Adoptive immunotherapy after HLA mismatched stem cell transplantation

Abstract

Stem cell transplantation (SCT) is an accepted treatment for patients with hematological malignancies. Stem cell donor-derived T cells mediate both beneficial Graft-versus-Leukemia (GvL) effects and detrimental Graft-versus-Host Disease (GvHD). Relapse of the original disease can be treated with infusions of donor lymphocytes (DLI). Like SCT, DLI elicits both GvHD and GvL. The risk of severe GvHD is especially high if the stem cell donor and patient are not fully matched for human leukocyte antigens (HLA). To minimize GvHD after HLA-mismatched SCT DLI should consist of pre-selected donor T cells that display reactivity restricted to the patient's residual leukemic or hematopoietic cells. This thesis focuses on exploring the alloHLA-A2 T cell repertoire and testing the feasibility of generating alloHLA-A2-restricted T cells specific for the hematopoietic system-restricted minor Histocompatibility antigens (mHags) HA-1 or HA-2. We describe several new methods of alloHLA-restricted antigen-specific T cell stimulation. However, we also show that alloHLA-recognition by T cells is inherently crossreactive. Unfortunately, currently available technologies can not readily distinguish between crossreactive and antigen-specific alloHLA-restricted T cells. We therefore conclude that generation of alloHLA-restricted antigen-specific T cells is as yet not feasibible in a clinical setting.