Bone marrow central memory and memory stem T-cell exhaustion in AML patients relapsing after HSCT

Noviello, Maddalena; Manfredi, Francesco; Ruggiero, Eliana; Perini, Tommaso; Oliveira, Giacomo; Cortesi, Filippo; Simone, P. De; Toffalori, Cristina; Gambacorta, Valentina; Greco, Raffaella; Peccatori, Jacopo; Casucci, Monica; Casorati, Giulia; Onozawa, Masahiro; Teshima, Takanori; Griffioen, Marieke; Halkes, Constantijn J.M.; Falkenburg, J.H. Frederik; Stölzel, Friedrich; Altmann, Heidi; Bornhäuser, Martin; Waterhouse, Miguel; Zeiser, Robert; Finke, Jürgen; Cieri, Nicoletta; Bondanza, Attilio; Vago, Luca; Ciceri, Fabio; Bonini, Chiara

doi:10.1038/s41467-019-08871-1

Cited by 145 publications

(162 citation statements)

References 51 publications

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“…The exhausted BM-T cell phenotype was associated with a restricted TCR repertoire, impaired effector functions and leukemia-reactive specificities. Furthermore, early detection of severely exhausted BM-memory stem T cells predicted relapse (202). Interestingly, IR-positive T cells infiltrating the BM of AML patients at relapse displayed a greater ability to recognize matched leukemic blasts after in vitro expansion compared with their IR-negative counterparts.…”

Section: Relapse and Immune Evasion Mechanisms After Haplo-hctmentioning

confidence: 99%

“…Interestingly, IR-positive T cells infiltrating the BM of AML patients at relapse displayed a greater ability to recognize matched leukemic blasts after in vitro expansion compared with their IR-negative counterparts. This suggest that IR expression marks lymphocytes enriched for tumor specificity whose activity could be unleashed with therapeutic check-point blockade, although innovative targeted strategies will be required to avoid exacerbation of GVHD in the HCT context (202).…”

Section: Relapse and Immune Evasion Mechanisms After Haplo-hctmentioning

confidence: 99%

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Key Aspects of the Immunobiology of Haploidentical Hematopoietic Cell Transplantation

et al. 2020

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Hematopoietic stem cell transplantation from a haploidentical donor is increasingly used and has become a standard donor option for patients lacking an appropriately matched sibling or unrelated donor. Historically, prohibitive immunological barriers resulting from the high degree of HLA-mismatch included graft-vs.-host disease (GVHD) and graft failure. These were overcome with increasingly sophisticated strategies to manipulate the sensitive balance between donor and recipient immune cells. Three different approaches are currently in clinical use: (a) ex vivo T-cell depletion resulting in grafts with defined immune cell content (b) extensive immunosuppression with a T-cell replete graft consisting of G-CSF primed bone marrow and PBSC (GIAC) (c) T-cell replete grafts with post-transplant cyclophosphamide (PTCy). Intriguing studies have recently elucidated the immunologic mechanisms by which PTCy prevents GVHD. Each approach uniquely affects post-transplant immune reconstitution which is critical for the control of post-transplant infections and relapse. NK-cells play a key role in haplo-HCT since they do not mediate GVHD but can successfully mediate a graft-vs.-leukemia effect. This effect is in part regulated by KIR receptors that inhibit NK cell cytotoxic function when binding to the appropriate HLA-class I ligands. In the context of an HLA-class I mismatch in haplo-HCT, lack of inhibition can contribute to NK-cell alloreactivity leading to enhanced anti-leukemic effect. Emerging work reveals immune evasion phenomena such as copy-neutral loss of heterozygosity of the incompatible HLA alleles as one of the major mechanisms of relapse. Relapse and infectious complications remain the leading causes impacting overall survival and are central to scientific advances seeking to improve haplo-HCT. Given that haploidentical donors can typically be readily approached to collect additional stem-or immune cells for the recipient, haplo-HCT represents a unique platform for cell-and immune-based therapies aimed at further reducing relapse and infections. The rapid advancements in our understanding of the immunobiology of haplo-HCT are therefore poised to lead to iterative innovations resulting in further improvement of outcomes with this compelling transplant modality.

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Section: Relapse and Immune Evasion Mechanisms After Haplo-hctmentioning

confidence: 99%

Section: Relapse and Immune Evasion Mechanisms After Haplo-hctmentioning

confidence: 99%

Key Aspects of the Immunobiology of Haploidentical Hematopoietic Cell Transplantation

et al. 2020

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“…Further studies are needed to understand the durability of these responses, whether dosing can be adjusted to improve the safety profile while retaining efficacy, and how patientsʼ prior GVHD prophylaxis might impact their risk of GVHD. In AML patients, Noviello et al have demonstrated that the detection of severely exhausted (PD‐1 + Eomes + T‐bet − ) T cells in the bone marrow shortly after transplant predicts relapse . This finding suggests the possibility that intervention with immune checkpoint inhibitors could be used to prevent relapse in patients with early evidence of T cell exhaustion following transplant, but the aforementioned safety concerns currently limit the appeal of such an approach.…”

Section: Immune Checkpoint Inhibitorsmentioning

confidence: 99%

Harnessing the immune system after allogeneic stem cell transplant in acute myeloid leukemia

Sterling

Webster

2020

American J Hematol

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Allogeneic stem cell transplantation (allo-SCT) is the most successful and widely used immunotherapy for the treatment of acute myeloid leukemia (AML), as a result of its anti-leukemic properties driven by T cells and natural killer (NK) cells, leading to a graft-vs-leukemia (GVL) effect. Despite its essential role in AML treatment, relapse after allo-SCT is common and associated with a poor prognosis. There is longstanding interest in developing immunologic strategies to augment the GVL effect posttransplant to prevent relapse and improve outcomes. In addition to prophylactic maintenance strategies, the GVL effect can also be used in relapsed patients to reinduce remission. While immune checkpoint inhibitors and other novel immune-targeted agents have been successfully used in the post-transplant setting to augment the GVL effect and induce remission in small clinical trials of relapsed patients, exacerbations of graft-vs-host disease (GVHD) have limited their broader use. Here we review advances in three areas of immunotherapy that have been studied in post-transplant AML: donor lymphocyte infusion (DLI), immune checkpoint inhibitors, and other monoclonal antibodies (mAbs), including antibody-drug conjugates (ADCs) and ligand receptor antagonists. We also discuss additional therapies with proposed immunologic mechanisms, such as hypomethylating agents, histone deacetylase inhibitors, and the FLT3 inhibitor sorafenib.

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“…Interestingly, these patients also have a greater number of early-differentiated memory stem T cells and central memory T cells with multiple inhibitory receptors than those of patients who remain in CR. Moreover, relapse is effectively predicted by the early identification of BM memory stem T cells displaying a severely exhausted phenotype (PD1+, Eomes+, T-bet-) [14].…”

Section: Immune-checkpoint Receptors and Co-inhibitor Receptorsmentioning

confidence: 99%

“…Currently, the relevance of this tight interaction has been further substantiated by the demonstration that post-transplant AML relapse is not caused by the development of additional genetic alterations as in patients relapsing after chemotherapy [8], but by the loss or down-regulation of major histocompatibility (MHC) class II genes [9,10]. This seminal finding has paved the way for identifying and revealing other novel potential mechanisms of immune escape that are operative not only in the transplant setting [11][12][13][14], but also in the chemotherapy setting [15,16]. Notably, clarifying studies on these immune escape mechanisms have allowed the development of targeted immunotherapies, which are already providing promising results [11,17].…”

Section: Introductionmentioning

confidence: 99%

Immune Escape after Hematopoietic Stem Cell Transplantation (HSCT): From Mechanisms to Novel Therapies

Bernasconi

Borsani

2019

Cancers

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Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Recent advances in understanding its molecular basis have opened the way to new therapeutic strategies, including targeted therapies. However, despite an improvement in prognosis it has been documented in recent years (especially in younger patients) that allogenic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative treatment in AML and the first therapeutic option for high-risk patients. After allo-HSCT, relapse is still a major complication, and is observed in about 50% of patients. Current evidence suggests that relapse is not due to clonal evolution, but instead to the ability of the AML cell population to escape immune control by a variety of mechanisms including the altered expression of HLA-molecules, production of anti-inflammatory cytokines, relevant metabolic changes and expression of immune checkpoint (ICP) inhibitors capable of “switching-off” the immune response against leukemic cells. Here, we review the main mechanisms of immune escape and identify potential strategies to overcome these mechanisms.

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Bone marrow central memory and memory stem T-cell exhaustion in AML patients relapsing after HSCT

Cited by 145 publications

References 51 publications

Key Aspects of the Immunobiology of Haploidentical Hematopoietic Cell Transplantation

Key Aspects of the Immunobiology of Haploidentical Hematopoietic Cell Transplantation

Harnessing the immune system after allogeneic stem cell transplant in acute myeloid leukemia

Immune Escape after Hematopoietic Stem Cell Transplantation (HSCT): From Mechanisms to Novel Therapies

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