A highly efficient and faithful MDS patient-derived xenotransplantation model for pre-clinical studies

Song, Yuanbin; Rongvaux, Anthony; Taylor, Ashley; Jiang, Tingting; Tebaldi, Toma; Balasubramanian, Kunthavai; Bagale, Arun; Terzi, Yunus Kasım; Gbyli, Rana; Wang, Xiaman; Fu, Xiaoying; Gao, Yimeng; Zhao, Jun; Podoltsev, Nikolai A.; Xu, Mina L.; Neparidze, Natalia; Wong, Ellice; Torres, Richard; Bruscia, Emanuela M.; Kluger, Yuval; Manz, Markus G.; Flavell, Richard A.; Halene, Stephanie

doi:10.1038/s41467-018-08166-x

Cited by 58 publications

(49 citation statements)

References 55 publications

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“…Until today, the vast majority of xenografted mouse models used to explore the anti-leukemia potential of primary human NK cells have focused on human leukemia cell lines. One of the major reasons for this is that engraftment of primary AML, CML, and MDS cells has historically been difficult, with only recently reaching robust and reliable engraftment rates in optimized models (54–56). Furthermore, the use of human leukemia cell lines enables the researcher to introduce luciferase and/or fluorescent proteins (such as green fluorescent protein; GFP) to efficiently track the tumor burden in the mice.…”

Section: Evidence For Nk Cell-mediated Targeting Of Malignant Myeloidmentioning

confidence: 99%

Natural Killer Cells in Myeloid Malignancies: Immune Surveillance, NK Cell Dysfunction, and Pharmacological Opportunities to Bolster the Endogenous NK Cells

2019

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Natural killer (NK) cells are large granular lymphocytes involved in our defense against certain virus-infected and malignant cells. In contrast to T cells, NK cells elicit rapid anti-tumor responses based on signals from activating and inhibitory cell surface receptors. They also lyse target cells via antibody-dependent cellular cytotoxicity, a critical mode of action of several therapeutic antibodies used to treat cancer. A body of evidence shows that NK cells can exhibit potent anti-tumor activity against chronic myeloid leukemia (CML), acute myeloid leukemia (AML), and myelodysplastic syndromes (MDS). However, disease-associated mechanisms often restrain the proper functions of endogenous NK cells, leading to inadequate tumor control and risk for disease progression. Although allogeneic NK cells can prevent leukemia relapse in certain settings of stem cell transplantation, not all patients are eligible for this type of therapy. Moreover, remissions induced by adoptively infused NK cells are only transient and require subsequent therapy to maintain durable responses. Hence, new strategies are needed to trigger full and durable anti-leukemia responses by NK cells in patients with myeloid malignancies. To achieve this, we need to better understand the interplay between the malignant cells, their microenvironment, and the NK cells. This review focuses on mechanisms that are involved in suppressing NK cells in patients with myeloid leukemia and MDS, and means to restore their full anti-tumor potential. It also discusses novel molecular targets and approaches, such as bi- and tri-specific antibodies and immune checkpoint inhibitors, to redirect and/or unleash the NK cells against the leukemic cells.

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Section: Evidence For Nk Cell-mediated Targeting Of Malignant Myeloidmentioning

confidence: 99%

Natural Killer Cells in Myeloid Malignancies: Immune Surveillance, NK Cell Dysfunction, and Pharmacological Opportunities to Bolster the Endogenous NK Cells

2019

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“…The most likely mechanism resulting in enhanced BM erythropoiesis in kit mutant mice is the cell intrinsic impairment of erythropoiesis in these mice ( 65 ). Interestingly, human erythro- and megakaryopoiesis were also found to be enhanced in an another recently developed immunodeficient mouse model (namely MISTRG mice), following the xenotransplantation of human HSPCs ( 66 ). The authors of this work postulated that the expression of human cytokines from the endogenous murine loci (replacing murine encoding cytokines), by providing a more physiologic expression of human cytokines, synergistically promotes a more competitive human hematopoiesis including the efficient development of human RBCs and platelets ( 66 ).…”

Section: Improved Erythropoiesis and Megakaryopoiesis In Current Immumentioning

confidence: 99%

Advances in Human Immune System Mouse Models for Studying Human Hematopoiesis and Cancer Immunotherapy

2021

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Immunotherapy has established itself as a promising tool for cancer treatment. There are many challenges that remain including lack of targets and some patients across various cancers who have not shown robust clinical response. One of the major problems that have hindered the progress in the field is the dearth of appropriate mouse models that can reliably recapitulate the complexity of human immune-microenvironment as well as the malignancy itself. Immunodeficient mice reconstituted with human immune cells offer a unique opportunity to comprehensively evaluate immunotherapeutic strategies. These immunosuppressed and genetically modified mice, with some overexpressing human growth factors, have improved human hematopoietic engraftment as well as created more functional immune cell development in primary and secondary lymphoid tissues in these mice. In addition, several new approaches to modify or to add human niche elements to further humanize these immunodeficient mice have allowed a more precise characterization of human hematopoiesis. These important refinements have opened the possibility to evaluate not only human immune responses to different tumor cells but also to investigate how malignant cells interact with their niche and most importantly to test immunotherapies in a more preclinically relevant setting, which can ultimately lead to better success of these drugs in clinical trials.

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“…Patient-derived xenografts. PBMCs from HLA-B*40:01 + patients with active CBFB-MYH11 + AML were engrafted in immunodeficient MISTRG mice following an established protocol (87)(88)(89)(90). Briefly, newborn mice were sublethally irradiated (150 cGy).…”

Section: Author Contributionsmentioning

confidence: 99%

CBFB-MYH11 fusion neoantigen enables T cell recognition and killing of acute myeloid leukemia

Biernacki¹,

Foster²,

Woodward³

et al. 2020

Journal of Clinical Investigation

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Proteins created from recurrent fusion genes like CBFB-MYH11 are prevalent in acute myeloid leukemia (AML), often necessary for leukemogenesis, persistent throughout the disease course, and highly leukemia specific, making them attractive neoantigen targets for immunotherapy. A nonameric peptide derived from a prevalent CBFB-MYH11 fusion protein was found to be immunogenic in HLA-B*40:01 + donors. High-avidity CD8 + T cell clones isolated from healthy donors killed CBFB-MYH11 + HLA-B*40:01 + AML cell lines and primary human AML samples in vitro. CBFB-MYH11-specific T cells also controlled CBFB-MYH11 + HLA-B*40:01 + AML in vivo in a patient-derived murine xenograft model. High-avidity CBFB-MYH11 epitope-specific T cell receptors (TCRs) transduced into CD8 + T cells conferred antileukemic activity in vitro. Our data indicate that the CBFB-MYH11 fusion neoantigen is naturally presented on AML blasts and enables T cell recognition and killing of AML. We provide proof of principle for immunologically targeting AML-initiating fusions and demonstrate that targeting neoantigens has clinical relevance even in low-mutational frequency cancers like fusion-driven AML. This work also represents a first critical step toward the development of TCR T cell immunotherapy targeting fusion gene-driven AML.

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A highly efficient and faithful MDS patient-derived xenotransplantation model for pre-clinical studies

Cited by 58 publications

References 55 publications

Natural Killer Cells in Myeloid Malignancies: Immune Surveillance, NK Cell Dysfunction, and Pharmacological Opportunities to Bolster the Endogenous NK Cells

Natural Killer Cells in Myeloid Malignancies: Immune Surveillance, NK Cell Dysfunction, and Pharmacological Opportunities to Bolster the Endogenous NK Cells

Advances in Human Immune System Mouse Models for Studying Human Hematopoiesis and Cancer Immunotherapy

CBFB-MYH11 fusion neoantigen enables T cell recognition and killing of acute myeloid leukemia

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