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  • 1
    Online Resource
    Online Resource
    Chimeric antigen receptor T cells for acute myeloid leukemia
    Wiley ; 2023
    In:  European Journal of Haematology
    Details
    In: European Journal of Haematology, Wiley
    Abstract: The use of T cells expressing chimeric antigen receptors (CARs) that can target and eliminate cancer cells has revolutionized the treatment of B‐cell malignancies. In contrast, CAR T cells have not yet become a routine treatment for myeloid malignancies such as acute myeloid leukemia (AML) or myeloproliferative neoplasms (MPNs). For these disease entities, allogeneic hematopoietic cell transplantation (allo‐HCT) relying on polyclonal allo‐reactive T cells is still the major cellular immunotherapy used in clinical routine. Here, we discuss major hurdles of CAR T‐cell therapy for myeloid malignancies and novel approaches to enhance their efficacy and reduce toxicity. Heterogeneity of the malignant myeloid clone, CAR T‐cell induced toxicity against normal hematopoietic cells, lack of long‐term CAR T‐cell persistence, and loss or downregulation of targetable antigens on myeloid cells are obstacles for successful CAR T cells therapy against AML and MPNs. Strategies to overcome these hurdles include pharmacological interventions, for example, demethylating therapy to increase target antigen expression, multi‐targeted CAR T cells, and gene‐therapy based approaches that delete the CAR target antigen in the hematopoietic cells of the recipient to protect them from CAR‐induced myelotoxicity. Most of these approaches are still in preclinical testing but may reach the clinic in the coming years. In summary, we report on barriers to CAR T‐cell use against AML and novel therapeutic strategies to overcome these challenges, with the goal of clinical treatment of myeloid malignancies with CAR T cells.
    Type of Medium: Online Resource
    ISSN: 0902-4441 , 1600-0609
    URL: Article
    DOI: 10.1111/ejh.14047
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2027114-1
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  • 2
    Online Resource
    Online Resource
    Targeting MDM2 enhances antileukemia immunity after allogeneic transplantation via MHC-II and TRAIL-R1/2 upregulation
    American Society of Hematology ; 2022
    In:  Blood Vol. 140, No. 10 ( 2022-09-08), p. 1167-1181
    Details
    In: Blood, American Society of Hematology, Vol. 140, No. 10 ( 2022-09-08), p. 1167-1181
    Abstract: Patients with acute myeloid leukemia (AML) often achieve remission after allogeneic hematopoietic cell transplantation (allo-HCT) but subsequently die of relapse driven by leukemia cells resistant to elimination by allogeneic T cells based on decreased major histocompatibility complex II (MHC-II) expression and apoptosis resistance. Here we demonstrate that mouse-double-minute-2 (MDM2) inhibition can counteract immune evasion of AML. MDM2 inhibition induced MHC class I and II expression in murine and human AML cells. Using xenografts of human AML and syngeneic mouse models of leukemia, we show that MDM2 inhibition enhanced cytotoxicity against leukemia cells and improved survival. MDM2 inhibition also led to increases in tumor necrosis factor-related apoptosis-inducing ligand receptor-1 and -2 (TRAIL-R1/2) on leukemia cells and higher frequencies of CD8+CD27lowPD-1lowTIM-3low T cells, with features of cytotoxicity (perforin+CD107a+TRAIL+) and longevity (bcl-2+IL-7R+). CD8+ T cells isolated from leukemia-bearing MDM2 inhibitor-treated allo-HCT recipients exhibited higher glycolytic activity and enrichment for nucleotides and their precursors compared with vehicle control subjects. T cells isolated from MDM2 inhibitor-treated AML-bearing mice eradicated leukemia in secondary AML-bearing recipients. Mechanistically, the MDM2 inhibitor-mediated effects were p53-dependent because p53 knockdown abolished TRAIL-R1/2 and MHC-II upregulation, whereas p53 binding to TRAILR1/2 promotors increased upon MDM2 inhibition. The observations in the mouse models were complemented by data from human individuals. Patient-derived AML cells exhibited increased TRAIL-R1/2 and MHC-II expression on MDM2 inhibition. In summary, we identified a targetable vulnerability of AML cells to allogeneic T-cell–mediated cytotoxicity through the restoration of p53-dependent TRAIL-R1/2 and MHC-II production via MDM2 inhibition.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.2022016082
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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