Susceptibility of malignant plasma cells to HA-1H specific lysis suggests a role for the minor histocompatibility antigen HA-1 in the graft-versus-myeloma effect

Holloway, Penny A.; Kaldenhoven, Niels; Dijk, Mirjam van; Bloem, Andries C.; Lau, Wim de; Zee, Ruurd van der; Kircher-Eibl, Brigitte; Mutis, Tuna; Lokhorst, Henk M.

doi:10.1038/sj.leu.2403445

Cited by 12 publications

(10 citation statements)

References 12 publications

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“…As expected, both CTLs mediated effective dose-dependent survival inhibition of the relevant MM cell line. In this experimental setting, the inhibition of survival represents multiple myeloma cell lysis by the CTLs (3), which is also confirmed by our previous findings (19,21). Coculture with any of the accessory cells significantly inhibited this cytotoxic effect (Fig.…”

Section: Accessory Cells Inhibit Ctl-mediated Lysis Of Multiple Myelosupporting

confidence: 73%

“…The HLA-DP4 restricted, minor histocompatibility antigen (mHag)-specific CD4 þ CTL clone 3AB11; the HLA-A2-restricted mHag-specific CD8 þ CTL clone HA-1; the HLA-A2-specific CD8 þ CTL clone 1E4; and the HLA-A2-restricted WT-1-specific T-cell receptor transferred polyclonal CTLs were previously described in detail with respect to their antigen-specific and HLA-restricted cytotoxic capacity against the relevant HLA-matched and antigen-positive multiple myeloma cells (18)(19)(20)(21). CTLs were expanded using a feeder cell-cytokine mixture and cryopreserved until use as described (19).…”

Section: Cell Culturementioning

confidence: 99%

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Accessory Cells of the Microenvironment Protect Multiple Myeloma from T-Cell Cytotoxicity through Cell Adhesion-Mediated Immune Resistance

Haart

Donk

Minnema

et al. 2013

Clinical Cancer Research

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Purpose: Cellular immunotherapy frequently fails to induce sustained remissions in patients with multiple myeloma, indicating the ability of multiple myeloma cells to evade cellular immunity. Toward a better understanding and effective therapeutic modulation of multiple myeloma immune evasion mechanisms, we here investigated the role of the tumor microenvironment in rendering multiple myeloma cells resistant to the cytotoxic machinery of T cells.Experimental Design: Using a compartment-specific, bioluminescence imaging-based assay system, we measured the lysis of luciferase-transduced multiple myeloma cells by CD4 þ or CD8 þ CTLs in the presence versus absence of adherent accessory cells of the bone marrow microenvironment. We simultaneously determined the level of CTL activation by measuring the granzyme B release in culture supernatants. Conclusion: These results reveal the cell adhesion-mediated induction of apoptosis resistance as a novel immune escape mechanism and provide a rationale to improve the efficacy of cellular therapies by pharmacologic modulation of CAM-IR.

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Section: Accessory Cells Inhibit Ctl-mediated Lysis Of Multiple Myelosupporting

confidence: 73%

Section: Cell Culturementioning

confidence: 99%

Accessory Cells of the Microenvironment Protect Multiple Myeloma from T-Cell Cytotoxicity through Cell Adhesion-Mediated Immune Resistance

Haart

Donk

Minnema

et al. 2013

Clinical Cancer Research

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“…Consequently, mismatched hematopoiesis-restricted mHags might be therapeutically exploited to evoke strong GvL effects with low risk of GvHD [10]. The hematopoiesis-restricted mHag HA-1 appears particularly suitable for immunotherapeutic purposes since it is highly immunogenic [13] and its expression is shared by virtually all hematopoietic cells including normal [14] and leukemic progenitors [15,16], lymphoma [17] and multiple myeloma cells [18]. Only the HA-1 H but not the HA-1 R allele forms immunogenic T-cell epitopes (in HLA-A2 and –B60) [10].…”

Section: Introductionmentioning

confidence: 99%

“…Since HA-1 CTLs isolated after allogeneic SCT eliminate both malignant and non-malignant host hematopoietic cells [14–18,20] in vitro and in vivo, we hypothesized that a sustained immune reconstitution with HA-1 CTLs is associated with a persistently complete donor chimerism after allogeneic SCT. Here, we studied for the first time the relationship between the long-term HA-1 specific immune response and host hematopoiesis levels after T-cell replete HLA-matched, HA-1 mismatched SCT.…”

Section: Introductionmentioning

confidence: 99%

Possible Role of Minor H Antigens in the Persistence of Donor Chimerism after Stem Cell Transplantation; Relevance for Sustained Leukemia Remission

et al. 2015

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Persistent complete donor chimerism is an important clinical indicator for remissions of hematological malignancies after HLA-matched allogeneic stem cell transplantation (SCT). However, the mechanisms mediating the persistence of complete donor chimerism are poorly understood. The frequent coincidence of complete donor chimerism with graft-versus-leukemia effects and graft-versus-host disease suggests that immune responses against minor histocompatibility antigens (mHags) are playing an important role in suppressing the host hematopoiesis after allogeneic SCT. Here, we investigated a possible relationship between donor immune responses against the hematopoiesis-restricted mHag HA-1 and the long-term kinetics of host hematopoietic chimerism in a cohort of 10 patients after allogeneic HLA-matched, HA-1 mismatched SCT. Functional HA-1 specific CTLs (HA-1 CTLs) were detectable in 6/10 patients lysing host-type hematopoietic cells in vitro. Presence of HA-1 CTLs in the peripheral blood coincided with low host hematopoiesis levels quantified by highly sensitive mHag specific PCR. Additionally, co-incubation of host type CD34+ cells with HA-1 CTLs isolated after allogeneic SCT prevented progenitor and cobblestone area forming cell growth in vitro and human hematopoietic engraftment in immunodeficient mice. Conversely, absence or loss of HA-1 CTLs mostly coincided with high host hematopoiesis levels and/or relapse. In summary, in this first study, presence of HA-1 CTLs paralleled low host hematopoiesis levels. This coincidence might be supported by the capacity of HA-1 CTLs isolated after allogeneic SCT to specifically eliminate host type hematopoietic stem/progenitor cells. Additional studies involving multiple mismatched mHags in more patients are required to confirm this novel characteristic of mHag CTLs as factor for the persistence of complete donor chimerism and leukemia remission after allogeneic SCT.

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“…Alternatively, expansion in vivo in patients is likely on transfer and can be boosted by vaccination on a continuing basis (44). Patients with other HA-1-expressing tumors, including myeloma (45,46) and some epithelial cancers (47), could also be vaccinated. Thus, DNA fusion vaccines offer a novel approach to induce alloreactive CD8 + T-cell responses which are capable of mediating graft-versusleukemia responses in the stem-cell transplant setting.…”

Section: Discussionmentioning

confidence: 99%

DNA Fusion Vaccines Induce Epitope-Specific Cytotoxic CD8+ T Cells against Human Leukemia-Associated Minor Histocompatibility Antigens

Rice¹,

Dunn²,

Piper

et al. 2006

Cancer Research

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The graft-versus-leukemia effect of allogeneic stem-cell transplantation is believed to be mediated by T-cell recognition of minor histocompatibility antigens on recipient cells. For minor histocompatibility antigens HA-1 and HA-2, normal cell expression is restricted to hemopoietic cells, and boosting the immune response to these antigens may potentiate graft-versus-leukemia effect without accompanying graftversus-host disease. To increase efficacy, expansion of HA-1-or HA-2-specific CTL before transplantation is desirable. However, primary HA-1-or HA-2-specific CTL expanded in vitro are often of low avidity. An alternative approach is to prime specific CTL responses in vivo by vaccination. Clearly, donor vaccination must be safe and specific. We have developed DNA fusion vaccines able to induce high levels of epitope-specific CTL using linked CD4 + T-cell help. The vaccines incorporate a domain of tetanus toxin (DOM) fused to a sequence encoding a candidate MHC class I binding peptide. This design generates antitumor CD8 + T-cell responses and protective immunity in preclinical models. For clinical application, we constructed vaccines encoding HLA-A*0201-restricted peptides from human HA-1 and HA-2, which were fused to DOM, and tested their performance in HLA-A*0201-transgenic mice. Priming induced epitope-specific, IFN;-producing CD8 + T cells with cytotoxic function boosted to high levels with electroporation. Strikingly, these mouse T cells efficiently killed human lymphoblastoid cell lines expressing endogenous HA-1 or HA-2. High avidity is indicated by the independence of cytolysis from CD8/MHC class I interaction. These safe epitope-specific vaccines offer a potential strategy to prime HA-1-or HA-2-specific CTL in transplant donors before adoptive transfer.

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Susceptibility of malignant plasma cells to HA-1H specific lysis suggests a role for the minor histocompatibility antigen HA-1 in the graft-versus-myeloma effect

Cited by 12 publications

References 12 publications

Accessory Cells of the Microenvironment Protect Multiple Myeloma from T-Cell Cytotoxicity through Cell Adhesion-Mediated Immune Resistance

Accessory Cells of the Microenvironment Protect Multiple Myeloma from T-Cell Cytotoxicity through Cell Adhesion-Mediated Immune Resistance

Possible Role of Minor H Antigens in the Persistence of Donor Chimerism after Stem Cell Transplantation; Relevance for Sustained Leukemia Remission

DNA Fusion Vaccines Induce Epitope-Specific Cytotoxic CD8+ T Cells against Human Leukemia-Associated Minor Histocompatibility Antigens

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