Good News from Naples
Good News from Naples

Good News from Naples

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Written by Fas Kuiters

A subscriber to the Site had an interesting find of an article published in the Journal of Surgical Research, describing the placebo controlled clinical study of PAD (Peripheral Arterial Disease) patients with chronic ulcers treated with ADRCs from Celution. By my assessment this study is one of several European Celution device based clinical studies, which culminated in Cytori receiving market authorization (added claim to Celution for intended use of: therapy against chronic wounds- reported August 2012). As described in my other article: Another backdoor Slider,  EU regulations allow the device pathway for same day surgical and AUTOLOGOUS procedures, whereby the extracted cells remain property of the patient and ONLY can be used for this SAME patient as per the "Placed on the Market" principle.  This article is presented in "key elements" style instead of my usual long stories to keep our focus on the facts-

 

Therapy with autologous adipose-derived regenerative cells for the care of chronic ulcer of lower limbs in patients with peripheral arterial disease

  • Authors: Gerardo Marino, MDCorresponding author contact information, E-mail the corresponding author, Marco Moraci, MD, Emilia Armenia, MD, Consiglia Orabona, MD, Renato Sergio, MD, Gabriele De Sena, MD, Vincenza Capuozzo, MD, Manlio Barbarisi, MD, Francesco Rosso, MD, Giovanni Giordano, MD, Francesco Iovino, MD, Alfonso Barbarisi
    Laboratory of Applied Biotechnology, Department of Anesthesiology, Surgery, and Emergency Sciences, Second University of Naples, Naples, Italy- Link to article: HERE
    Considerations: 
    1. As stated before, in my opinion this may very well be one of the several COMPLETED studies leading up to the several therapeutic claims on Celution already achieved and which are NOT included in the 23 clinical studies reported by Cytori to be ongoing in the EU at present.
    2. You may "google" like crazy to find the referenced studies in the various global clinical trials databases- you will not find them. EU Directive 93/42 (reference # 1) on Medical Devices Article 20 even regulates the "confidentiality" of the data, which however are stored in a central "Databank" for use of Competent Authorities and Notified Bodies only. The database is called EUDAMED
  1. Before reviewing the abstract and some other data from the study, it is vital to know the key measurement for blood flow for PAD/CLI patients, which is the ABI (Arm Brachial Index) also simply referred to as Ankle Arm Ratio, which is the ratio of the blood pressure in the lower legs to the blood pressure in the arms. Compared to the arm, lower blood pressure in the leg is an indication of blocked arteries (peripheral vascular disease or PVD). The ABI is calculated by dividing the systolic blood pressure at the ankle by the systolic blood pressures in the arm. Wikipedia has a nice classification table thereof: HERE
  2. The ABSTRACT  - Background (click images to enlarge)
    An ulcer is a trophic lesion with loss of tissue that often has a multifactorial genesis. It typically diverges from the chronic-ulcer-naples1 physiologic processes of regeneration because it rarely tends to heal spontaneously. In this study, we used purified adipose-derived stem and regenerative cells (ADRCs) extracted from autologous fat, for the care of chronic ulcers of the lower limbs of arteriopathic patients. The primary objective of this study was complete re-epithelization of chronic ulcers; the secondary objective was a decrease in diameter and depth.
    Methods
    From January 2010 to January 2012, 20 patients with peripheral arterial disease, with an ankle-brachial index (ABI) between 0.30–0.40, in the age range 60–70 y (14 men and six women), with chronic ulcers of the lower limb, were involved in the study. Only 10 arteriopathic patients (seven men and three women) with chronic ulcers of the lower limb were surgically treated. Using the Celution system, we isolated a solution of ADRCs in about 150 min. The isolated cells were injected through a 10-mL syringe into the edges of the ulcer, taking care to spread it in all directions. Using a small amount of Celution extract, we performed cell characterization by flow cytometry analysis and cell viability assay.
    Results
    {eblogads left}We monitored patients treated with ADRC or untreated at 4, 10, 20, 60, and 90 d. In all cases treated with ADRC, we found a reduction in both diameter and depth of the ulcer, which led to a decrease in pain associated with the ulcer process. In six of 10 cases there was complete healing of the ulcer. Characterization of the cells by FACS clearly showed that the ADRC cells contained adipose-derived stem cells. Viability assays demonstrated that partial or total closure of the ulcer was attributable exclusively to ADRC cells present in the Celution extract, and not to growth factors extracted during the process of purification of the Celution and injected together with the cells.
    Conclusions
    For the first time, the Celution method has been applied for the care of chronic ulcers in the lower extremity of patients with peripheral arterial disease. Our results demonstrate that the technique is feasible for autologous cell application and is not associated with adverse events. Moreover, the transplantation of autologous stem cells extracted with Celution may represent a valuable method for the treatment of chronic ulcers in lower limbs of arteriopathic patients.
    5. Some Additional Data on the patient population and the standard of care applied to ALL patients:
    Of the 20 patients, 18 had diabetes mellitus type 2 for about 20 years. In addition, of the 20 patients, five had heart disease and 6 had chronic obstructive pulmonary disease. All patients underwent revascularization procedures for the reactivation of blood flow, without obtaining ulcer healing.They had all been treated for 5 mo with traditional methods (disinfection and cleaning, and surgical and enzymatic debridement with collagenase), and for 5 mo with advanced dressings (nonadherent dressings and antiseptic [silver], polyurethane foams, and gauze to control exudates), without remarkable results
    6. Some Additional Data on Results: Patients who recovered completely had an ABI between 0.8 and 0.9, whereas others with a reduction in the diameter of the ulcer had an ABI between 0.5 and 0.6. During this treatment protocol, no additional revascularization was required and there were no allergic reactions.

     Discussion and comparison to Dermagraft

    1. The treated population consisted of patients with a combination of severe medical issues besides severe PAD- the clinical trial for Dermagraft (Shire- extracellular matrix of human fibroblasts plus scaffold) treating diabetic ulcers, which is an approved treatment in the US, had inclusion criteria, which required an ABI of 0,8 to be able to participate in the clinic. See record at Clinicaltrials.gov The standard revascularization procedures described above (which also included angioplasty) did not produce a sufficient bloodflow in the extremeties to sustain the healing process i.e. control and 4 treated patients remained at ABI of 0.5 and 0.6.

    2. The treated woundsize had a mean of 50 square cm (compare Dermograft < 6 cm²), however with a wide variation. Dermagraft

    3. The statement "patients who recovered completely had an ABI between 0.8 and 0.9" translates of course to a 100% healing rate in case the related perfusion or bloodflow in the extremeties is achieved.

    4. The hypothesis can be made in view of these results, that despite localized treatment of the wound, a partial systemic impact has been achieved in the extremeties through angionesis in the surrounding tissue resulting in this improved ABI with the six treated patients.

    5. Looking at the Dermagraft efficacy curves- it shows natural healing after standard of care of 15% at ABI >0.8 and a doubling thereof i.e. 30% with additional Dermagraft treatment. One can only conclude that ADRC treatment therefore (with 100% under this condition) is a highly superior treatment option.

    6. In view of the above- possibly a systemic intramuscular- or vascular treatment with ADRCs may have been more effective for all treated patients. From a regulatory perspective this was however at the time of the clinic not possible since Celution did not have the CE tool claim for this delivery option. This was only achieved mid 2012 and therefore will likely lead to further studies.

     

     

    Characterization and Mechanisms of Therapeutic Action

    Introduction

    The study is very interesting and recommended for reading. It also includes a materials and methods section, which describes the flow cytometry analysis of the stromal compartment of the cell populations used. The authors concluded that: Adipose-derived stem (i.e. stromal) cells are pluripotent and are the basis for the regeneration process of the ulcer because they can proliferate and differentiate into different cell types. Furthermore, the multicellular composition of the Celution extract stimulates the reconstruction of different tissues damaged by the ulcerative process.
    Whether that conclusion is absolutely correct remains to be seen. In the case of fresh Adipose Derived Regenerative Cells (ADRCs) the exact roles of all the different subpopulations when delivered in combination in vivo are still unknown.  There is evidence that macrophages and T cells in addition to the “SVF or stromal” progenitors, endothelial lineage cells and smooth muscle progenitors may all participate to some degree in improving the body’s response to acute and chronic injury.  The jury is still out as to which cell(s) is/are most important in clinical efficacy.

    Mind the Gap: Challenges in Characterizing and Quantifying Cell- and Tissue-Based Therapies for Clinical Translation (reference # 2)

    Is the title co-written by one of the few scientists in the regenerative field, whom I completely trust to have an un-biased and highly competent view in respect of the themes he writes about. Professor David J Williams, visionary and now Chairman of Termis, whom I have been "reading" now for the past 8 years. No surprise therefore this layman accepts most, that has been written in the referenced paper, but just has a different view on the last line of the paper, which expresses that "hopefully the clinician and the patient will be willing to wait for these more effective cell- and tissue-based therapies". I strongly disagree with this in view of the slow regulatory progress and view proven safety and reasonable efficacy expressed in published peer reviewed scientific papers as initial yardsticks to controlled access to these therapies.

    Product Potency

    As stated in the Williams paper- Potency is defined by the FDA as ‘‘the specific ability or capacity of the product, as indicated by appropriate laboratory tests or by adequately controlled clinical data obtained through the administration of the product in the manner intended, to effect a given result’’. Efficacy generally refers to the ability of a drug or medicinal treatment to cause a functional response in the patient, and is proportional to the potency of the therapy.
    This basically implies a positive correlation between administration of the product and patient outcomes after treatment. So for clinical trial purposes the clinician ought to know, what he administers, what it does i.e. the mechanisms of therapeutic action and the likely impact on the patient. Luckely for the cell therapy industry technological advances have been made to assess the potency and likely therapeutic mechanism of cells before administration to a patient. The Scottish Company Sistemic -LINK HERE- has developed miRNA based quality control tools named SistemicQC which, can monitor cells and stem cells for identity, potency, purity, characterisation, markers for differentiation staging, benchmarking cell model, and QC of batch-to- batch consistency.
    This clearly is what David Williams was looking for and the technology already has been adopted by some leading Cell Companies like Cytori, who made a call to the FDA early in 2012 to change the approved protocol for the cardiac ischemia clinic ATHENA to include SistemicQC in that clinical protocol. According to experts, the FDA never has been so fast to OK the change. A few days versus the usual months long reviews.Scientists at Cytori already tested the SistemicQC analysis tool and concluded in a paper presented at IFATS in 2012:  We have applied a novel, powerful approach, based on the miRNA profiles of the cell populations, which can be used for ADRC characterization to better define cellular composition and mechanisms of action. Application of this information may enable the identification of ADRC efficacy and safety biomarkers in upcoming clinical trials.
     

    Some concluding thoughts

    Early clinical results in the regenerative field seem to point to an equal- to probably even superior efficacy of fresh mononuclear ADRCs versus compositions of plastic-adherent progenitors from the marrow, be they allogeneic or autologous, in the cardiac- and wound healing medical fields. Variability of autologous fresh harvesting always seemed like a negative versus the loss of potency in culturing for clinical development. The above described developments go a long way in resolving the variability issue. 

     

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