Safety and efficacy of antigen-specific regulatory T-cell therapy for patients with refractory Crohn's disease.

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.

Isolation of functional autologous collagen-II specific IL-10 producing Tr1 cell clones from rheumatoid arthritis blood.

IL-10 producing regulatory type 1 (Tr1) cells represents a subpopulation of CD4+ regulatory cells able to prevent in vitro bystander T-cell proliferation and to inhibit a wide range of inflammatory diseases in mice. Our aim was to evaluate the frequency and function of joint specific Tr1 cells in the peripheral blood of severe Rheumatoid Arthritis (RA) patients. The collagen II protein was chosen to isolate Tr1 cells specific for a joint antigen. We successfully isolated Tr1 clones from 9 out of 11 RA patients. We showed that cells from patients display the same phenotype and surface marker regulation as previously shown for human Tr1 cells, characterized by expression of markers of regulation (FoxP3, CD25) at the activated but not at the resting state. Importantly, cells from patients showed Tr1 cytokine secretion (IL-10 and IFN-γ) and immunosuppressive action on bystander T cell proliferation. Based on these results, we demonstrated that collagen II specific Tr1 cells can be isolated from the blood of severe refractory patients and that these cells are not altered in their phenotype and function.

Clinical grade production of IL-10 producing regulatory Tr1 lymphocytes for cell therapy of chronic inflammatory diseases.

IL-10 producing regulatory type 1 (Tr1) cells represents a subpopulation of CD4(+) regulatory cells able to prevent in vitro bystander T-cell proliferation and to cure ongoing chronic colitis in mice. In order to assess the efficacy and tolerance of Tr1 cell therapy in a Phase I/IIa clinical trial in patients displaying severe Crohn's disease, we set up a reproducible manufacturing process for the GMP production of human ovalbumin specific Tr1 cells. Procedures used for Tr1-cell production include the use of Drosophila derived artificial Antigen Presenting Cells transfected with specific stimulatory molecules. Characterization of the human cell therapy product shows an in vitro suppressive activity on T-cell proliferation dependent on the production of both IL-10 and TGF-beta. Manufactured Tr1 cells display a regulatory phenotype including Foxp3, GITR and CTLA-4 surface expression. In vitro toxicity studies of human Tr1 cell product show a safety profile compatible with the use of these regulatory Tr1 lymphocytes for cell therapy.