Base edited "universal" donor CAR T-cell strategies for acute myeloid leukaemia.

IF 13.4 1区 医学 Q1 HEMATOLOGY
Renuka Kadirkamanathan, Christos Georgiadis, Arnold Kloos, Akshay Joshi, Annie Etuk, Roland Preece, Oliver Gough, Axel Schambach, Martin Sauer, Michael Heuser, Waseem Qasim
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Abstract

Acute myeloid leukaemia (AML) is often aggressive and life-threatening with limited curative options. Immunotherapies including chimeric antigen receptor (CAR) T-cell approaches are under investigation, but high levels of disease heterogeneity remain a major hurdle to achieving durable responses. Targeting of multiple antigens may ensure complete immunological coverage of leukaemic blast populations, but such antigens are often also present on healthy haematopoietic populations. To address likely aplasia, strategies can be designed to bridge CAR T-cell therapies to allogeneic stem-cell transplantation (allo-SCT), as demonstrated in recent anti-CD7 CAR T-cell studies. Here we report that monotherapy using base edited "universal" donor CAR T cells against CD33, CLL-1, or CD7 delivered inhibition of AML in immunodeficient mice when antigen expression was homogenous, but combined use of BE-CAR33 and BE-CARCLL-1 T cells was required to address heterogenous CLL-1-/+CD33-/+ disease. We also demonstrate that removal of shared CD7 antigens enabled compatibility of BE-CAR33 and BE-CARCLL-1 with BE-CAR7 T cells, including in a patient-derived xenograft (PDX) model of AML. Therapeutic strategies envisage 'pick and mix' applications of base edited "universal" CAR T cells in combination determined by patient-specific antigen profiles. Such approaches also offer the possibility of deep, cell-based, de-bulking and conditioning ahead of allo-SCT and subsequent donor-derived reconstitution.

碱基编辑“通用”供体CAR - t细胞策略治疗急性髓性白血病。
急性髓性白血病(AML)通常具有侵袭性,危及生命,治疗选择有限。包括嵌合抗原受体(CAR) t细胞方法在内的免疫疗法正在研究中,但高水平的疾病异质性仍然是实现持久反应的主要障碍。靶向多种抗原可以确保白血病母细胞群体的完全免疫覆盖,但这些抗原通常也存在于健康的造血群体中。最近的抗cd7 CAR - t细胞研究表明,为了解决可能的发育不全,可以设计将CAR - t细胞疗法与同种异体干细胞移植(alloc - sct)相结合的策略。在这里,我们报告了使用碱基编辑的“通用”供体CAR - T细胞对抗CD33、CLL-1或CD7的单药治疗在抗原表达同质的免疫缺陷小鼠中可抑制AML,但需要联合使用BE-CAR33和BE-CARCLL-1 T细胞来解决异质性CLL-1-/+CD33-/+疾病。我们还证明,去除共享的CD7抗原可以使BE-CAR33和BE-CARCLL-1与BE-CAR7 T细胞兼容,包括在患者来源的AML异种移植(PDX)模型中。治疗策略设想“挑选和混合”碱基编辑的“通用”CAR - T细胞的应用,根据患者特异性抗原谱确定组合。这种方法还提供了在同种异体细胞移植和随后的供体来源重建之前进行深层、基于细胞的去体积化和调理的可能性。
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来源期刊
Leukemia
Leukemia 医学-血液学
CiteScore
18.10
自引率
3.50%
发文量
270
审稿时长
3-6 weeks
期刊介绍: Title: Leukemia Journal Overview: Publishes high-quality, peer-reviewed research Covers all aspects of research and treatment of leukemia and allied diseases Includes studies of normal hemopoiesis due to comparative relevance Topics of Interest: Oncogenes Growth factors Stem cells Leukemia genomics Cell cycle Signal transduction Molecular targets for therapy And more Content Types: Original research articles Reviews Letters Correspondence Comments elaborating on significant advances and covering topical issues
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