Anti third party central memory t cells, methods of producing same and use of same in transplantation and disease treatment

Abstract

A method of generating an isolated population of cells comprising anti-third party cells having a central memory T-lymphocyte (Tcm) phenotype, the cells being tolerance-inducing cells and / or endowed with anti-disease activity, and capable of homing to the lymph nodes following transplantation is disclosed. The method comprising: (a) contacting peripheral blood mononuclear cells (PBMC) with a third party antigen or antigens in the presence of IL-21 so as to allow enrichment of antigen reactive cells; and (b) culturing the cells resulting from step (a) in the presence of IL-21, IL-15 and IL-7 in an antigen free environment so as to allow proliferation of cells comprising the central memory T-lymphocyte (Tcm) phenotype.

Description

FIELD AND BACKGROUND OF THE INVENTION[0001]The present invention, in some embodiments thereof, relates to tolerance inducing and / or graft versus leukemia reactive anti-third party cells comprising central memory T-lymphocyte phenotype and, more particularly, but not exclusively, to methods of generating same and to the use of same in transplantation and in disease treatment.[0002]Bone marrow (BM) transplantation offers a curative treatment for many patients with hematological malignancies and other hematological disorders. However, the BM graft contains donor T cells which respond to the host antigens (Ags) and cause multi-system graft-versus-host disease (GVHD). In the early 80's bone marrow transplant (BMT), without the deleterious effect of GVHD, was demonstrated in the haploidentical (three HLA loci mismatched) settings, in severe combined immunodeficiency (SCID) patients. The problem of GVHD, which is almost uniformly lethal in such settings, was completely prevented by T cell ...

AI Technical Summary

Benefits of technology

The present invention provides a method for generating a population of cells with a central memory T-lymphocyte (Tcm) phenotype, which are tolerance-inducing cells and / or endowed with anti-disease activity, that can homing to lymph nodes after transplantation. The method involves contacting peripheral blood mononuclear cells (PBMC) with a third party antigen or antigens in the presence of IL-21 to enrich antigen reactive cells, and then culturing these cells in an antigen-free environment with IL-21, IL-15, and IL-7 to allow proliferation of cells with the Tcm phenotype.

Problems solved by technology

However, in leukemia patients, the clinical outcome of T cell depleted BM was disappointing, as the benefit of GVHD prevention was offset by a markedly increased rate of graft rejection.

Nevertheless, this strategy is hampered by opportunistic infections due to slow immune reconstitution and considerable toxicities of the immunosuppressants.

While in high risk leukemia patients such transplant-related mortality can be acceptable, it would be intolerable if applied to patients with a long life expectancy.

Yet, the marked levels of host immune cells surviving the mild preparatory regimens, represents a difficult barrier for the engraftment of donor cells.

However, a significant increase in the BM inoculum has been difficult to achieve in humans.

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