最新突破新一代CART可高效鉴别肿瘤

2015年9月2日 讯 /生物谷BIOON/ --近日，来自国外一项临床前试验结果显示，一种工程化嵌合抗原受体（Chimeric antigen receptor，CAR）T细胞的技术—亲和力调整技术或可帮助科学家们有效区分癌细胞和正常细胞，从而帮助研究者在抵御实体瘤的过程中降低免疫疗法对机体正常细胞的毒性。

许多实体癌症都含有较高水平的特定蛋白质，比如ErbB2和EGFR，这种特定蛋白质或可作为抗癌疗法的合适靶点，然而诸如这样的蛋白质在正常细胞中水平较低，正因为如此，发育成为靶向作用肿瘤细胞中特定蛋白质的CAR T细胞就会识别并且攻击含有该蛋白质的正常细胞，从而引发更加严重的毒性。

为了开发出可以有效区分癌细胞和正常细胞的CAR T细胞，研究者利用突变的4D5抗体的序列构建了可以携带scFvs（重组单链抗体）的一组CARs；4D5抗体对ErbB2的亲和力不断发生着变化，下一步研究者将不同的scFvs掺入到了CAR中，从而就会产生一系列CAR T细胞，而这种新形成的CAR T细胞就会通过三个数量级来改变同ErbB2蛋白的亲和力。

随后研究者进行了一系列实验来检测亲和力调节的CAR T细胞的功能，结果发现高亲和力的CAR T细胞并不能有效区分正常细胞和肿瘤细胞，然而低亲和力的CAR T细胞则对含有高水平ErbB2蛋白的肿瘤细胞较为敏感，而对含有低水平ErbB2蛋白的正常细胞并不敏感；随后研究者开发出了一种可以靶向作用EGFR的具有低亲和力的CAR T细胞，结果显示，这种类型的CAR T细胞可以有效区分正常细胞和肿瘤细胞。

最后研究者Zhao说道，并不像普通的期望那样，即降低CAR T细胞的亲和力就可以降低其活力，我们的研究发现降低其亲和力实际上或许会达到相反的效果，即相比高亲和力的CAR T细胞而言，较低亲和力的CAR T细胞会对表达高水平靶向蛋白的肿瘤细胞具有更强的反应性，可以有效将肿瘤细胞和正常细胞进行区分。（生物谷Bioon.com）

Newly engineered CAR T cells can better discriminate between cancer and normal cells
A new development in engineering chimeric antigen receptor (CAR) T cells, called affinity tuning, can make the CAR T cells spare normal cells and better recognize and attack cancer cells, which may help lower the toxicity associated with this type of immunotherapy when used against solid tumors, according to a preclinical study.

Many solid cancers have high levels of certain proteins such as ErbB2 and EGFR, which make them suitable targets for anticancer therapies. However, such proteins are also present at low levels in normal cells. Because of this, CAR T cells that are developed to target one of these proteins on tumor cells also recognize and attack normal cells that have the protein, causing severe toxicity. Zhao and colleagues are working to address this challenge.

To develop CAR T cells that can distinguish between cancer and normal cells, Zhao and colleagues first constructed a panel of CARs with the scFvs using sequences from mutated 4D5 antibodies that had varying affinities to ErbB2, a protein present at high levels in some solid tumors, including breast cancer. Next, they incorporated different scFvs into the CAR backbone or "construct," such that they resulted in a range of CAR T cells—from those that had high affinity to ErbB2 to those that had low affinity to ErbB2. The newly engineered CAR T cells varied in their affinity to ErbB2 by three orders of magnitude.

The researchers then conducted a series of experiments to test the functionality of the affinity-tuned CAR T cells and found that high-affinity CAR T cells did not discriminate tumor cells from normal cells and attacked all of them, whereas low-affinity CAR T cells were sensitive to tumor cells that had high levels of ErbB2 and not to normal cells that had low levels of the protein.

Next, they tested the engineered CAR T cells in mice that bore human cells with high levels of ErbB2 on one side of their bodies and human cells with normal levels of ErbB2 on the other side of their bodies. Here again, low-affinity CAR T cells selectively eliminated cells that had high levels of ErbB2 but had no effect on cells that had normal levels of the protein.......

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静候佳音

只要找到好的区分 癌细胞与正常细胞的方法  cart 将实现重大突破。。。期待中~！

期待中

多谢分享，

免疫疗法是下一步方向，看到底能发展到哪一步了。加油！战友们！

CART接近普通患者的距离有多远?

确实一个简单而有效的思路。