Transfer of idiotypic protein primed allogeneic marrow grafts elicits potent graft-versus-myeloma effects in mice

Zeis, Matthias; Steinmann, Jörg; Petrela, Elizana; Hartung, G; Schmitz, Norbert; Uharek, Lutz

doi:10.1038/sj.bmt.1702785

Cited by 9 publications

(8 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Utilising the same myeloma model we recently showed that immunisation of healthy MHC-identical bone marrow donors with the HOPC-derived idiotype protein induced a powerful antitumoural effect post transplant in which Idspecific CD8 + T cells were involved. 32 These data are in line with recent studies in humans by Li et al 33 demonstrating that idiotype-specific CD8 + T cells derived from immunised healthy stem cell donors can recognise and kill fresh autologous myeloma cells. In the autologous setting, Ö sterborg and coworkers 34 treated myeloma patients with the purified serum M-component by repeated intradermal injections together with soluble granulocyte-macrophage colony-stimulating factor (GM-CSF).…”

Section: Discussionsupporting

confidence: 81%

Idiotype protein-pulsed dendritic cells produce strong anti-myeloma effects after syngeneic stem cell transplantation in mice

Zeis

Frenzke

Schmitz

et al. 2002

Bone Marrow Transplant

Self Cite

View full text Add to dashboard Cite

Summary:Dendritic cell (DC) vaccination represents an interesting immunotherapeutic option in the treatment of several malignancies. In multiple myeloma (MM) patients, vaccination with autologous idiotype (Id) protein-pulsed DC is feasible, but their antitumoral effectiveness was rather limited. To improve the therapeutic potential of DC therapy, we studied the immunological effects of syngeneic peripheral blood stem cell transplantation (PBSCT) given in conjunction with Id-loaded DC. Balb/c mice were inoculated i.p. with 5 × 10 5 of HOPC myeloma cells (Balb/c origin). Animals were immunized with three injections of 5 × 10 5 DC pulsed with the IgG2a HOPC or with a control immunoglobulin (Ig control ). Some experimental groups of myeloma-bearing animals received total body irradiation (7.5 Gy) and a subsequent transplant of 2 × 10 7 syngeneic peripheral blood progenitor cells (PBPC) followed by DC therapy beginning at day 10 post transplant. Animals receiving DC therapy or syngeneic PBPCT alone neither induce longterm survival nor tumor-specific CTL reactivity in vitro. In marked contrast, combination of syngeneic PBPC transplantation and subsequent DC therapy resulted in 78% survival after a follow-up of 180 days. In addition, this treatment modality conferred a generation of Id peptide-specific CD8-mediated T cell reactivity. These data provide a rationale for DC-based vaccination in multiple myeloma patients administered post syngeneic transplantation. Multiple myeloma (MM) is a malignant plasma cell disorder derived from a B cell clone. 1 Median survival time of untreated MM patients is less than 1 year. Treatment with alkylating agents induces a clinical response in about 50% of the patients and prolongs survival to a median of approximately 3 years. Although autologous 2,3 or allogeneic stem cell transplantation 4 can improve the outcome in subgroups of patients, the course of MM is still almost invariably fatal. New therapeutic approaches to control or eradicate the malignant clone are definitely needed.The idiotype (Id) that is expressed on the immunoglobulin (Ig) produced by B cell lymphomas and myelomas is clonally restricted to tumour cells and thus can serve as a tumour-specific antigen. Early studies by Sirisinha and Eisen 5 and Lynch et al 6 showed that immunisation with purified Ig derived from a mineral oil-induced plasmacytoma (MOPC) induced anti-idiotypic immunity in syngeneic mice. These findings could be confirmed in several other B cell tumour models. [7][8][9] In most of these studies, anti-Id immunity was dependent on T cells rather than on anti-Id antibodies. Bogen et al have shown that Id-specific CD4 + T cells are essential for tumour protection in the MOPC myeloma model. 9-12 Several experimental and clinical data suggest that dendritic cells (DC) specialised to optimally present antigens can be used to enhance the antitumour T cell response. [13][14][15][16][17][18] In a murine B cell lymphoma model, Flamand et al 16 have shown that a specific anti-Id immunity can be generated in the h...

show abstract

Section: Discussionsupporting

confidence: 81%

Idiotype protein-pulsed dendritic cells produce strong anti-myeloma effects after syngeneic stem cell transplantation in mice

Zeis

Frenzke

Schmitz

et al. 2002

Bone Marrow Transplant

Self Cite

View full text Add to dashboard Cite

show abstract

“…35 Idiotype protein vaccination of donor DBA/2 (H-2 d ) mice, similarly, induced GvT against the HOPC myeloma after BMT using BALB/c (H-2 d ) recipients, but it is not clear whether GvT was mediated by T cells and/or antibody in this model. 37 In the current study, the GvT reactions that resulted in cures required the adoptive transfer of donor CD4 ϩ T cells combined with CD8 ϩ T cells. Transplantation of the CD4 ϩ or CD8 ϩ T cells from WT1-vaccinated donors failed to protect against FBL3 leukemia progression.…”

Section: Donor Immunization Augments Gvt 5327mentioning

confidence: 99%

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

Kohrt¹,

Müller²,

Baker³

et al. 2011

Blood

View full text Add to dashboard Cite

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...

show abstract

“…Currently, only two immunocompetent murine models have been described in which allo-SCT is associated with a GvM effect [13], [14], but these models do not resemble human MM disease [13] or do not use allo-SCT as a curative treatment for established disease [14]. So far, an immunocompetent murine GvM model in which allo-SCT is used for the treatment of established MM that resembles human disease, marked by bone marrow tropism and osteolytic lesions, has not been described.…”

Section: Introductionmentioning

confidence: 99%

Establishment of a Murine Graft-versus-Myeloma Model Using Allogeneic Stem Cell Transplantation

et al. 2014

View full text Add to dashboard Cite

BackgroundMultiple myeloma (MM) is a malignant plasma cell disorder with poor long-term survival and high recurrence rates. Despite evidence of graft-versus-myeloma (GvM) effects, the use of allogeneic hematopoietic stem cell transplantation (allo-SCT) remains controversial in MM. In the current study, we investigated the anti-myeloma effects of allo-SCT from B10.D2 mice into MHC-matched myeloma-bearing Balb/cJ mice, with concomitant development of chronic graft-versus-host disease (GvHD).Methods and resultsBalb/cJ mice were injected intravenously with luciferase-transfected MOPC315.BM cells, and received an allogeneic (B10.D2 donor) or autologous (Balb/cJ donor) transplant 30 days later. We observed a GvM effect in 94% of the allogeneic transplanted mice, as the luciferase signal completely disappeared after transplantation, whereas all the autologous transplanted mice showed myeloma progression. Lower serum paraprotein levels and lower myeloma infiltration in bone marrow and spleen in the allogeneic setting confirmed the observed GvM effect. In addition, the treated mice also displayed chronic GvHD symptoms. In vivo and in vitro data suggested the involvement of effector memory CD4 and CD8 T cells associated with the GvM response. The essential role of CD8 T cells was demonstrated in vivo where CD8 T-cell depletion of the graft resulted in reduced GvM effects. Finally, TCR Vβ spectratyping analysis identified Vβ families within CD4 and CD8 T cells, which were associated with both GvM effects and GvHD, whereas other Vβ families within CD4 T cells were associated exclusively with either GvM or GvHD responses.ConclusionsWe successfully established an immunocompetent murine model of graft-versus-myeloma. This is the first murine GvM model using immunocompetent mice that develop MM which closely resembles human MM disease and that are treated after disease establishment with an allo-SCT. Importantly, using TCR Vβ spectratyping, we also demonstrated the presence of GvM unique responses potentially associated with the curative capacity of this immunotherapeutic approach.

show abstract

Transfer of idiotypic protein primed allogeneic marrow grafts elicits potent graft-versus-myeloma effects in mice

Cited by 9 publications

References 24 publications

Idiotype protein-pulsed dendritic cells produce strong anti-myeloma effects after syngeneic stem cell transplantation in mice

Idiotype protein-pulsed dendritic cells produce strong anti-myeloma effects after syngeneic stem cell transplantation in mice

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

Establishment of a Murine Graft-versus-Myeloma Model Using Allogeneic Stem Cell Transplantation

Contact Info

Product

Resources

About