Donor lymphocyte infusion (DLI) into patients with a relapse of their leukemia or multiple myeloma after allogeneic stem cell transplantation (alloSCT) has been shown to be a successful treatment approach. The hematopoiesis-restricted minor histocompatibility antigens (mHAgs) HA-1 or HA-2 expressed on malignant cells of the recipient may serve as target antigens for alloreactive donor T cells. Recently we treated three mHAg HA-1-and͞or HA-2-positive patients with a relapse of their disease after alloSCT with DLI from their mHAg HA-1-and͞or HA-2-negative donors. Using HLA-A2͞HA-1 and HA-2 peptide tetrameric complexes we showed the emergence of HA-1-and HA-2-specific CD8 ؉ T cells in the blood of the recipients 5-7 weeks after DLI. The appearance of these tetramer-positive cells was followed immediately by a complete remission of the disease and restoration of 100% donor chimerism in each of the patients. Furthermore, cloned tetramer-positive T cells isolated during the clinical response specifically recognized HA-1 and HA-2 expressing malignant progenitor cells of the recipient and inhibited the growth of leukemic precursor cells in vitro. Thus, HA-1-and HA-2-specific cytotoxic T lymphocytes emerging in the blood of patients after DLI demonstrate graft-versus-leukemia or myeloma reactivity resulting in a durable remission. This finding implies that in vitro generated HA-1-and HA-2-specific cytotoxic T lymphocytes could be used as adoptive immunotherapy to treat hematological malignances relapsing after alloSCT.T reatment of patients with leukemia relapsing after allogeneic stem cell transplantation (alloSCT) by donor lymphocyte infusion (DLI) can induce long-lasting complete remissions through graft-versus-leukemia (GVL) reactivity (1-4). Complete molecular remissions (mCRs) of relapsed chronic myeloid leukemia (CML) in chronic phase have been obtained in 70-80% of treated patients (5-7). In contrast, patients with relapsed acute leukemia or CML in accelerated phase or blast crisis respond in only 20-35% of the cases (3,7,8). In a minority of patients with relapsed or persistent multiple myeloma, a graft-versus-myeloma effect after DLI has been demonstrated as well (9-11).Little is known about the nature and kinetics of antileukemic T cell responses involved in the GVL or graft-versus-myeloma effect after DLI. In patients with relapsed CML after alloSCT who have been treated with low-dose DLI, the time to achieve an mCR may vary from several weeks to 1 year (5, 12). Previously we showed that 5-15 weeks after DLI for relapsed CML significantly increased numbers of cytotoxic T lymphocytes (CTLs) recognizing malignant hematopoietic progenitor cells (HPCs) could be detected in peripheral blood of the recipients (13).In HLA genotypically identical donor-recipient pairs alloreactive donor T cells may recognize minor histocompatibility antigens (mHAgs) expressed on recipient cells (14). Ubiquitously expressed mHAgs such as HY (15-20), HA-3, HA-4, HA-6, HA-7 (14, 15), and HA-8 (21) may play a role in both graftversus-hos...

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Minor histocompatibility antigens (mHags) play an important role in both graft-versustumor effects and graft-versus-host disease (GVHD) after allogeneic stem cell transplantation. We applied biochemical techniques and mass spectrometry to identify the peptide recognized by a dominant tumor-reactive donor T-cell reactivity isolated from a patient with relapsed multiple myeloma who underwent transplantation and entered complete remission after donor lymphocyte infu- IntroductionAllogeneic stem cell transplantation (SCT) is a curative treatment in patients with hematologic cancers. In addition to the antitumor effects of chemotherapy, antibody treatment and/or irradiation administered as the conditioning regimen prior to transplantation, an allogeneic graft-versus-tumor (GVT) immunoreactivity significantly contributes to the curative potential of this therapy. [1][2][3][4][5] This GVT reactivity following HLA-matched SCT has been demonstrated to be mediated primarily by T cells from the donor. All reactive T cells from donor origin may not only mediate the beneficial GVT effect but are also responsible for the development of graft-versus-host disease (GVHD), which is the major detrimental complication after allogeneic SCT. 6,7 T-cell depletion of the stem cell graft removes both GVHD and GVT effect. [8][9][10] The antitumor reactivity can be reintroduced in case of persistent or relapsed hematologic malignancies after transplantation by donor lymphocyte infusion (DLI). [11][12][13][14][15] Whereas profound antitumor effects are frequently associated with GVHD in patients responding to DLI, postponed administration of DLI has been associated with a decreased risk of severe GVHD, and clinical observations indicate that more subtle antitumor reactivities can also be observed in the absence of GVHD. [16][17][18] The main targets of both GVHD and GVT reactivity after HLA-matched allogeneic SCT are minor histocompatibility antigens (mHags). [19][20][21] mHags are peptides differentially expressed by donor and recipient that can be recognized in the context of self-HLA molecules. mHags may arise from differential processing of peptides due to polymorphisms in the gene encoding the protein or by direct polymorphisms in the peptide sequence that is presented in the HLA molecules. 22,23 The clinical manifestation of immune responses against mHags is likely to be determined by the specific tissue expression of the proteins encoding these antigens. Whereas mHags constitutively expressed in many tissues are likely to be targets for combined alloreactive GVHD and GVT responses, T-cell responses directed against antigens that are restricted to the hematopoietic cell lineages including the malignant T cells of hematopoietic origin are likely to mediate a GVT reactivity without severe GVHD. 21,[24][25][26][27][28][29][30][31] However, antigens with variable expression in tissues may also be targets for relatively specific GVT responses because these proteins may not be expressed or recognized on normal tissues under steady state c...