Pierre Desreumaux1, Arnaud Foussat2, Matthieu Allez3, Laurent Beaugerie4, Xavier Hébuterne5, Yoram Bouhnik6, Maria Nachury7, Valérie Brun8, Hervé Bastian2, Nathalie Belmonte2, Michel Ticchioni9, Agnès Duchange10, Patricia Morel-Mandrino11, Virginie Neveu12, Nathalie Clerget-Chossat8, Miguel Forte8, Jean-Frédéric Colombel13. 1. Department of Hepatogastroenterology and Centre d'Investigation Clinique, Huriez Hospital, Lille, France. 2. R&D, TxCell, Valbonne, France. 3. Gastroenterology and Centre d'Investigation Clinique, Saint-Louis Hospital, Paris, France. 4. Gastroenterology and Centre d'Investigation Clinique, St Antoine Hospital, Paris, France. 5. Gastroenterology and Unité de Recherche Clinique, L'Archet 2 Hospital, Nice, France. 6. Gastroenterology, Beaujon, Clichy, France. 7. Gastroenterology and Centre d'Investigation Clinique, Jean Minjoz Hospital, Besançon, France. 8. Clinical, TxCell, Valbonne, France. 9. Immunology, L'Archet 1 Hospital, Nice, France. 10. Manufacturing, TxCell, Valbonne, France. 11. Centre Régina, Nice, France. 12. Effi-Stat, Paris, France. 13. Department of Hepatogastroenterology and Centre d'Investigation Clinique, Huriez Hospital, Lille, France. Electronic address: jean-frederic.colombel@chru-lille.fr.
Abstract
BACKGROUND & AIMS: New therapeutic strategies are needed for patients with refractory Crohn's disease (CD). We evaluated data from the Crohn's And Treg Cells Study (CATS1) to determine the safety and efficacy of antigen-specific T-regulatory (Treg) cells for treatment of patients with refractory CD. METHODS: We performed a 12-week, open-label, multicenter, single-injection, escalating-dose, phase 1/2a clinical study in 20 patients with refractory CD. Ovalbumin-specific Treg cells (ova-Tregs) were isolated from patients' peripheral blood mononuclear cells (PBMCs), exposed to ovalbumin, and administrated intravenously. Safety and efficacy were assessed using clinical and laboratory parameters. We evaluated proliferation of PBMCs in response to ovalbumin. RESULTS: Injections of ova-Tregs were well tolerated, with 54 adverse events (2 related to the test reagent) and 11 serious adverse events (3 related to the test reagent, all recovered). Overall, a response, based on a reduction in Crohn's Disease Activity Index (CDAI) of 100 points, was observed in 40% of patients at weeks 5 and 8. Six of the 8 patients (75%) who received doses of 10(6) cells had a response at weeks 5 and 8, with a statistically significant reduction in CDAI. In this group, remission (based on CDAI ≤150) was observed in 3 of 8 patients (38%) at week 5 and 2 of 8 patients (25%) at week 8. CONCLUSIONS: Administration of antigen-specific Tregs to patients with refractory CD (CATS1) was well tolerated and had dose-related efficacy. The ovalbumin-specific immune response correlated with clinical response, supporting immune-suppressive mechanisms of ova-Tregs. The consistency of results among different assessment methods supports the efficacy of ova-Tregs; this immune therapy approach warrants further clinical and mechanistic studies in refractory CD. Eudract, Number: 2006-004712-44.
BACKGROUND & AIMS: New therapeutic strategies are needed for patients with refractory Crohn's disease (CD). We evaluated data from the Crohn's And Treg Cells Study (CATS1) to determine the safety and efficacy of antigen-specific T-regulatory (Treg) cells for treatment of patients with refractory CD. METHODS: We performed a 12-week, open-label, multicenter, single-injection, escalating-dose, phase 1/2a clinical study in 20 patients with refractory CD. Ovalbumin-specific Treg cells (ova-Tregs) were isolated from patients' peripheral blood mononuclear cells (PBMCs), exposed to ovalbumin, and administrated intravenously. Safety and efficacy were assessed using clinical and laboratory parameters. We evaluated proliferation of PBMCs in response to ovalbumin. RESULTS: Injections of ova-Tregs were well tolerated, with 54 adverse events (2 related to the test reagent) and 11 serious adverse events (3 related to the test reagent, all recovered). Overall, a response, based on a reduction in Crohn's Disease Activity Index (CDAI) of 100 points, was observed in 40% of patients at weeks 5 and 8. Six of the 8 patients (75%) who received doses of 10(6) cells had a response at weeks 5 and 8, with a statistically significant reduction in CDAI. In this group, remission (based on CDAI ≤150) was observed in 3 of 8 patients (38%) at week 5 and 2 of 8 patients (25%) at week 8. CONCLUSIONS: Administration of antigen-specific Tregs to patients with refractory CD (CATS1) was well tolerated and had dose-related efficacy. The ovalbumin-specific immune response correlated with clinical response, supporting immune-suppressive mechanisms of ova-Tregs. The consistency of results among different assessment methods supports the efficacy of ova-Tregs; this immune therapy approach warrants further clinical and mechanistic studies in refractory CD. Eudract, Number: 2006-004712-44.
Authors: Shok Ping Lim; Benedetta Costantini; Syed A Mian; Pilar Perez Abellan; Shreyans Gandhi; Marc Martinez Llordella; Juan Jose Lozano; Rita Antunes Dos Reis; Giovanni A M Povoleri; Thanos P Mourikis; Ander Abarrategi; Linda Ariza-McNaughton; Susanne Heck; Jonathan M Irish; Giovanna Lombardi; Judith C W Marsh; Dominique Bonnet; Shahram Kordasti; Ghulam J Mufti Journal: Blood Date: 2020-08-13 Impact factor: 22.113