Potent antitumor effect of T cells armed with anti-GD2 bispecific antibody.
Potent antitumor effect of T cells armed with anti-GD2 bispecific antibody.
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DOI：
10.1002/pbc.28971
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发表时间：
2021-07
影响因子：
3.2
通讯作者：
中科院分区：
文献类型：
--
作者：
使用IgG(L)-scFv格式的人源化3f8双特异性抗体（hu3F8- bsab），其中抗cd3 huOKT3 scFv与hu3F8轻链的羧基端融合，对GD2（+）肿瘤具有有效的抗肿瘤细胞毒性。为了克服癌症患者体内T细胞数量和功能的不足，在使用hu3F8-BsAb进行过继转移之前，可以在体外使T细胞恢复活力和扩增，从而潜在地减少直接给药BsAb的毒副作用。使用CD3/CD28微球体外扩增和活化正常志愿者的T细胞8天。收集活化T细胞（ATCs），与GMP级hu3F8-BsAb在室温下共孵育20分钟。在BALB-Rag2−/−IL-2R-γc-KO （BRG）小鼠体内和体外测试了这些武装ATCs对人GD2（+）细胞系和PDXs异种移植物的细胞毒性。Hu3F8-BsAb武装ATCs在体外对GD2（+）肿瘤表现出强大的抗原特异性肿瘤细胞毒性。在体内，携带hu3F8-BsAb的t细胞对GD2（+）黑色素瘤和神经母细胞瘤异种移植小鼠具有高度的细胞毒性，并伴有t细胞浸润，无明显副作用。每个t细胞只需要zeptomole（10−21）量的BsAb就能达到最大的抗肿瘤效果。肿瘤反应是t细胞剂量的函数。如果自体T细胞能够在体外被激活和扩增，BsAb武装T细胞作为与重组BsAb联合治疗成人和儿科肿瘤的下一代细胞疗法可能具有临床应用价值。
Humanized 3F8-bispecific antibody (hu3F8-BsAb) using the IgG(L)-scFv format, where the anti-CD3 huOKT3 scFv is fused with the carboxyl end of the hu3F8 light chain, has potent anti-tumor cytotoxicity against GD2(+) tumors. To overcome the insufficient number and function of T cells in cancer patients, they can be rejuvenated and expanded ex vivo before arming with hu3F8-BsAb for adoptive transfer, potentially reducing toxic side effects from direct BsAb administration. T cells from normal volunteers were expanded and activated ex vivo using CD3/CD28 beads for 8 days. Activated T cells (ATCs) were harvested and co-incubated with a GMP grade hu3F8-BsAb at room temperature for 20 minutes. These armed ATCs were tested for cytotoxicity in vitro and in vivo against human GD2(+) cell lines and PDXs xenografts in BALB-Rag2−/−IL-2R-γc-KO (BRG) mice. Hu3F8-BsAb armed ATCs showed robust antigen-specific tumor cytotoxicity against GD2(+) tumors in vitro. In vivo, T-cells armed with hu3F8-BsAb were highly cytotoxic against GD2(+) melanoma and neuroblastoma xenografts in mice, accompanied by T-cell infiltration without significant side effects. Only zeptomole (10−21) quantities of BsAb per T-cell was required for maximal antitumor effects. Tumor response was a function of T-cell dose. BsAb armed T cells may have clinical utility as the next generation of cytotherapy combined with recombinant BsAb against human tumors for both adult and pediatrics, if autologous T-cells can be activated and expanded ex vivo.
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影响因子：
6.4
作者：
Cheng M;Ahmed M;Xu H;Cheung NK
通讯作者：
Cheung NK
病毒特异性的T细胞设计为共表达肿瘤特异性受体：神经母细胞瘤个体中的持久性和抗肿瘤活性。
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
7.3
作者：
Mirzaei HR;Rodriguez A;Shepphird J;Brown CE;Badie B
通讯作者：
Badie B
影响因子：
45.3
作者：
Cheung, Nai-Kong V.;Cheung, Irene Y.;Modak, Shakeel
通讯作者：
Modak, Shakeel
影响因子：
20.3
作者：
Louis, Chrystal U.;Savoldo, Barbara;Brenner, Malcolm K.
通讯作者：
Brenner, Malcolm K.