Article

Induction of tumor immunity following allogeneic stem cell transplantation.

Cancer Vaccine Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Advances in Immunology (Impact Factor: 7.26). 02/2006; 90:133-73. DOI: 10.1016/S0065-2776(06)90004-2
Source: PubMed

ABSTRACT The curative potential of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for many hematologic malignancies derives in large part from reconstitution of normal donor immunity and the development of a potent graft-versus-leukemia (GVL) immune response capable of rejecting tumor cell in vivo. Elucidation of the mechanisms of GVL by studies of animal models and analysis of clinical data has yielded important insights into how clinically effective tumor immunity is generated following allo-HSCT. These studies have identified NK cells and B cells as well as T cells as important mediators of the GVL response. A variety of antigenic targets of the GVL response have also been identified, and include tumor-associated antigens as well as minor histocompatibility antigens. The principles of effective GVL can now be applied to the development of novel therapies that enhance the therapeutic benefit of allogeneic HSCT while minimizing the toxicities associated with treatment. Moreover, many components of this approach that result in elimination of tumor cells following allogeneic HSCT can potentially be adapted to enhance the effectiveness of tumor immunity in the autologous setting.

0 Bookmarks
 · 
53 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Notch signaling can regulate both hematopoietic progenitors and alloimmune T cells in the setting of allogeneic bone marrow or hematopoietic cell transplantation (allo-HCT). Ex vivo culture of multipotent blood progenitors with immobilized Delta-like ligands induces supraphysiological Notch signals and can markedly enhance progenitor expansion. Infusion of Notch-expanded progenitors shortened myelosuppression in preclinical and early clinical studies, while accelerating T cell reconstitution in preclinical models. Notch also plays an essential role in vivo to regulate pathogenic alloimmune T cells that mediate graft-versus-host disease (GVHD), the most severe complication of allo-HCT. In mouse allo-HCT models, Notch inhibition in donor-derived T cells or transient blockade of Delta-like ligands after transplantation profoundly decreased GVHD incidence and severity, without causing global immunosuppression. These findings identify Notch in T cells as an attractive therapeutic target to control GVHD. In this review, we discuss these contrasting functions of Notch signaling with high translational significance in allo-HCT patients.
    Blood reviews 08/2013; · 7.19 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Post-transcriptional modification of histones by methylation plays important roles in regulating Ag-driven T-cell responses. We have recently drawn correlations between allogeneic T-cell responses and the histone methyltransferase Ezh2, which catalyzes histone H3 lysine 27 trimethylation. The functional relevance of Ezh2 in T-cell alloimmunity remains unclear. Here, we identify a central role of Ezh2 in regulating allogeneic T cell proliferation, differentiation and function. Conditional loss of Ezh2 in donor T cells inhibited GVHD in mice after allogeneic BM transplantation. Although Ezh2-deficient T cells were initially activated to proliferate upon alloantigenic priming, their ability to undergo continual proliferation and expansion was defective during late stages of GVHD induction. This effect of Ezh2 ablation was largely independent of the proapoptotic molecule Bim. Unexpectedly, as a gene silencer, Ezh2 was required to promote the expression of transcription factors Tbx21 and Stat4. Loss of Ezh2 in T cells specifically impaired their differentiation into IFN-γ-producing effector cells. However, Ezh2 ablation retained anti-leukemia activity in alloreactive T cells, leading to improved overall survival of the recipients. Our findings justify investigation of modulating Ezh2 as a therapeutic strategy for the treatment of GVHD and other T cell-mediated inflammatory disorders.
    Blood 10/2013; · 9.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Whole tumor cell-based vaccines administered within the first 2 to 3 months after allogeneic stem cell transplantation stand out as a promising approach to enhance graft-vs.-leukemia responses. Herein, the implications of this finding for the development of strategies to improve the outcome of patients subjected to allogeneic stem cell transplantation are discussed.
    Oncoimmunology. 11/2013; 2(11):e26587.