Novel two-chain structure utilizing KIRS2/DAP12 domain improves the safety and efficacy of CAR-T cells in adults with r/r B-ALL.
Novel two-chain structure utilizing KIRS2/DAP12 domain improves the safety and efficacy of CAR-T cells in adults with r/r B-ALL.
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DOI：
10.1016/j.omto.2021.08.014
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发表时间：
2021-12-17
期刊：
影响因子：
--
通讯作者：
Chen B
中科院分区：
文献类型：
--
作者：
Sun M;Xu P;Wang E;Zhou M;Xu T;Wang J;Wang Q;Wang B;Lu K;Wang C;Chen B
表达嵌合抗原受体(CARS)的工程化T细胞已成为治疗血液系统恶性肿瘤的一种有前途的疗法。使用不同的信号域优化CAR结构可以改变CAR-T细胞的广泛属性，包括抗肿瘤活性、长期持久性和安全性。在这项研究中，我们开发了一种基于KIRS2/Dap12的针对B细胞急性淋巴细胞白血病(B-ALL)抗原CD19的新型CAR结构，并在体内外和成人复发/难治(r/r)B-ALL患者中比较了该结构在转导T细胞和针对CD19的标准第二代CAR-T细胞中的抗肿瘤效果和安全性。我们发现，KIRS2/Dap12受体注入4-1BB共刺激结构域可以通过显著增加促炎性白介素2(IL-2)的产生来增强抗肿瘤效果，尤其是与抗原阳性的肿瘤细胞共同培养时。此外，CD19-KIRS2/Dap12-BB CAR-T细胞检测结果令人振奋，在I期临床试验中，4例(100%)患者输注CAR-T后完全应答，且严重细胞因子释放综合征(CRS)发生率高。鉴于这些令人鼓舞的发现，CD19-KIRS2/Dap12-BB CAR-T细胞是安全的，并可导致成人r/r B-ALL患者的临床反应，表明对该疗法的进一步评估是有必要的。最近，以CD19为靶点的CAR-T细胞已被FDA批准用于血液系统恶性肿瘤的治疗，并取得了显著的临床效果。S的研究结果表明，未来r/r B-ALL患者可以受益于KIRS2/Dap12-BB CAR-T细胞。
Engineered T cells that express chimeric antigen receptors (CARs) have been a promising therapy for hematologic malignancies. The optimization of CAR structure using different signaling domains can alter a wide range of CAR-T cell properties, including anti-tumor activity, long-term persistence, and safety. In this study, we developed a novel CAR structure based on KIRS2/Dap12 for B cell acute lymphoblastic leukemia (B-ALL) antigen CD19 and compared the anti-tumor efficacy and safety of this construct in transduced T cells with standard second-generation CAR-T cells targeting CD19 for B-ALL in vitro and in vivo and in adult relapsed/refractory (r/r) B-ALL patients. We discovered that KIRS2/Dap12 receptor infused with 4-1BB co-stimulation domain could enhance anti-tumor efficacy by remarkably increasing the production of pro-inflammatory interleukin-2 (IL-2), especially when co-cultured with antigen-positive tumor cells. In addition, CD19-KIRS2/Dap12-BB CAR-T cells showed the inspiring outcome that complete responses were seen in 4 of 4 (100%) patients without neurotoxicity and a high rate of severe cytokine release syndrome (CRS) after CAR-T infusion in a phase I clinical trial. Given these encouraging findings, CD19-KIRS2/Dap12-BB CAR-T cells are safe and can lead to clinical responses in adult patients with r/r B-ALL, indicating that further assessment of this therapy is warranted. Recently, CD19-targeted CAR-T cells have been approved by the FDA for hematologic malignancy therapy and achieve outstanding clinical outcome. Chen et al.’s findings indicate that r/r B-ALL patients can benefit from the KIRS2/Dap12-BB CAR-T cells in the future.
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影响因子：
8.7
作者：
Lanier LL
通讯作者：
Lanier LL
影响因子：
16.6
作者：
Helsen CW;Hammill JA;Lau VWC;Mwawasi KA;Afsahi A;Bezverbnaya K;Newhook L;Hayes DL;Aarts C;Bojovic B;Denisova GF;Kwiecien JM;Brain I;Derocher H;Milne K;Nelson BH;Bramson JL
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影响因子：
82.9
作者：
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通讯作者：
Mackall, Crystal L.
DOI：
10.1056/nejmoa1707447
发表时间：
2017-12-28
期刊：
The New England journal of medicine
影响因子：
--
作者：
Neelapu SS;Locke FL;Bartlett NL;Lekakis LJ;Miklos DB;Jacobson CA;Braunschweig I;Oluwole OO;Siddiqi T;Lin Y;Timmerman JM;Stiff PJ;Friedberg JW;Flinn IW;Goy A;Hill BT;Smith MR;Deol A;Farooq U;McSweeney P;Munoz J;Avivi I;Castro JE;Westin JR;Chavez JC;Ghobadi A;Komanduri KV;Levy R;Jacobsen ED;Witzig TE;Reagan P;Bot A;Rossi J;Navale L;Jiang Y;Aycock J;Elias M;Chang D;Wiezorek J;Go WY
通讯作者：
Go WY
DOI：
10.1007/978-981-15-1580-4_9
发表时间：
2020-01-01
期刊：
LECTIN IN HOST DEFENSE AGAINST MICROBIAL INFECTIONS
影响因子：
--
作者：
Angata, Takashi
通讯作者：
Angata, Takashi