Prérequis pour une production académique des cellules CART conforme aux bonnes pratiques pharmaceutiques (BPF). Recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC)

The extraordinary and unexpected success of cellular immunotherapy using genetically engineered T-cells to express a chimeric antigen receptor (CAR) targeting CD19, in the treatment of refractory or relapsing B-hematological malignancies, has provided a real therapeutic hope. Indeed, remission rates reach more than 80 % in patients at a stage, without any other possibilities of treatment, notably in the child's acute lymphoblastic leukemia. These results, initially resulting from academic research, led to Food and Drug accreditation for market access of two innovative autologous therapy drugs, Kimryah® and Yescarta®. Based on the impressive clinical results, mainly so far in hematological malignancies (LAL, MM, LBDGC, etc.), the development of several types of cells expressing a CAR receptor suggests a wide range of future applications, particularly in the field of solid tumors. However, while the development of CAR-T cells now appears to be in the hands of private pharmaceuticals companies, the logistical constraints, the cryopreservation and the very high cost of these personalized medicines may ultimately limit their use. The development of academic productions by CAR-T cells could bypass some of these disadvantages. The strong innovation capacity of healthcare institutions associated with research units allows them to identify the ideal tumor target and efficient performing cells. Thus, authorized production platforms could allow for shorter administration times and reasonable production costs for national health systems. The aim of this workshop is to identify the requirements for the academic production of CAR-T cells, while respecting the research standards useful to establish proof of concept, but also at the preclinical development stage, leading in fine to the manufacture, through an authorized pharmaceutical establishment, of the innovative therapy drug, and in accordance with Good Manufacturing Practice (GMP). The ultimate goal is to make these innovative and high-performance medicines available to as many patients as possible

Effectiveness of a Closed-System Transfer Device in Reducing Surface Contamination in a New Antineoplastic Drug-Compounding Unit: A Prospective, Controlled, Parallel Study.

The objective of this randomized, prospective and controlled study was to investigate the ability of a closed-system transfer device (CSTD; BD-Phaseal) to reduce the occupational exposure of two isolators to 10 cytotoxic drugs and compare to standard compounding devices.The 6-month study started with the opening of a new compounding unit. Two isolators were set up with 2 workstations each, one to compound with standard devices (needles and spikes) and the other using the Phaseal system. Drugs were alternatively compounded in each isolator. Sampling involved wiping three surfaces (gloves, window, worktop), before and after a cleaning process. Exposure to ten antineoplastic drugs (cyclophosphamide, ifosfamide, dacarbazine, 5-FU, methotrexate, gemcitabine, cytarabine, irinotecan, doxorubicine and ganciclovir) was assessed on wipes by LC-MS/MS analysis. Contamination rates were compared using a Chi2 test and drug amounts by a Mann-Whitney test. Significance was defined for p<0.05. Overall contamination was lower in the "Phaseal" isolator than in the "Standard" isolator (12.24% vs. 26.39%; p < 0.0001) although it differed according to drug. Indeed, the contamination rates of gemcitabine were 49.3 and 43.4% (NS) for the Standard and Phaseal isolators, respectively, whereas for ganciclovir, they were 54.2 and 2.8% (p<0.0001). Gemcitabine amounts were 220.6 and 283.6 ng for the Standard and Phaseal isolators (NS), and ganciclovir amounts were 179.9 and 2.4 ng (p<0.0001).This study confirms that using a CSTD may significantly decrease the chemical contamination of barrier isolators compared to standard devices for some drugs, although it does not eliminate contamination totally

Prérequis nécessaires pour la mise en place de protocoles de recherche clinique évaluant des thérapies cellulaires et géniques par lymphocytes T dotés de récepteur chimérique à l’antigène (CAR T-cells) : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC)

International audienc

Compounding activity for the ten drugs studied throughout the study.

<p>Data correspond to the number of preparations (N) and prepared doses for each of the 10 studied drugs. Doses are expressed in mg and are presented as mean±standard deviation.</p

Antineoplastic drug contamination rate of the barrier isolators before cleaning procedure.

<p>Histograms represent the proportion of positive samples including traces. Error bars represent the confidence intervals.</p

Scheme of the isolators and biodecontamination systems.

<p>The two isolators have two workstations each. In one isolator (Standard devices), the preparations are compounded only with spikes and needles. In the other isolator (Phaseal), the compounding process involves only Phaseal devices. Three biodecontamination systems are connected to the isolators. Sterilization is performed with hydrogen peroxide. The central biodecontamination system is an aeraulic barrier. There is no airflow between the two isolators.</p

Comparison of contamination rates (in %) and contamination amounts (in ng) between Standard and Phaseal devices according to drug.

<p>Contamination rates are computed taking traces into account. Contamination amounts correspond to the cumulative amount per sampling day.</p

Contamination measured for gloves before cleaning process.

<p>Results for contamination rates are presented as number of positive samples/number of measured samples (n/N) and in %. Drug amounts are expressed in ng/glove. Drugs are classified according to the frequency of positive samples in the Standard group.</p