, sterility and viability. Intradermal injection of such DC vaccines in AML patients is safe.
A paired study, with 42 patients in each group with stage I-IIIa NSCLC after surgery, was performed. Patients received chemotherapy alone (CT) or chemotherapy and DC-activated CIK cell treatment (immuno-CT). Disease-free survival (DFS) and overall survival were evaluated.
The cytotoxicity of CIK cells was significantly enhanced by DC activation. The 2-year overall survival rate in the immuno-CT group was significantly improved compared with the CT group (94.7 ± 3.6% versus 78.8 ± 7.0%, P < 0.05). The 2-year DFS of these two groups showed no significant difference. DC-activated CIK cell treatment increased production of cytokines that have known anti-tumor effects, including IFN-γ, MIG, TNF-agr and TNF-β, in patients who had no progression, but they were not found in patients who developed recurrence/metastasis.
Eight patients (four hepatitis B, one hepatitis C, one alcoholic, and two cryptogenic) with end-stage liver disease having Model for End-Stage Liver Disease score >/=10 were included. Autologous MSCs were taken from iliac crest. Approximately, 30-50 million MSCs were proliferated and injected into peripheral or the portal vein.
Our data show that MSCs injection can be used for the treatment of end-stage liver disease with satisfactory tolerability. Furthermore, this treatment may improve clinical indices of liver function in end-stage liver disease.
We report the safety and feasibility of autologous CD133+ cell implantation into the lower extremity muscles of patients with critical limb ischemia, whose only other option was limb amputation.
There were no complications from either leukapheresis or injection. Stem cell injection prevented leg amputation in seven of the nine patients.
There was a trend towards the improvement in pain-free treadmill walking time (P=0.13) and exercise capacity (P=0.16) at 1 year. Lower extremity limb salvage was achieved for seven of the nine treated patients.
After failed or impossible operative and / or interventional revascularisation and after unsuccessful maximum conservative therapy, 51 patients with impending major amputation due to severe critical limb ischaemia had autologous bone marrow cells (BMC) transplanted into the ischaemic leg.
Clinically most important, patients with limb salvage improved from a mean Rutherford category of 4.9 at baseline to 3.3 at 6 months (p = 0.0001). Analgesics consumption was reduced by 62 %. Total walking distance improved in non-amputees from zero to 40 metres. Three severe periprocedural adverse events resolved without sequelae, and no unexpected long-term adverse events occurred.
Conclusions: In no-option patients with end-stage critical limb ischaemia due to peripheral artery disease, bone marrow cell transplantation is a safe procedure which can improve leg perfusion sufficiently to reduce major amputations and permit durable limb salvage.
tolerance induction in solid organ transplant
In January 2001, a 54-year-old man with Child-Pugh B hepatitis B-related cirrhosis and chronic myeloid leukemia (CML), in the accelerated phase, underwent sequential transplantations: HSCTwith reduced intensity conditioning (RICHSCT) followed by living donor LT (LDLT) from the same human leukocyte antigen (HLA)-matched sibling donor.
The patient is still disease free without immunosuppressants for more than 7 years after transplantation.
The second patient was a 19-year-old woman with Child-Pugh B liver cirrhosis that developed 1 year after she received a myeloablative HSCT from an HLA-matched sibling donor for acute myeloid leukemia. We performed a LDLT using a liver graft from the same donor She is still alive, maintaining full donor chimerism with normal liver function, without immunosuppressants for 6 years.
The cases presented were not intended to induce allograft tolerance, but they demonstrate that lymphohematopoietic full donor chimerism can maintain stable allograft tolerance without the need for life-long immunosuppressants.
28-year-old male patient with a 4-week history of type 1 diabetes mellitus… Six weeks after the diagnosis, 4 doses of cyclophosphamide 50 mg/kg body weight were again administered together with antithymocyte globulin, and autologous hematopoietic cells were transplanted.
Insulin requirement started to drop from the first course of plasmapheresis, and the patient has remained normoglycemic with no need of exogenous insulin or other hypoglycemic agents since the third week after the procedure, which has been 5 months until publication of this report.
The course of the disease and the type of treatment may suggest that such medical procedures could eliminate autoaggressive mechanism in diabetes and prevent further degeneration of insulin-producing cells, thus becoming a new therapeutic option for patients with type 1 diabetes mellitus.
Connotea tag: clinical trials 
PATRICK LANDMANN / SCIENCE PHOTO LIBRARY