Aranzazu Jauregui-Amezaga1, Raquel Cabezón2, Anna Ramírez-Morros1, Carolina España2, Jordi Rimola3, Concepció Bru3, Susana Pinó-Donnay1, Marta Gallego1, Maria Carme Masamunt1, Ingrid Ordás1, Miguel Lozano4, Joan Cid4, Julian Panés1, Daniel Benítez-Ribas5, Elena Ricart1. 1. Gastroenterology Department, Hospital Clínic de Barcelona, Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBERhed], Hospital Clínic de Barcelona, Barcelona, Spain. 2. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBERhed], Hospital Clínic de Barcelona, Barcelona, Spain Fundació Clínic, Hospital Clínic de Barcelona and Centre Esther Koplowitz, Barcelona, Spain. 3. Radiology Department, Hospital Clínic de Barcelona, Barcelona, Spain. 4. Hemotherapy and Hemostasis Department, Hospital Clínic de Barcelona, Barcelona, Spain. 5. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBERhed], Hospital Clínic de Barcelona, Barcelona, Spain.
Abstract
BACKGROUND AND AIMS: Ex vivo-generated autologous tolerogenic dendritic cells [tolDCs] can restore immune tolerance in experimental colitis. The aim of this study was to determine the safety and tolerability of administration of autologous tolDCs in refractory Crohn's disease [CD] patients. METHODS: A phase-I, single-centre, sequential-cohorts, dose-range study was designed. Stable tolDCs were generated ex vivo from monocytes following a previously developed protocol, and administered by sonography-guided intraperitoneal injection. Six sequential refractory-CD cohorts were established: the first three cohorts received a single intraperitoneal injection of tolDCs at escalating doses [2 x 10(6)/5 x 10(6)/10 x 10(6)]; and the last three cohorts received three biweekly intraperitoneal injections at same escalating doses. Safety was sequentially evaluated. Patients were assessed from week 0 to 12 and followed up for 1-year period for safety. RESULTS: Nine patients were included. No adverse effects were detected during tolDC injection or follow-up. Three patients withdrew from the study due to CD worsening. Crohn's Disease Activity Index [CDAI] decreased from 274 [60] {mean (standard deviation [SD])} to 222 [113] [p = 0.3]; one [11%] patient reached clinical remission [CDAI < 150] and two [22%] clinical response [CDAI decrease ≥ 100]. Crohn's Disease Endoscopic Index of Severity [CDEIS] decreased from 18 [5] to 13 [8] [p = 0.4]; lesions improved markedly in three patients [33%]. Quality of life (inflammatory bowel disease questionnaire [IBDQ]) changed from 125 [27] to 131 [38] [p = 0.7]; remission [IBDQ at Week 12 ≥ 170] was reached in one [11%] case and response [IBDQ score increase ≥ 16] in two [22%]. CONCLUSIONS: Intraperitoneal administration of autologous tolDCs appears safe and feasible in refractory CD patients. Further studies should be developed to test clinical benefit, determine the optimal administration route and dose, and monitor the immune responses; See [www.eudract.ema.europa.eu, EudraCT number 2007-003469-42; www.aemps.gob.es number PEI 08-049].
BACKGROUND AND AIMS: Ex vivo-generated autologous tolerogenic dendritic cells [tolDCs] can restore immune tolerance in experimental colitis. The aim of this study was to determine the safety and tolerability of administration of autologous tolDCs in refractory Crohn's disease [CD] patients. METHODS: A phase-I, single-centre, sequential-cohorts, dose-range study was designed. Stable tolDCs were generated ex vivo from monocytes following a previously developed protocol, and administered by sonography-guided intraperitoneal injection. Six sequential refractory-CD cohorts were established: the first three cohorts received a single intraperitoneal injection of tolDCs at escalating doses [2 x 10(6)/5 x 10(6)/10 x 10(6)]; and the last three cohorts received three biweekly intraperitoneal injections at same escalating doses. Safety was sequentially evaluated. Patients were assessed from week 0 to 12 and followed up for 1-year period for safety. RESULTS: Nine patients were included. No adverse effects were detected during tolDC injection or follow-up. Three patients withdrew from the study due to CD worsening. Crohn's Disease Activity Index [CDAI] decreased from 274 [60] {mean (standard deviation [SD])} to 222 [113] [p = 0.3]; one [11%] patient reached clinical remission [CDAI < 150] and two [22%] clinical response [CDAI decrease ≥ 100]. Crohn's Disease Endoscopic Index of Severity [CDEIS] decreased from 18 [5] to 13 [8] [p = 0.4]; lesions improved markedly in three patients [33%]. Quality of life (inflammatory bowel disease questionnaire [IBDQ]) changed from 125 [27] to 131 [38] [p = 0.7]; remission [IBDQ at Week 12 ≥ 170] was reached in one [11%] case and response [IBDQ score increase ≥ 16] in two [22%]. CONCLUSIONS: Intraperitoneal administration of autologous tolDCs appears safe and feasible in refractory CDpatients. Further studies should be developed to test clinical benefit, determine the optimal administration route and dose, and monitor the immune responses; See [www.eudract.ema.europa.eu, EudraCT number 2007-003469-42; www.aemps.gob.es number PEI 08-049].
Authors: Ross John Porter; Caroline Andrews; Daniel Paul Brice; Scott Kenneth Durum; Mairi Hall McLean Journal: Inflamm Bowel Dis Date: 2018-09-15 Impact factor: 5.325
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Authors: M J Mansilla; S Presas-Rodríguez; A Teniente-Serra; I González-Larreategui; B Quirant-Sánchez; F Fondelli; N Djedovic; D Iwaszkiewicz-Grześ; K Chwojnicki; Đ Miljković; P Trzonkowski; C Ramo-Tello; E M Martínez-Cáceres Journal: Cell Mol Immunol Date: 2021-05-06 Impact factor: 22.096