A phase I clinical trial of adoptive T cell therapy using IL-12 secreting MUC-16(ecto) directed chimeric antigen receptors for recurrent ovarian cancer.
A phase I clinical trial of adoptive T cell therapy using IL-12 secreting MUC-16(ecto) directed chimeric antigen receptors for recurrent ovarian cancer.
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DOI：
10.1186/s12967-015-0460-x
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发表时间：
2015-03-28
影响因子：
7.4
通讯作者：
Brentjens RJ
中科院分区：
文献类型：
--
作者：
Koneru M;O'Cearbhaill R;Pendharkar S;Spriggs DR;Brentjens RJ
复发性铂耐药卵巢癌没有治疗选择，需要开发新的治疗方法，包括免疫治疗。患者来源的T细胞可以被遗传修饰以以HLA非依赖性方式表达对肿瘤相关抗原特异性的嵌合抗原受体（汽车），具有有希望的临床前结果。MUC 16 ecto在大多数上皮性卵巢癌中高度表达，但在正常组织中表达水平较低，为这种癌症提供了极好的免疫靶点。进一步修饰以分泌IL-12的CAR T细胞显示增强的细胞毒性、持久性和肿瘤微环境的调节。我们提出了一项针对复发性MUC-16 ecto+卵巢癌患者的剂量递增I期临床试验，以测试静脉内和腹膜内给药的安全性以及含有安全消除基因的分泌IL-12的自体MUC-16 ecto CAR T细胞的初步疗效。这项试验针对MUC-16 ecto，一种新的有前途的肿瘤相关抗原。这将是首次将CAR T细胞直接腹膜内注射到人类腹部肿瘤部位。此外，基因修饰细胞分泌IL-12的能力将潜在地增强CAR T细胞的持久性并调节肿瘤微环境。出于安全性目的，消除基因已被纳入CAR T细胞中，以减轻任何靶向、非肿瘤或其他不可预见的毒性。
Recurrent platinum-resistant ovarian cancer has no curative options, necessitating the development of novel treatments, including immunotherapy. Patient-derived T cells can be genetically modified to express chimeric antigen receptors (CARs) specific to tumor-associated antigens in an HLA-independent manner, with promising preclinical results. MUC16ecto is highly expressed on most epithelial ovarian carcinomas but at low levels on normal tissues, offering an excellent immunotherapeutic target for this cancer. CAR T cells further modified to secrete IL-12 show enhanced cytotoxicity, persistence, and modulation of the tumor microenvironment. We propose a dose escalation phase I clinical trial for patients with recurrent MUC-16ecto+ ovarian cancer to test the safety of intravenous and intraperitoneal administration and the preliminary efficacy of autologous IL-12 secreting, MUC-16ecto CAR T cells containing a safety elimination gene. This trial targets MUC-16ecto, a novel and promising tumor-associated antigen. This will be the first time CAR T cells are injected intraperitoneally directly into the site of the tumor within the abdomen in humans. Furthermore, the ability of genetically modified cells to secrete IL-12 will potentially enhance CAR T cell persistence and modulate the tumor microenvironment. For safety purposes, an elimination gene has been incorporated into the CAR T cells to mitigate any on-target, off-tumor or other unforeseen toxicity.
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DOI：
10.1084/jem.20021910
发表时间：
2003-05-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Curtsinger JM;Lins DC;Mescher MF
通讯作者：
Mescher MF
影响因子：
11.5
作者：
Kershaw, Michael H.;Westwood, Jennifer A.;Hwu, Patrick
通讯作者：
Hwu, Patrick
DOI：
10.3109/08860228009065326
发表时间：
1980-01-01
期刊：
JOURNAL OF DIALYSIS
影响因子：
--
作者：
DIAZBUXO, JA;CHANDLER, JT;WALKER, PJ
通讯作者：
WALKER, PJ
影响因子：
17.1
作者：
Brentjens RJ;Davila ML;Riviere I;Park J;Wang X;Cowell LG;Bartido S;Stefanski J;Taylor C;Olszewska M;Borquez-Ojeda O;Qu J;Wasielewska T;He Q;Bernal Y;Rijo IV;Hedvat C;Kobos R;Curran K;Steinherz P;Jurcic J;Rosenblat T;Maslak P;Frattini M;Sadelain M
通讯作者：
Sadelain M
影响因子：
4.7
作者：
Alvarez RD;Sill MW;Davidson SA;Muller CY;Bender DP;DeBernardo RL;Behbakht K;Huh WK
通讯作者：
Huh WK