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Background & Aim Mesenchymal Stromal Cells (MSCs) are involved in several clinical trials in the field of Advanced Therapeutic Medicinal Products (ATMPs) for their properties and therapeutic potential. However, the production of MSCs is currently done in multi-plates culture chambers (CellSTACK, Corning) that only allow the production of a limited number of cells and it's time consuming. This therefore represents a constraint, especially for allogeneic uses. Now, the major challenge is to increase this production capacity. The use of a bioreactor would overcome this problem. The Xpansion® bioreactor (Pall) is composed of a controller and single-use bioreactors. Similar in concept to CellSTACK, the Xpansion bioreactors are composed of stacked cell culture plates that are sold in four variations: 10, 50, 100, and 200. Although the plastic of the bioreactor plates is identical to those of the CellSTACK, the feasibility and equivalence of quality and expansion of the MSCs produced using the Xpansion bioreactor had to be demonstrated. Methods, Results & Conclusion Preliminary tests were carried out on the smallest model of the Xpansion bioreactor product line: The XP10 (10 culture plates). All experiments were performed in parallel with a CellSTACK manipulation. The tests were performed using MSCs at passage 0 (from bone marrow or adipose tissue) or raw materials. Quantitative and qualitative tests were carried out at the end of the culture. From raw material or MSCs, cell densities obtained after 6 days of culture are equivalent in both the Xpansion bioreactor and CellSTACK, demonstrating similar cell growth. The average cell expansion rates in the Xpansion (XP10) bioreactor and CellSTACK are 24.39 times and 21.69 times (n=3), respectively. The flow cytometry analysis showed that the phenotype and viability of the MSCs from the bioreactor were not altered by this culture method. Preliminary tests on the Xpansion bioreactor have demonstrated the feasibility of MSCs cell expansion without affecting the quality of the finished product compared to the current method in CellSTACK. In addition, using a bioreactor allows the production of cells in large quantities by managing only one culture chamber while reducing the risk of contamination and operation time. Additionally, using a bioreactor improves monitoring of culture parameters and scalability. Manufacturing MSCs in this bioreactor would make the graft of a larger number of patients from the same initial collection possible.

Evidence from animal models replicating postradical prostatectomy erectile dysfunction (pRP-ED) suggests intracavernous injection of bone marrow-mononuclear cells (BM-MNCs) as a promising treatment approach for pRP-ED. We conducted a phase 1/2 pilot clinical trial of intracavernous autologous BM-MNC injection to treat pRP-ED (NCT01089387). Twelve patients with localized prostate cancer and vasculogenic pRP-ED refractory to maximal medical treatment were divided into four equal groups treated with escalating BM-MNC doses (2×10 7 , 2×10 8 , 1×10 9 , 2×10 9 ). Tolerance was the primary endpoint. Secondary endpoints were the effects on erectile function and penile vascularization at 6 mo, as assessed using the International Index of Erectile Function-15 and Erection Hardness Scale questionnaires, and color duplex Doppler ultrasound. We measured the peak systolic velocity in cavernous arteries and assessed endothelial function using the penile nitric oxide release test. No serious side effects occurred. At 6 mo versus baseline, significant improvements of intercourse satisfaction (6.8±3.6, 3.9±2.5, p =0.044) and erectile function (17.4±8.9, 7.3±4.5, p =0.006) domains of the International Index of Erectile Function-15 and Erection Hardness Scale (2.6±1.1, 1.3±0.8, p =0.008) were observed in the total population. Spontaneous erections showed significantly greater improvement with the higher doses. Clinical benefits were associated with improvement of peak systolic velocity and of % penile nitric oxide release test and sustained after 1 yr. Our results need to be confirmed by phase 2 clinical trials. Patient summary We report a phase 1/2 pilot clinical trial investigating cell therapy with injection of bone marrow mononucleated cells to treat postradical prostatectomy erectile dysfunction. No serious side effects occurred. Improvements of erectile function and penile vascularization were noted. Further studies are required to confirm these preliminary results.

We recently reported stage I of a phase 1/2 clinical trial of cell therapy to treat postradical prostatectomy erectile dysfunction (INSTIN, INtra-cavernous STem-cell INjection clinical trial, NCT01089387). In this first stage, four doses of intracavernous autologous bone marrow mononuclear cells (BM-MNCs) were tested in 12 patients. Here, we report the results of stage II, in which six additional patients received the optimal dose identified in stage I (10 9 BM-MNCs), and the long-term results in the 12 patients included in stage I. The objectives were to assess the safety and efficacy of this new treatment. In stage II, no patients had side effects, and the erectile function improvements were similar to those seen in stage I: after 6 months, significant improvements versus baseline were noted in International Index of Erectile Function-15 intercourse satisfaction (7.8±3.1 vs 2.2±3.4, p =0.033) and erectile function (18±8.3 vs 3.7±4.1, p =0.035) domains. In stage I patients, after a mean follow-up of 62.1±11.7 mo, there were no prostate cancer recurrences, and erectile function scores were somewhat lower compared with the 1-yr time point. These findings suggest that intracavernous BM-MNC injections are safe and improve erectile function. The decline in erectile function over time suggests a need for assessing repeated injections. Patient summary We report a phase 1/2 pilot clinical trial of cell therapy consisting in intracavernous injection of bone marrow mononuclear cells to treat postradical prostatectomy erectile dysfunction. Erectile function was improved after 6 mo in the patients given 1×10 9 cells. No serious side effects (life threatening or requiring hospitalisation) occurred after a mean follow-up of 62.1 mo in the first 12 patients.

Monoclonal rat anti-idiotypic antibody (Ab2) BR3E4 mimicking the colorectal carcinoma (CRC)-associated epitope CO17-1A induced antigen-specific humoral and cellular immune responses in mice and rabbits. Ab2 BR3E4 was administered in a phase I trial to CRC patients either as intact IgG or as F(ab′) 2 coupled to keyhole limpet hemocyanin (KLH). There was a trend for the F(ab′) 2 -KLH-immunized patients to show higher immune response rates (18/21 and 5/15 patients with anti-anti-idiotypic antibodies and T cells, respectively) than the IgG-immunized patients (15/23 and 3/15 patients positive). Clinical responses were rare in these patients with liver metastases.

Il existe 18 unites de therapie cellulaire (UTC) a l’EFS. Les centres de soins peuvent etre eloignes de ces UTC et des delais variables entre la preparation des PTC et leurs injections aux patients sont ainsi observes. La stabilite des PTC a fait l’objet d’une validation pour obtenir les autorisations procedes pour chaque PTC. Nous avons realise une etude nationale sur la stabilite des greffons decongeles de CSH autologues de sang peripherique afin d’avoir des donnees sur un nombre plus eleve de produits. Il s’agissait pour chacune des 18 UTC de decongeler 5 PTC en attente de destruction. Les greffons decongeles etaient conserves en poche entre 4 oC et 10 oC et des echantillons etaient preleves a T0, T0 + 2 heures (h), T0 + 4 h et T0 + 6 h. Pour chaque echantillon ont ete determines: la viabilite des CD34+ et des CD45+ et la concentration des CD34+ viables pour calculer le rendement de recuperation par rapport a la congelation. Ces donnees ont ete obtenues par cytometrie en flux en utilisant une technique de quantification en simple plateforme. Le travail presente correspond a un point d’etape. Sept sur 18 UTC ont fourni a ce jour des resultats pour 25 PTC (28 % des PTC prevus). Cette premiere cohorte suggere que la qualite des PTC serait encore acceptable apres 6 heures de conservation entre 4 °C et 10 °C puisque la viabilite des CD34+ passe de 87,9 % en moyenne a T0 a 84,7 % a T0 + 6 h. Nous n’avons pas observe de correlation entre la contamination en cellules granuleuses des PTC ou la concentration de CNT a la congelation et le rendement de recuperation des CD34+. Plus de donnees sont necessaires pour consolider ces premieres conclusions et effectuer une etude multivariee.