Donor immunization with WT1 peptide augments antileukemic activity after MHC-matched bone marrow transplantation

Abstract

The curative potential of MHC-matched allogeneic bone marrow transplantation (BMT) is in part because of immunologic graft-versus-tumor (GvT) reactions mediated by donor T cells that recognize host minor histocompatibility antigens. Immunization with leukemia-associated antigens, such as Wilms Tumor 1 (WT1) peptides, induces a T-cell population that is tumor antigen specific. We determined whether allogeneic BMT combined with immunotherapy using WT1 peptide vaccination of donors induced more potent antitumor activity than either therapy alone. WT1 peptide vaccinations of healthy donor mice induced CD8 ؉ T cells that were specifically reactive to WT1-expressing FBL3 leukemia cells. We found that peptide immunization was effective as a prophylactic vaccination before tumor challenge, yet was ineffective as a therapeutic vaccination in tumor-bearing mice. BMT from vaccinated healthy MHCmatched donors, but not syngeneic donors, into recipient tumor-bearing mice was effective as a therapeutic maneuver and resulted in eradication of FBL3 leukemia. The transfer of total CD8 ؉ T cells from immunized donors was more effective than the transfer of WT1-tetramer ؉ CD8 ؉ T cells and both required CD4 ؉ T-cell help for maximal antitumor activity. These findings show that WT1 peptide vaccination of donor mice can dramatically enhance GvT activity after MHC-matched allogeneic BMT. (Blood. 2011;118(19):5319-5329) IntroductionAllogeneic hematopoietic cell transplantation (HCT) can be curative for patients with high risk leukemia and other hematolymphoid malignancies. 1 The curative potential is in part because of immunologic graft-versus-tumor (GvT) reactions mediated by T cells contained in the donor graft. 2,3 Several lines of clinical evidence have validated the importance of GvT reactions. There were significantly higher relapse rates in acute and chronic myeloid leukemia patients who received syngeneic (identical twin) or T-cell depleted (TCD) grafts compared with recipients who received T-cell replete allografts from human leukocyte antigen (HLA)-matched donors. 4 In transplant recipients who had leukemia relapse, the infusion of donor lymphocytes induced sustained complete remissions, including molecular remissions in some patients. 5,6 The effector T-cell populations that mediate GvT reactions and their target antigens remain relatively poorly defined. After HLA-matched allogeneic HCT, GvT reactions are predominantly mediated by the donor T cells that recognize host minor histocompatibility antigens (mHAgs). 7-9 Donor CD8 ϩ and CD4 ϩ T-cell clones that are cytotoxic for target cells expressing recipient mHAgs presented by major histocompatibility complex (MHC) class I and class II molecules, respectively, can be isolated from recipients of T-cell replete grafts. 10 Despite the potential for donor T-cell mediated GvT reactions, the main reason for an unsuccessful outcome after allogeneic HCT remains disease relapse.One obvious strategy to enhance GvT reactions would be to generate cytotoxic T lymphocytes (CTLs) against tum...

Changes in the autoantibody pattern during allogeneic stem-cell transplantation for acute myeloid leukemia complicated by systemic lupus erythematosus

“…Donor CD4 + T cells may contribute to the expansion of plasmablasts and LLPCs, as is the case with the WT1-peptide immunization model. 12 The clinical findings that anti-RP155 Abs have been observed in systemic sclerosis but not in SLE 13 also support the hypothesis that the auto-Abs were derived from donor cells and not patient cells. However, the presence of auto-Ab against RNP70 could not be explained by this hypothesis.…”

Nonmyeloablative TLI-ATG conditioning for allogeneic transplantation: mature follow-up from a large single-center cohort

“…41 Developing methods to immunize the donor immune cell inoculum to tumor antigens, such as WT1 in AML/MDS or complementarity-determining region-3 in B-cell malignancies, may further boost GVT activity. [42][43][44] Finally, our group recently showed that an anti-CD117 (c-KIT) antibody can deplete MDS hematopoietic stem cells and restore normal donor hematopoiesis in xenografted mice. 45 Combining this c-KIT antibody with TLI-ATG conditioning for patients with MDS and AML may deplete stem cell niches, thereby improving donor cell engraftment and chimerism.…”

Review of the Results of WT1 Peptide Vaccination Strategies for Myelodysplastic Syndromes and Acute Myeloid Leukemia from Nine Different Studies

“…Priming donor T-lymphocytes in vitro to increase the frequency of tumor-specific precursors prior to adoptive transfer has been tested in murine models of leukemia ( 47 ), and has proven feasible in patients with multiple myeloma ( 48 ), and lymphoid neoplasms albeit without demonstration of clinical benefit in the latter population ( 49 ).…”