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Clinical Efficacy of Ovasave® is Linked to Lytic Molecule Expression
S62
Poster Abstracts
176 CLINICAL EFFICACY OF OVASAVE® IS LINKED TO LYTIC MOLECULE EXPRESSION J. Gertner-Dardenne, N. Belmonte, A. Foussat R&D, TxCell, Valbonne, France Regulatory T (Treg) cells play a crucial role in the maintenance of tolerance and are an ideal target for the development of therapies designed to suppress inflammation in an antigen-specific manner. TxCell develops cellular immunotherapy based on Ag-specific Type 1 Treg (Ag-Treg). Ag-Treg are identified by their capacity to produce high levels of interleukin 10 (IL-10), which contributes to their ability to suppress pathological immune responses. Another mechanism by which Ag-Treg cells control immune responses is the killing of myeloid cells. To date GZMB is the only lytic molecule described to drive this killing. Here we show that Ova-Treg cells (Ovasave®), a product from ASTrIA platform for the treatment of patients with Crohn’s disease (currently in PhIIb), express and secrete other lytic molecules. Analysis of Drug Products generated during the PhI/IIa clinical trial on Crohn’s disease indicate a major role of Granzyme expression in the mechanism of action of Ovasave® as their expression was correlated with clinical efficacy.
177 INVESTIGATING THE ROLE OF REPROGRAMMING MONOCYTE/MACROPHAGES AS A POTENTIAL CELL-BASED THERAPY FOR OSTEOARTHRITIS A. Gomez-Aristizabal1,2,3, S. Viswanathan1,2,3 1 Arthritis Program, UHN, Toronto, Ontario, Canada, 2IBBME, University of Toronto, Toronto, Ontario, Canada, 3Cell therapy program, UHN, Toronto, Ontario, Canada
M1 monocyte/macrophages (Mφ) produce high levels of pro-inflammatory cytokines, while M2-Mφ are associated with anti-inflammatory properties and homeostasis. We hypothesize that M2-Mφs could be an alternative therapy to mesenchymal stromal cells (MSC) for treating osteoarthritis (OA), based on a) involvement of macrophages in OA, and b) MSC-mediated reprogramming of Mφs into M2 sub-types. Monocytes, isolated from healthy donors, were treated for 2 days with medium+IL10/TGFβ or +IFNγ/LPS and characterized by flow cytometry and PCR, and tested for their functional capacity to inhibit T helper (Th) cell proliferation. The stability of the reprogrammed M2-Mφ was challenged by exposing them to IFNγ/LPS (1 day) stimulation or late OA synovium and cartilage explants (2 days, 1 donor). OA synovium and cartilage changes were also analyzed after being exposed to M0-, M1- and M2-Mφ. A 2-day reprogramming is sufficient to demark a defined M1 and M2 phenotype: M2-Mφ were CD163hiCD86low and HLA-DRlow, while the opposite was true for M1-Mφ. Reprogrammed M2-Mφ decreased the proliferation of Th cells in contrast with M1-Mφ. M2-Mφ were relatively stable as demonstrated by their resistance to secondary induction towards a M1 phenotype, including a preserved capacity to inhibit Th cell proliferation. In coculture with OA synovium and cartilage, M1-Mφ intensified their M1 phenotype, while M0 and M2-Mφ preserved higher levels of CD163 (Fig. A). The cocultured M1-Mφ upregulated catabolic and inflammatory factors while M0- and M2-Mφ upregulated anabolic factors in OA cartilage, and decreased iNOS levels in synovium (Fig B, C). In summary, monocytes can be efficiently reprogrammed by a 2-day exposure to soluble factors, and reprogrammed M2-Mφs are resilient to inflammatory challenges such as those in an OA environment. Importantly, tissues from latestage OA respond to signals from reprogrammed Mφs, indicating that Mφs could indeed serve as therapeutic strategy for OA.
Poster Abstracts
176 CLINICAL EFFICACY OF OVASAVE® IS LINKED TO LYTIC MOLECULE EXPRESSION J. Gertner-Dardenne, N. Belmonte, A. Foussat R&D, TxCell, Valbonne, France Regulatory T (Treg) cells play a crucial role in the maintenance of tolerance and are an ideal target for the development of therapies designed to suppress inflammation in an antigen-specific manner. TxCell develops cellular immunotherapy based on Ag-specific Type 1 Treg (Ag-Treg). Ag-Treg are identified by their capacity to produce high levels of interleukin 10 (IL-10), which contributes to their ability to suppress pathological immune responses. Another mechanism by which Ag-Treg cells control immune responses is the killing of myeloid cells. To date GZMB is the only lytic molecule described to drive this killing. Here we show that Ova-Treg cells (Ovasave®), a product from ASTrIA platform for the treatment of patients with Crohn’s disease (currently in PhIIb), express and secrete other lytic molecules. Analysis of Drug Products generated during the PhI/IIa clinical trial on Crohn’s disease indicate a major role of Granzyme expression in the mechanism of action of Ovasave® as their expression was correlated with clinical efficacy.
177 INVESTIGATING THE ROLE OF REPROGRAMMING MONOCYTE/MACROPHAGES AS A POTENTIAL CELL-BASED THERAPY FOR OSTEOARTHRITIS A. Gomez-Aristizabal1,2,3, S. Viswanathan1,2,3 1 Arthritis Program, UHN, Toronto, Ontario, Canada, 2IBBME, University of Toronto, Toronto, Ontario, Canada, 3Cell therapy program, UHN, Toronto, Ontario, Canada
M1 monocyte/macrophages (Mφ) produce high levels of pro-inflammatory cytokines, while M2-Mφ are associated with anti-inflammatory properties and homeostasis. We hypothesize that M2-Mφs could be an alternative therapy to mesenchymal stromal cells (MSC) for treating osteoarthritis (OA), based on a) involvement of macrophages in OA, and b) MSC-mediated reprogramming of Mφs into M2 sub-types. Monocytes, isolated from healthy donors, were treated for 2 days with medium+IL10/TGFβ or +IFNγ/LPS and characterized by flow cytometry and PCR, and tested for their functional capacity to inhibit T helper (Th) cell proliferation. The stability of the reprogrammed M2-Mφ was challenged by exposing them to IFNγ/LPS (1 day) stimulation or late OA synovium and cartilage explants (2 days, 1 donor). OA synovium and cartilage changes were also analyzed after being exposed to M0-, M1- and M2-Mφ. A 2-day reprogramming is sufficient to demark a defined M1 and M2 phenotype: M2-Mφ were CD163hiCD86low and HLA-DRlow, while the opposite was true for M1-Mφ. Reprogrammed M2-Mφ decreased the proliferation of Th cells in contrast with M1-Mφ. M2-Mφ were relatively stable as demonstrated by their resistance to secondary induction towards a M1 phenotype, including a preserved capacity to inhibit Th cell proliferation. In coculture with OA synovium and cartilage, M1-Mφ intensified their M1 phenotype, while M0 and M2-Mφ preserved higher levels of CD163 (Fig. A). The cocultured M1-Mφ upregulated catabolic and inflammatory factors while M0- and M2-Mφ upregulated anabolic factors in OA cartilage, and decreased iNOS levels in synovium (Fig B, C). In summary, monocytes can be efficiently reprogrammed by a 2-day exposure to soluble factors, and reprogrammed M2-Mφs are resilient to inflammatory challenges such as those in an OA environment. Importantly, tissues from latestage OA respond to signals from reprogrammed Mφs, indicating that Mφs could indeed serve as therapeutic strategy for OA.