Myeloid leukemic progenitor cells can be specifically targeted by minor histocompatibility antigen LRH-1–reactive cytotoxic T cells

Norde, Wieger J.; Overes, Ingrid; Maas, Frans; Fredrix, Hanny; Vos, Johanna C. M.; Kester, Michel G.D.; Voort, Robbert van der; Jedema, Inge; Falkenburg, J.H. Frederik; Schattenberg, A.V.M.B.; Witte, Theo M. de; Dolstra, Harry

doi:10.1182/blood-2008-04-153825

Cited by 42 publications

(41 citation statements)

References 37 publications

(59 reference statements)

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“…3 Lymphoid-restricted histocompatibility antigen 1 (LRH-1) is an example of a mHAg that has already proven to be a relevant target antigen in the post-transplant setting of AML (Table 1). 85 This was illustrated by the finding that leukemia patients receiving DLI mounted a functional LRH-1-specific CTL response. 85 Evidence for the in vivo immunogenicity of a particular antigen may also be inferred from the demonstration of naturally occurring antigen-specific immune responses in AML patients.…”

Section: Criterion 4: Immunogenicity Humoral and Cellular Immune Respmentioning

confidence: 99%

“…85 This was illustrated by the finding that leukemia patients receiving DLI mounted a functional LRH-1-specific CTL response. 85 Evidence for the in vivo immunogenicity of a particular antigen may also be inferred from the demonstration of naturally occurring antigen-specific immune responses in AML patients. 4 As shown in Table 1, spontaneous B-cell immune responses have been observed against different AML-associated antigens.…”

Section: Criterion 4: Immunogenicity Humoral and Cellular Immune Respmentioning

confidence: 99%

“…3 Perhaps, the most extensively studied GvL antigens have been mHAgs, such as LRH-1, which is known to serve as a GvL target structure in patients with AML. 3,85 Because of its hematopoiesis-restricted expression pattern, LRH-1 is considered particularly amenable to induce GvL without detrimental 'on-target' alloimmune reactivity against normal host tissues (that is, graft-versus-host-disease). 84 Unfortunately, the practical applicability of mHAgs for passive immunotherapy is rather limited because of the relative infrequency of mHAg disparities between the donor and recipient, which is a premise for alloimmune recognition, and the low frequencies of some MHC alleles that restrict these antigens.…”

Section: Criterion 5: Clinical Relevancementioning

confidence: 99%

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Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia

2012

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The graft-versus-leukemia effect of allogeneic hematopoietic stem cell transplantation (HSCT) has shown that the immune system is capable of eradicating acute myeloid leukemia (AML). This knowledge, along with the identification of the target antigens against which antileukemia immune responses are directed, has provided a strong impetus for the development of antigen-targeted immunotherapy of AML. The success of any antigen-specific immunotherapeutic strategy depends critically on the choice of target antigen. Ideal molecules for immune targeting in AML are those that are: (1) leukemia-specific; (2) expressed in most leukemic blasts including leukemic stem cells; (3) important for the leukemic phenotype; (4) immunogenic; and (5) clinically effective. In this review, we provide a comprehensive overview on AML-related tumor antigens and assess their applicability for immunotherapy against the five criteria outlined above. In this way, we aim to facilitate the selection of appropriate target antigens, a task that has become increasingly challenging given the large number of antigens identified and the rapid pace at which new targets are being discovered. The information provided in this review is intended to guide the rational design of future antigen-specific immunotherapy trials, which will hopefully lead to new antileukemia therapies with more selectivity and higher efficacy.

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Section: Criterion 4: Immunogenicity Humoral and Cellular Immune Respmentioning

confidence: 99%

Section: Criterion 4: Immunogenicity Humoral and Cellular Immune Respmentioning

confidence: 99%

Section: Criterion 5: Clinical Relevancementioning

confidence: 99%

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Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia

2012

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“…Adaptive immune responses, including alloreactive responses, terminate in a contraction phase, leaving a small pool of long-lived MiHA-specific memory cells (4). Unfortunately, despite the presence of these memory cells, many patients with a hematological malignancy relapse posttransplant (5,6), suggesting that MiHA-specific T cell functionality is affected. Tumor cells are known to evade immune attack via multiple mechanisms (7), among which is interference with T cell activation.…”

mentioning

confidence: 99%

B and T Lymphocyte Attenuator Mediates Inhibition of Tumor-Reactive CD8+ T Cells in Patients After Allogeneic Stem Cell Transplantation

Hobo

Norde

Schaap

et al. 2012

The Journal of Immunology

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Allogeneic stem cell transplantation (allo-SCT) can cure hematological malignancies by inducing alloreactive T cell responses targeting minor histocompatibility antigens (MiHA) expressed on malignant cells. Despite induction of robust MiHA-specific T cell responses and long-term persistence of alloreactive memory T cells specific for the tumor, often these T cells fail to respond efficiently to tumor relapse. Previously, we demonstrated the involvement of the coinhibitory receptor programmed death-1 (PD-1) in suppressing MiHA-specific CD8+ T cell immunity. In this study, we investigated whether B and T lymphocyte attenuator (BTLA) plays a similar role in functional impairment of MiHA-specific T cells after allo-SCT. In addition to PD-1, we observed higher BTLA expression on MiHA-specific CD8+ T cells compared with that of the total population of CD8+ effector-memory T cells. In addition, BTLA’s ligand, herpes virus entry mediator (HVEM), was found constitutively expressed by myeloid leukemia, B cell lymphoma, and multiple myeloma cells. Interference with the BTLA–HVEM pathway, using a BTLA blocking Ab, augmented proliferation of BTLA+PD-1+ MiHA-specific CD8+ T cells by HVEM-expressing dendritic cells. Notably, we demonstrated that blocking of BTLA or PD-1 enhanced ex vivo proliferation of MiHA-specific CD8+ T cells in respectively 7 and 9 of 11 allo-SCT patients. Notably, in 3 of 11 patients, the effect of BTLA blockade was more prominent than that of PD-1 blockade. Furthermore, these expanded MiHA-specific CD8+ T cells competently produced effector cytokines and degranulated upon Ag reencounter. Together, these results demonstrate that BTLA–HVEM interactions impair MiHA-specific T cell functionality, providing a rationale for interfering with BTLA signaling in post-stem cell transplantation therapies.

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“…7 Furthermore, distinct minor histocompatibility antigens expressed on AML progenitor cells, which are recognized by CD8 þ T cells, are emerging, and have been proposed as target antigens for immunotherapy. 8 In summary, we report the fascinating case of a primary refractory AML patient who achieved complete remission after an allogeneic SCT with graft failure, lasting now for more than 16 months. This remission coincided with the oligoclonal expansion of autologous CD8 þ T cells, suggesting that CB-SCT triggered the induction and expansion of autologous cytotoxic T cells that cross-react with the AML clone.…”

Section: Letters To the Editormentioning

confidence: 87%

Failure is not fatal: long-term remission in refractory acute myeloid leukemia (AML) after graft failure of cord blood stem cells

et al. 2010

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Figure 2 Expansion of autologous CD8 þ T cells after CB-SCT. (a) Depicts the kinetics of the lymphocytosis after nonmyeloablative conditioning with FC, ATG and TBI and subsequent CB-SCT (indicated by the arrow). (b) Illustrates the immunophenotype of expanded T cells. Displayed are the forward (FSC) and sideward scatter (SSC) characteristics with gating on the lymphocyte population (left hand box), and staining with anti-CD3 and anti-CD8mAbs, revealing that 83.3% of the lymphocytes were CD8 positive (center box). Staining with anti-CD57 and anti-CD94mAbs (righthand box) also revealed that these CD8 þ T cells displayed a phenotype consistent with large granular lymphocytes (LGLs), which is in keeping with the morphology of these activated lymphocytes (Figures 1c and d). Letters to the Editor

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Myeloid leukemic progenitor cells can be specifically targeted by minor histocompatibility antigen LRH-1–reactive cytotoxic T cells

Cited by 42 publications

References 37 publications

Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia

Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia

B and T Lymphocyte Attenuator Mediates Inhibition of Tumor-Reactive CD8+ T Cells in Patients After Allogeneic Stem Cell Transplantation

Failure is not fatal: long-term remission in refractory acute myeloid leukemia (AML) after graft failure of cord blood stem cells

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