汽车T细胞疗法：Teaching an old immune system new tricks to fight cancer

多年来，癌症治疗的主要类型一直是手术，放射线和化学疗法。但是现在，随着新型癌症疗法的出现，可能会改变。
汽车T细胞疗法，一种immunotherapy可以通过加强患者的免疫系统来治疗癌症，以便它可以攻击肿瘤，最近是由FDA批准。
这种类型的治疗的潜力是巨大的，尽管这是一个非常复杂的程序，涉及操纵患者自己的细胞，但它也是一种引人入胜的治疗方法，值得关注和更深入地看待其能力的本质。
为了更好地理解这种治疗方法，我们需要仔细研究它的核心部分：免疫系统。

当免疫系统遇到癌细胞时

One way to describe what may happen to the immune system when it first encounters cancerous cells is to compare it to a student taking an exam:
As students, our main goal is to learn new things. Our knowledge is tested in an exam, where we have (of course) studied so hard that we know the curriculum by heart, and we are able to answer all the questions. The goal is then to pass the subject and go on to learning about the next new thing.
现在想象一下自己坐在其中一项考试中。
您（再次）学习了如此努力，以至于您会心中了解整个课程，并且可以轻松回答每个任务。
But then you encounter a problem you never experienced before: You turn the page, and it turns out to be blank.

You ask your professor if some kind of mistake has been made. But it is not a mistake. There is, indeed, an assignment on the blank page.
But you can’t see any assignment. To you, it’s a just blank page.
现在怎么办？
Nothing.
您无法解决作业，因此您将页面空白。
像学生一样，免疫系统面临某些任务。例如，免疫系统具有识别不同结构的能力，包括熟悉的结构（我们自己的组织）和外来（病毒，细菌或感染细胞）。
当发现外国结构时，免疫系统就会知道适当的反应：摧毁它们并确保我们身体的健康和安全。
However, if the foreign structure is not identified or recognized, the immune system cannot respond.
In other words, the immune system will react to it like you reacted to the blank page at the exam.
那么，它做什么？
Nothing.
该页面留为空白，外国对象不能被销毁。

癌症：空白页

癌症是免疫系统的一个难题：它是从我们自己的细胞中发展而来的本质上熟悉的，但它与体内所有其他细胞也有很大不同。
There are many types of cancer, all distinct in cause and location. Despite that, they all have several attributes in common. These are called thehallmarks of cancer。One of the hallmarks is the ability to avoid immune recognitionthrough various mechanisms，从而使癌症繁殖并避免破坏。
That means the cancer seems like a blank page, making it difficult for the immune system to recognize it.
When the cancer is not recognized, the immune system simply cannot destroy the cancerous tissue.

汽车T细胞疗法：填充空白

科学家长期以来一直在寻求利用免疫系统或模拟免疫功能来治疗癌症。A lingering question has been: Can we teach the patient’s own immune system to recognize cancer and destroy it?
Finally, this year, the question was answered with a resounding “yes” whenFDA批准了Yescarta™,第二种嵌合抗原受体（CAR）T细胞治疗，用于具有某些类型的大型B细胞淋巴瘤（对常规疗法反应）的患者。似乎科学家到达了一个转折点，使该领域的进步得以加速。
Now, let’s dig a little deeper into how the treatment works.

汽车T细胞疗法如何工作？

CAR T-cell therapy teaches the patient’s immune cells to recognize the cancer, activate the immune system, and kill the cancer.
治疗需要advantage of a type of adoptive cell transfer, which means that it involves the transfer of cells into a patient with the purpose of fighting a disease. The cells in question are, as the name implies, T-cells, a type of white blood cell.

T细胞的功能之一是识别我们自己细胞表面上的外国或癌症相关分子（称为抗原）的某些部分。T细胞用结合特定抗原的受体来完成此操作。一种思考受体和抗原结合的方法可以是想象锁中的钥匙（抗原）配件（受体）。结合素数通过免疫系统破坏细胞。
Let’s break down the steps of CAR T-cell therapy a little:

Step 1

汽车T细胞疗法的第一步是从患者的血液中获取T细胞。这是通过将患者的血液通过将T细胞与其他类型的血细胞分开的机器过滤的。

Step 2

然后，在实验室中修饰T细胞，以产生可以识别癌细胞表面抗原的受体。这涉及几个较小的步骤：
嵌合抗原受体（这是CARpart of CAR T-cell therapy) means that the receptor is made of different parts of several receptors. In other words, the best parts of multiple receptors are combined to create one receptor with efficient antigen-binding and immune activation.
为了使T细胞产生这种工程的受体，利用了另一个（也许是出乎意料的部分）的帮助：一种病毒。
尝试我们的病毒基因疗法模拟，以了解有关如何使用改良病毒治疗人类疾病的更多信息。
The T-cells are infected by a disarmed retrovirus, which causes an insertion of viral DNA into the genome of the T-cells. The inserted viral DNA carries a DNA sequence for the chimeric antigen receptor. Under the right circumstances,the insertion into the T-cell genome will lead to production of the CAR and its subsequent placement on the surface of the T-cell membrane.
The T-cells have now ‘learned’ to identify the cancer antigen, and the T-cells can recognize the previously blank page (the cancer) and activate the immune system to destroy the cancer.
The cells have hereby become CAR T-cells.

Step 3

下一个，允许汽车T细胞在实验室中繁殖。

Step 4

Finally, the CAR T-cells are re-injected into the patient. Here, the modified immune cells are free to roam all over the patient’s body and to hunt for cells presenting the antigen on their surface.
Take a look at this 3D animation of the entire process to get an even better idea of how CAR T-cell therapy works:

奇迹治疗？

The recently FDA-approved CAR T-cell therapy YESCARTA™ is engineered to recognize the CD19 protein on the surface of B-cells, another immune cell and the culprits of B-cell lymphomas.The results of the clinical trials that led to the FDA approval的Yescarta™用于B淋巴瘤治疗令人印象深刻the effect seems to be lasting。临床试验中的患者要么复发，要么对传统治疗没有反应，这一事实使结果变得更加非凡。
However, CAR T-cell therapy is not a miracle cancer cure. At least not for now.
The treatment is currently only administered as a last resort, when chemotherapy and all other treatment has failed.
On top of that, CAR T-cell therapy can, like all other forms of cancer treatment, induce serious side effects, for example,细胞因子释放综合征正常B细胞​​也存在正常B细胞​​的正常B细胞​​量的减少。
治疗也非常昂贵，列出373,000美元。The production cost of the treatment needs to be lowered to make it more accessible, and one suggestion in this regard is to使用捐助者收获T细胞。
最后，与当今大多数癌症治疗一样，可悲的是，并非所有患者都按计划对汽车T细胞疗法做出反应。
但是，这是汽车T细胞疗法的真正潜力：从理论上讲，如果患者对第一个CAR T治疗反应，则可以针对另一种癌症。Yescarta™设计为靶向CD19，但是可以想象，如果我们了解其他癌症抗原的存在，则可以针对第二抗原开发新的治疗方法。
So, if the first bullet misses, and the patient does not respond to the first treatment, you have a second shot in the form of another CAR T-cell therapy targeting another antigen. All you need, in theory, is knowledge of the cancer and resources to develop the treatment. Such work is actually already being done, as scientists areexploring the CD22-antigen作为对CD19 CAR T细胞疗法反应的B细胞淋巴瘤CAR T细胞治疗的潜在靶标。

接下来是什么？

在这一领域中，仍然有很多知识要获得并实践，并且在汽车T细胞疗法实际上可以被视为“奇迹治疗”之前，还有很多要涵盖的理由：
该疗法需要更便宜，必须管理副作用，并且必须对其他类型的癌症（例如乳腺癌和结肠）进行新的汽车T细胞疗法，并在可以评估CAR T细胞疗法的真正影响之前进行开发和评估。并与理论潜力相比。
Despite all that, the fact that these treatments are slowly reaching the market is a promise of much bigger things to come. After all, it wasn’t long ago that we considered such extensive molecular modification to be something out of a science fiction book.
即使汽车T细胞疗法不会消除癌症作为人类疾病和死亡原因，但我们现在在我们的武器库中进行了另一种复杂的武器，以抗癌。