Off-the-shelf CAR-engineered natural killer cells targeting FLT3 enhance killing of acute myeloid leukemia.
Off-the-shelf CAR-engineered natural killer cells targeting FLT3 enhance killing of acute myeloid leukemia.
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DOI：
10.1182/bloodadvances.2022007405
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发表时间：
2023-10-24
期刊：
影响因子：
7.5
通讯作者：
Yu, Jianhua
中科院分区：
文献类型：
--
作者：
Mansour, Anthony G.;Teng, Kun-Yu;Li, Zhiyao;Zhu, Zheng;Chen, Hanyu;Tian, Lei;Ali, Aliya;Zhang, Jianying;Lu, Ting;Ma, Shoubao;Lin, Chih-Min;Caligiuri, Michael A.;Yu, Jianhua
现成的FLT3 CAR_sIL-15 NK细胞分泌IL-15，优先裂解人FLT3+ AML，激活T细胞。表达可溶性IL-15的FLT3 CAR_sIL-15 NK细胞可延长FLT3+ aml小鼠的生存期，且对正常造血无毒性。大多数急性髓性白血病（AML）患者死于该疾病或其并发症，尤其是老年患者。自然杀伤（NK）细胞在AML患者中显示出抗白血病活性；然而，据我们所知，携带靶向与AML相关抗原的嵌合抗原受体（CAR）的原代NK细胞作为疾病控制的“现成”产品尚未被探索。我们开发了冷冻的、现成的同种异体人NK细胞，其中含有CAR识别FLT3并分泌可溶性白细胞介素-15 (IL-15) (FLT3 CAR_sIL-15 NK)，以改善体内NK细胞的持久性和t细胞的活化。与缺乏FLT3 CAR或可溶性IL-15的活化NK细胞相比，FLT3 CAR_sIL-15 NK细胞对FLT3+ AML细胞系具有更高的细胞毒性和干扰素γ分泌。与对照NK细胞相比，冷冻和解冻的同种异体FLT3 CAR_sIL-15 NK细胞延长了MOLM-13 AML模型和原位患者来源的异种移植AML模型的存活时间。FLT3 CAR_sIL-15 NK细胞对健康血液单个核细胞或造血干细胞无细胞毒性。总的来说，我们的数据表明FLT3是一种AML相关抗原，可以被冷冻的、同种异体的、现成的FLT3 CAR_sIL-15 NK细胞靶向，这可能为AML的治疗提供一种新的方法。
Off-the-shelf FLT3 CAR_sIL-15 NK cells secrete IL-15, preferentially lyse human FLT3+ AML, and activate T cells. FLT3 CAR_sIL-15 NK cells expressing soluble IL-15 prolong survival of FLT3+ AML–bearing mice without toxicity to normal hematopoiesis. The majority of patients with acute myeloid leukemia (AML) succumb to the disease or its complications, especially among older patients. Natural killer (NK) cells have been shown to have antileukemic activity in patients with AML; however, to our knowledge, primary NK cells armed with a chimeric antigen receptor (CAR) targeting antigens associated with AML as an “off-the-shelf” product for disease control have not been explored. We developed frozen, off-the-shelf allogeneic human NK cells engineered with a CAR recognizing FLT3 and secreting soluble interleukin-15 (IL-15) (FLT3 CAR_sIL-15 NK) to improve in vivo NK cell persistence and T-cell activation. FLT3 CAR_sIL-15 NK cells had higher cytotoxicity and interferon gamma secretion against FLT3+ AML cell lines when compared with activated NK cells lacking an FLT3 CAR or soluble IL-15. Frozen and thawed allogeneic FLT3 CAR_sIL-15 NK cells prolonged survival of both the MOLM-13 AML model as well as an orthotopic patient-derived xenograft AML model when compared with control NK cells. FLT3 CAR_sIL-15 NK cells showed no cytotoxicity against healthy blood mononuclear cells or hematopoietic stem cells. Collectively, our data suggest that FLT3 is an AML-associated antigen that can be targeted by frozen, allogeneic, off-the-shelf FLT3 CAR_sIL-15 NK cells that may provide a novel approach for the treatment of AML.
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影响因子：
17.1
作者：
Fedorov VD;Themeli M;Sadelain M
通讯作者：
Sadelain M
CD33在造血干细胞中的遗传失活，使CAR T细胞免疫疗法患有急性髓样白血病。
影响因子：
64.5
作者：
Kim MY;Yu KR;Kenderian SS;Ruella M;Chen S;Shin TH;Aljanahi AA;Schreeder D;Klichinsky M;Shestova O;Kozlowski MS;Cummins KD;Shan X;Shestov M;Bagg A;Morrissette JJD;Sekhri P;Lazzarotto CR;Calvo KR;Kuhns DB;Donahue RE;Behbehani GK;Tsai SQ;Dunbar CE;Gill S
通讯作者：
Gill S
影响因子：
1.8
作者：
Bochtler T;Fröhling S;Weichert W;Endris V;Thiede C;Hutter B;Hundemer M;Ho AD;Krämer A
通讯作者：
Krämer A
影响因子：
4.6
作者：
Han J;Chu J;Keung Chan W;Zhang J;Wang Y;Cohen JB;Victor A;Meisen WH;Kim SH;Grandi P;Wang QE;He X;Nakano I;Chiocca EA;Glorioso Iii JC;Kaur B;Caligiuri MA;Yu J
通讯作者：
Yu J
影响因子：
12.4
作者：
Gomes-Silva, Diogo;Atilla, Erden;Mamonkin, Maksim
通讯作者：
Mamonkin, Maksim