A herceptin-based chimeric antigen receptor with modified signaling domains leads to enhanced survival of transduced T lymphocytes and antitumor activity.
A herceptin-based chimeric antigen receptor with modified signaling domains leads to enhanced survival of transduced T lymphocytes and antitumor activity.
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DOI：
10.4049/jimmunol.0900447
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发表时间：
2009-11-01
期刊：
影响因子：
--
通讯作者：
Morgan RA
中科院分区：
文献类型：
--
作者：
Zhao Y;Wang QJ;Yang S;Kochenderfer JN;Zheng Z;Zhong X;Sadelain M;Eshhar Z;Rosenberg SA;Morgan RA
为了产生用于具有ErbB 2表达肿瘤的癌症患者的过继免疫疗法的嵌合Ag受体（汽车），最初将来源于人源化mAb 4D 5赫赛汀（曲妥珠单抗）的单链Ab连接至来源于CD 28和CD 3 γ的T细胞信号传导结构域以产生针对ErbB 2的CAR。表达4D 5 CAR的人PBL表现出针对ErbB 2+肿瘤的Ag特异性活性。然而，对于用该4D 5 CAR转导的PBL，注意到转基因表达的逐渐丧失。当CAR的CD 3 β信号传导结构域被截短或突变时，未观察到CAR表达的丧失，表明CD 3 β信号传导引起转基因减少，这得到表达具有CD 3 β ITAM突变的4D 5汽车的T细胞不太倾向于凋亡的发现的支持。通过将4-1BB胞质结构域添加到CD 28-CD 3 β信号传导部分，我们发现4D 5 CAR转导的PBL中的转基因持久性增加。此外，具有4-1BB序列的构建体在4D 5 CAR转导的T细胞中表现出增加的细胞因子分泌和裂解活性。更重要的是，表达这种新版本的4D 5 CAR的PBL不仅可以有效地裂解自体新鲜肿瘤细胞，而且可以在异种小鼠模型中强烈抑制肿瘤生长。
To generate chimeric Ag receptors (CARs) for the adoptive immunotherapy of cancer patients with ErbB2-expressing tumors, a single-chain Ab derived from the humanized mAb 4D5 Herceptin (trastuzumab) was initially linked to T cell signaling domains derived from CD28 and the CD3ζ to generate a CAR against ErbB2. Human PBLs expressing the 4D5 CAR demonstrated Ag-specific activities against ErbB2+ tumors. However, a gradual loss of transgene expression was noted for PBLs transduced with this 4D5 CAR. When the CD3ζ signaling domain of the CAR was truncated or mutated, loss of CAR expression was not observed, suggesting that the CD3ζ signaling caused the transgene decrease, which was supported by the finding that T cells expressing 4D5 CARs with CD3ζ ITAM mutations were less prone to apoptosis. By adding 4–1BB cytoplasmic domains to the CD28-CD3ζ signaling moieties, we found increased transgene persistence in 4D5 CAR-transduced PBLs. Furthermore, constructs with 4–1BB sequences demonstrated increased cytokine secretion and lytic activity in 4D5 CAR-transduced T cells. More importantly, PBLs expressing this new version of the 4D5 CAR could not only efficiently lyse the autologous fresh tumor digests, but they could strongly suppress tumor growth in a xenogenic mouse model.
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影响因子：
11.5
作者：
Kershaw, Michael H.;Westwood, Jennifer A.;Hwu, Patrick
通讯作者：
Hwu, Patrick
影响因子：
4.2
作者：
Hughes, MS;Yu, YYL;Morgan, RA
通讯作者：
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影响因子：
4.4
作者：
Elpek, Kutlu G.;Yolcu, Esma S.;Shirwan, Haval
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Shirwan, Haval
影响因子：
45.3
作者：
Dudley, ME;Wunderlich, JR;Rosenberg, SA
通讯作者：
Rosenberg, SA
影响因子：
5.8
作者：
Bernhard, Helga;Neudorfer, Julia;Peschel, Christian
通讯作者：
Peschel, Christian