Potent ex vivo armed T cells using recombinant bispecific antibodies for adoptive immunotherapy with reduced cytokine release.
Potent ex vivo armed T cells using recombinant bispecific antibodies for adoptive immunotherapy with reduced cytokine release.
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DOI：
10.1136/jitc-2020-002222
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发表时间：
2021-05
影响因子：
10.9
通讯作者：
Cheung NV
中科院分区：
文献类型：
--
作者：
Park JA;Santich BH;Xu H;Lum LG;Cheung NV
使用嵌合抗原受体（CAR）或双特异性抗体（BsAb）的基于T细胞的免疫疗法在血液恶性肿瘤中产生了令人印象深刻的反应。然而，主要的障碍仍然存在，包括细胞因子释放综合征，神经毒性，靶向脱瘤效应，对自体T细胞的依赖，以及大多数实体瘤的失败。BsAb武装的T细胞提供了一种安全的替代方案。我们使用IgG-[L]-scFv平台化的BsAb产生离体武装T细胞（EAT），其中抗CD 3（huOKT 3）scFv连接至肿瘤结合IgG的轻链。在多种癌细胞系和患者来源的异种移植小鼠模型中评价了EAT上的BsAb密度、体外细胞毒性、细胞因子释放、体内转运至肿瘤中及其抗肿瘤活性。研究了冷冻保存后EAT的功效，并研究了γ δ（γδ）T细胞作为不相关的替代效应T细胞。使用IgG-[L]-scFv BsAb平台，BsAb武装的T细胞的抗肿瘤效力得到实质性改善。当与单独的BsAb和T细胞注射相比时，EAT释放更少的TNF-α，并且更快地浸润肿瘤，同时实现稳健的抗肿瘤应答。EAT治疗的体内效力取决于用于武装的BsAb剂量、每次注射的EAT细胞数、EAT剂量的总数和治疗方案强度。冷冻保存后EAT的抗肿瘤效果得以保持，并且使用γδ T细胞的EAT与αβ T细胞-EAT一样安全有效。EAT对广谱的人类癌症靶点具有有效的抗肿瘤活性，具有显着的安全性。EAT的抗肿瘤作用与BsAb剂量、细胞数、总剂量和给药方案有关。EAT在冷冻保存后同样有效，第三方γδ-EAT的可行性为自体T细胞来源提供了替代方案。
T cell-based immunotherapies using chimeric antigen receptors (CAR) or bispecific antibodies (BsAb) have produced impressive responses in hematological malignancies. However, major hurdles remained, including cytokine release syndrome, neurotoxicity, on-target off-tumor effects, reliance on autologous T cells, and failure in most solid tumors. BsAb armed T cells offer a safe alternative. We generated ex vivo armed T cells (EATs) using IgG-[L]-scFv-platformed BsAb, where the anti-CD3 (huOKT3) scFv was attached to the light chain of a tumor-binding IgG. BsAb density on EAT, in vitro cytotoxicity, cytokine release, in vivo trafficking into tumors, and their antitumor activities were evaluated in multiple cancer cell lines and patient-derived xenograft mouse models. The efficacy of EATs after cryopreservation was studied, and gamma delta (γδ) T cells were investigated as unrelated alternative effector T cells. The antitumor potency of BsAb armed T cells was substantially improved using the IgG-[L]-scFv BsAb platform. When compared with separate BsAb and T cell injection, EATs released less TNF-α, and infiltrated tumors faster, while achieving robust antitumor responses. The in vivo potency of EAT therapy depended on BsAb dose for arming, EAT cell number per injection, total number of EAT doses, and treatment schedule intensity. The antitumor efficacy of EATs was preserved following cryopreservation, and EATs using γδ T cells were safe and as effective as αβ T cell-EATs. EATs exerted potent antitumor activities against a broad spectrum of human cancer targets with remarkable safety. The antitumor potency of EATs depended on BsAb dose, cell number and total dose, and schedule. EATs were equally effective after cryopreservation, and the feasibility of third-party γδ-EATs offered an alternative for autologous T cell sources.
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影响因子：
28.2
作者：
Gust J;Hay KA;Hanafi LA;Li D;Myerson D;Gonzalez-Cuyar LF;Yeung C;Liles WC;Wurfel M;Lopez JA;Chen J;Chung D;Harju-Baker S;Özpolat T;Fink KR;Riddell SR;Maloney DG;Turtle CJ
通讯作者：
Turtle CJ
影响因子：
7.3
作者：
Ehx G;Somja J;Warnatz HJ;Ritacco C;Hannon M;Delens L;Fransolet G;Delvenne P;Muller J;Beguin Y;Lehrach H;Belle L;Humblet-Baron S;Baron F
通讯作者：
Baron F
影响因子：
7.3
作者：
Fisher J;Anderson J
通讯作者：
Anderson J
影响因子：
11.5
作者：
Gajewski, Thomas F.
通讯作者：
Gajewski, Thomas F.
影响因子：
46.9
作者：
Choi, Bryan D.;Yu, Xiaoling;Maus, Marcela V.
通讯作者：
Maus, Marcela V.