IL-12 secreting tumor-targeted chimeric antigen receptor T cells eradicate ovarian tumors in vivo
IL-12 secreting tumor-targeted chimeric antigen receptor T cells eradicate ovarian tumors in vivo
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DOI：
10.4161/2162402x.2014.994446
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发表时间：
2015-03-01
期刊：
影响因子：
7.2
通讯作者：
Brentjens, Renier J.
中科院分区：
文献类型：
--
作者：
Koneru, Mythili;Purdon, Terence J.;Brentjens, Renier J.
一种治疗卵巢癌的新方法包括以卵巢癌细胞抗原为靶点的基因工程T细胞的免疫治疗。利用逆转录病毒转导，T细胞可以表达一种被称为嵌合抗原受体(CAR)的人造T细胞受体(TCR)。我们已经产生了一种针对MUC-16(Ecto)抗原的CAR，4H11-28Z，它在大多数卵巢肿瘤细胞上过度表达，是CA-125切割后MUC-16的保留部分。我们之前在SCID-Beige小鼠体内证明了表达4H11-28Z CAR基因的修饰T细胞可以根除人卵巢癌原位移植瘤。然而，尽管CAR T细胞能够定位于肿瘤，但它们在临床环境中的激活可以受到肿瘤微环境的抑制，这通常是内源性抗肿瘤免疫反应的结果。为了潜在地克服这一限制，我们最近开发了一种共表达MUC16(Ecto)Car和IL-12(4H11-28Z/IL-12)的结构。在体外，与4H11-28Z CAR T细胞相比，4H11-28Z/IL-12 CAR T细胞表现出更强的增殖能力和强劲的干扰素-γ分泌。在人卵巢癌移植瘤的SCID-Beige小鼠中，分泌IL-12的CAR T细胞显示出增强的抗肿瘤效果，其结果是延长了存活率，延长了T细胞的存续期，并提高了全身干扰素的水平。此外，由于预期将这些结果转化为I期临床试验，这将是第一个研究卵巢癌中分泌IL-12的CAR T细胞的临床试验，已经包括了一个消除基因，以允许在不可预见的或肿瘤外On Target毒性的情况下删除CAR T细胞。
A novel approach for the treatment of ovarian cancer includes immunotherapy with genetically engineered T cells targeted to ovarian cancer cell antigens. Using retroviral transduction, T cells can be created that express an artificial T cell receptor (TCR) termed a chimeric antigen receptor (CAR). We have generated a CAR, 4H11-28z, specific to MUC-16(ecto) antigen, which is the over-expressed on a majority of ovarian tumor cells and is the retained portion of MUC-16 after cleavage of CA-125. We previously demonstrated that T cells modified to express the 4H11-28z CAR eradicate orthotopic human ovarian cancer xenografts in SCID-Beige mice. However, despite the ability of CAR T cells to localize to tumors, their activation in the clinical setting can be inhibited by the tumor microenvironment, as is commonly seen for endogenous antitumor immune response. To potentially overcome this limitation, we have recently developed a construct that co-expresses both MUC16(ecto) CAR and IL-12 (4H11-28z/IL-12). In vitro, 4H11-28z/IL-12 CAR T cells show enhanced proliferation and robust IFN gamma secretion compared to 4H11-28z CAR T cells. In SCID-Beige mice with human ovarian cancer xenografts, IL-12 secreting CAR T cells exhibit enhanced antitumor efficacy as determined by increased survival, prolonged persistence of T cells, and higher systemic IFN gamma. Furthermore, in anticipation of translating these results into a phase I clinical trial which will be the first to study IL-12 secreting CAR T cells in ovarian cancer, an elimination gene has been included to allow for deletion of CAR T cells in the context of unforeseen or off-tumor ontarget toxicity.