Minor histocompatibility antigens: from identification to vaccination

Abstract

Allogeneic stem cell transplantation (allo-SCT) for hematological malignancy is applied since the late 1950. This therapy was initially designed to provide rescue to the bone marrow of leukemic patients after myeloablative irradiation and chemotherapy, but is currently mostly used to induce a therapeutic graft-versus-tumor (GvT) immune effect, which unfortunately often develops in accordance with adverse graft-versus-host disease (GvHD). Both GvT and GvHD develop mainly due to alloreactivity of donor T cells directed at polymorphic peptides on the recipient cells, the minor histocompatibility antigens (mHags). The mHag-specific T cell responses will induce either GvT or GvHD depending on the site of expression of the mHag-encoding gene. Specific targeting of hematopoietic cell-restricted mHags therefore offers a very appealing strategy for adoptive immunotherapy after allo-SCT, to augment the beneficial GvT without an increased risk of detrimental GvHD.

As identification strategies continue to improve, an enlarging arsenal of mHags becomes available, enabling us to carry out mHag-directed immunotherapy trials. With the optimization of the forward and possibly also reverse immunology methods the available panel of therapeutic mHags for clinical application in routine therapies will rapidly expand. Ultimate progress in mHag identification methods has been made by implementing the 1000 Genomes Project in existing genome wide association analyses. Nonetheless, it will expectedly take several years before all patients with less common HLA types can be treated with mHag-directed therapies. The first clinical trials of patients treated with mHag-specific T cell transfer have recently become available, demonstrating the feasibility of inducing tumor-specific T cell responses, even though clinical responses at this stage are generally short-lived and unpredictable. In this thesis we moreover show the feasibility, safety and efficacy of (mHag-loaded) DC vaccination in combination with DLI. Further optimization of both strategies is however required in the current stage. Methods to improve the immunogenicity of the mHag epitopes by chemical alterations are described in this thesis. Finally, the potential of combining mHag-specific therapy with additional measures directed at the improvement of effective antitumor immune responses is discussed.