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• W4311776406 abstract "Acute myeloid leukaemia (AML) is the most common, aggressive hematologic malignancy of adults in the United States. Globally, leukaemia is estimated to be the 11th most frequent cancer-related mortality, accounting for 311 594 deaths.1 More than 20 000 new cases of AML and approximately 11 000 AML-related deaths are estimated to occur in the United States.2 Although different therapeutic strategies and novel drug combinations have led to higher response rates and improved survival rates in AML patients, relapse remains a major clinical challenge. A considerable body of evidence suggests that disease initiation and progression, therapeutic resistance and relapse of AML are mainly driven by leukaemia stem cells, which are characterized by their unlimited capacity for self-renewal, tumour initiation and differentiation.3-5 In addition, AML patients with DNMT3A and FLT3 mutations have significantly higher recurrence rates and worse survival, and these mutations appear to confer a poor prognosis.6, 7 Despite significant progress in the development of newer FLT3 inhibitors with greater potency and specificity, drug toxicity and the emergence of resistance pose significant challenges.8 Thus, there is a critical need for therapeutic strategies that decrease the risk of relapse and improve the survival of AML patients. As an alternative to these inhibitors, more efficient and less harmful immunotherapy-based approaches such as adoptive transferring T cell therapy are in development for the treatment of AML. Chimeric antigen receptor (CAR)-T cells are engineered T-lymphocytes which have been developed in recent years as a breakthrough in cancer therapy.9 To mitigate the toxicity and improve the clinical application and efficacy of CAR-T cell therapy, various approaches have been developed, and a recent study by Tang et al.10 has provided significant advances.10 These authors engineered internal tandem duplication (ITD) mutations in an FLT3 knock-in clone and a DNMT3A-R882H mutant clone of the leukemic cell line SKM-1. One of the stem cell markers that is highly expressed in hematopoietic tumours is CD44, a transmembrane glycoprotein expressed on both normal and leukemic cells. Multiple functions are ascribed to CD44, including roles in differentiation and apoptosis.11, 12 The “high CD44” characteristic is generally associated with high tumorigenic potential, drug resistance and poor prognosis.13, 14 Tang et al. reported a significant increase of CD44v6 expression in FLT3- or DNMT3A-mutant AML cell lines or primary AML cells, whereas its expression was extremely low in normal hematopoietic stem cells, including bone marrow progenitor cells, indicating its safety as a therapeutic target. This suggested that CD44v6 may be an ideal target for FLT3- or DNMT3A-mutant AML treatment. To determine whether the connection between FLT3 or DNMT3A and CD44v6 is specific, the expression of other surface markers of AML, CD33 and CD123 was investigated and the findings demonstrated that only FLT3 mutation promoted the expression of CD33. Further insight was gained by evaluating the methylation of the CD44 promoter in FLT3- or DNMT3A- mutant AML cell lines via mass spectrometric analysis of DNA methylation. CD44 promoter methylation was lower in FLT3- or DNMT3A-mutant AML cell lines than other leukemic cell lines indicating that FLT3 and DNMT3A mutations suppress CpG methylation in the CD44 promoter, thus inducing CD44 and CD44v6 expression. As previous observations showed high levels of CD44v6 in AML and demonstrated the specificity of FLT3 and DNMT3A mutations in regulating CD44 expression, subsequent experiments interrogated the role of CAR-T therapy for FLT3 or DNMT3A mutant AML. First, Tang et al. constructed a CD44v6 CAR, containing CD44v6 single-chain variable fragment sequence derived from the humanized mAb bivatuzumab (BIWA-8), CD8α hinge and transmembrane domains, a 4-1BB costimulatory domain and a CD3ζ signalling domain, and then introduced this CD44v6 CAR into T cells (Figure 1). In contrast to non-transduced T (NT) cells, CD44v6 expression was inhibited in CD44v6 CAR-T cells and CD8+ T cells were decreased, although an increase in central and effector memory T cells was found. In order to assess the specific cytotoxicity of CD44v6 CAR-T cells against AML cells, CD44v6 CAR-T cells were co-cultured with CD44v6+ tumour cells as well as CD44v6− SKM-1 cells, K562 cells, as well as HUVECs, 293T and HTR8/SVneo cells. Analyzing cytotoxicity revealed that CD44v6 CAR-T cells specifically lysed CD44v6+ leukemic cells, but not CD44v6− leukemic cells or non-tumour cells. In addition, CD44v6 CAR-T cells were co-cultured with CD44v6+ colorectal cancer cells to confirm specificity and efficacy. During these experiments, CD44v6 CAR-T cells showed increased CD107 expression and secretion of cytokines, including interferon-γ, interleukin-6 and tumour necrosis factor-α, indicating T cell activation. As CD44v6 CAR-T cells specifically lysed CD44v6+ tumour cells, then CAR-T therapy may be used to target only leukemic cells with no cytotoxic effect on normal myeloid cells or other hematopoietic stem cells. In support of these results, Haist et al. also demonstrated the specificity and efficacy of a BIWA8-derived high-affinity CD44v6 CAR-T against head and neck squamous cell carcinoma cell lines containing different levels of CD44 expression.15 In order to support the correlation between CD44v6 expression and cytotoxicity of CD44v6 CAR-T cells, Tang et al. co-cultured peripheral blood mononuclear cells from FLT3 mutant AML patients, or healthy donors, with CD44v6 CAR-T cells and found more cytotoxicity against primary FLT3 mutant AML cells, but not healthy donor cells. An intriguing finding from this study is that CD44v6 CAR-T cells were an efficacious therapy for FLT3-mutant AML in xenograft animal models. The authors injected Luc+ MV4-11, a human AML cell line that carries FLT3-ITD mutation, and Luc+ SKM-1 cells subcutaneously into the groin of BALB/c-nu mice and, subsequently, inoculated CD44v6 CAR-T cells, NT cells or phosphate-buffered saline intratumorally in each mouse group and measured tumour burden by bioluminescent imaging. Additionally, NOG mice were injected intravenously with Luc+ SKM-1 or Luc+ SKM-1-FLT3 and the animals were treated with CD44v6 CAR-T cells. They found that CD44v6 CAR-T cells limited leukemic progression in Luc+ MV4-11 and Luc+ SKM-1-FLT3 compared to other control mouse groups, indicating that CD44v6 CAR-T could be a specific and effective therapeutic approach to target FLT3-mutant AML. As human CD44V6 and mouse CD44v6 are homologous, the safety of CD44v6 CAR-T cells in BALB/c mice was assessed and no differences in weight or the level of WBCs, HGB and platelets were found. Moreover, CD44v6 CAR-T did not affect kidney or liver function, suggesting that CD44v6 CAR-T could be a safe therapeutic approach in AML. Although immunotherapy has, increasingly, become one of the most promising treatment strategies for AML, limited clinical responses have been reported. This study establishes a technical platform to eradicate human FLT3/DNMT3A-mutant AML expressing CD44 with low toxicity to normal hematopoietic cells, thereby expediting the development of effective CAR-T cell-mediated immunotherapy. Thus, it is expected that CD44v6 CAR-T cells will serve as a safe and highly effective weapon to fight hematologic malignancies. The figure was created with software from BioRender.com. I appreciate the assistance of Dr Andrew Yeudall in reviewing the manuscript. The authors declare no conflict of interest." @default.
• W4311776406 created "2022-12-28" @default.
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• W4311776406 date "2022-12-01" @default.
• W4311776406 modified "2023-09-25" @default.
• W4311776406 title "CD44‐targeted chimeric antigen receptor‐T eradicates acute myeloid leukaemic stem cells" @default.
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• W4311776406 doi "https://doi.org/10.1002/ctd2.156" @default.
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