Release date: 2017-07-24

A few days ago, former US President Barack Obama wrote on Twitter on a rare occasion: "John McCain is an American hero and one of the most brave fighters I have ever seen. Cancer does not know what it is facing. An opponent. John, let the cancer go to hell!" In less than 24 hours, this tweet received 1.5 million "likes".

McCain is Obama's campaign opponent in the 2008 US presidential election. A day ago, his office announced to the outside world that the 80-year-old man had glioblastoma, one of the most common and invasive brain tumors - many people have spread to the brain when they are diagnosed. Multiple areas of the department, so it cannot be completely removed by surgery. Since there is currently no cure for this disease, a statistical data suggests that patients with glioblastoma who have relapsed after surgery may only live for six months.

"Science" official website believes that the findings of this study are expected to accelerate the treatment of glioblastoma with CAR-T therapy (Source: Science)

Coincidentally, yesterday, Science published a book in Science Translational Medicine, which introduced a strategy for treating glioblastoma with T-cell therapy. After the publication, this paper immediately received a lot of attention - this therapy is the CAR-T therapy that recently ignited the entire circle of medical people, one of its researchers is Professor Carl June, the pioneer of CAR-T therapy. .

One of the members of this research team is Professor Carl June, a pioneer of CAR-T therapy (Source: MIT Technology Review)

Let me briefly introduce the T-cell therapy of CAR-T. We know that T cells are warriors in the body's immune system. They are in the first line of the immune response and have the ability to kill cells. One of the potential targets of these T cells is cancer cells.

In order to enhance the killing effect of T cells on cancer cells, scientists have developed a new treatment: they first isolate T cells from patients, and then use bioengineering methods to transform these T cells to express "chimeric antigens." "chimeric antigen receptor" (CAR). These receptors specifically find antigens on the surface of cancer cells and help T cells recognize them. In addition, after T cells recognize cancer cells, these receptors can also activate T cells and enhance their activity. Subsequently, these engineered T cells are continuously expanded into a large army in vitro and eventually returned to the patient to attack the tumor.

In other words, "CAR" is like a wanted order for a T cell. When they see cancer cells, they attack unscrupulously.

General procedure for CAR-T therapy (Source: Memorial Sloan Kettering Cancer Center )

Since the concept of CAR-T therapy has been put forward, it has been consistently optimistic by many experts. A few weeks ago, a US FDA review committee unanimously supported the launch of Novartis' CAR-T therapy with a “10:0” vote. This also means that the first CAR-T therapy in history is very likely to come out this year.

However, due to several short plates of CAR-T therapy itself, few people think that it is expected to treat glioblastoma. First, it needs to extract T cells from the patient and then remodel. If the patient's T cell activity is not strong, the effect of CAR-T therapy will also be discounted. Unfortunately, patients with glioblastoma fall into this category.

Second, one potential side effect of CAR-T therapy is neurotoxicity. This side effect is related to how glioblastoma occurs in the brain, and no one knows.

Third, at present, CAR-T therapy is also limited to the treatment of leukemia and lymphoma. They belong to the category of “blood tumors” and are distinctly different from “solid tumors” such as glioblastoma. In the field of solid tumors, we have not seen convincing data to support the effects of CAR-T therapy.

Therefore, you can imagine how surprised readers when Professor Carl June and his partners published a paper on the use of CAR-T therapy to treat glioblastoma in the journal Science!

The study was published in the Science issue of Science Translational Medicine (Source: Science Translational Medicine)

As mentioned earlier, in CAR-T therapy, scientists need to engineer T cells to recognize antigens on the surface of cancer cells. For glioblastoma, this potential antigen is a mutant type of EGFR protein, EGFRvIII, which is the most common EGFR variant in human tumors. In glioblastoma, the expression of EGFRvIII is directly associated with the prognosis of the disease—the higher the expression, the worse the prognosis.

In a clinical trial, the researchers recruited a group of patients with glioblastoma who expressed EGFRvIII and had a relapse. Using T cells from these patients, the researchers developed CAR-T-EGFRvIII therapy that specifically targets cancer cells in patients.

The preliminary results satisfied the researchers. They found that the treatment was safe and had no serious side effects. In addition, T cells against EGFRvIII do not recognize humans and recognize normal EGFR proteins in humans. As an early clinical trial, this is exactly what researchers expect.

The safety is reliable, so what is the effect of this therapy? Since there is no way to directly assess whether these engineered T cells enter the brain to kill cancer cells, researchers can only use indirect methods to detect whether the EGFRvIII in the brain has decreased. Of the 10 patients who received T-cell infusion, 7 underwent brain surgery, which allowed researchers to obtain brain samples for comparison. The study found that 5 of these 7 patients had a significant decrease in EGFRvIII expression levels, supporting the effects of CAR-T-EGFRvIII therapy to a certain extent.

In some patients, EGFRvIII levels have decreased after CAR-T treatment (Source: Science Translational Medicine)

As we mentioned above, once a patient with glioblastoma relapses, it usually only has 6 months to live. In this study, 10 patients who underwent treatment had a median survival of approximately 8 months with a slight increase. However, the researchers also pointed out that considering the small patient population, the clinical efficacy of the study is not counted. The exact efficacy remains to be further verified.

The therapy currently has limited effect on the extension of overall survival (Source: Science Translational Medicine)

As an early trial, the significance of this study is to support the possibility of using innovative T-cell therapies to treat refractory brain tumors. In this paper, the previous three questions about CAR-T therapy for glioblastoma have been answered to a certain extent: even in patients with glioblastoma whose T cell activity is affected, their T cells are sufficient. Used to produce CAR-T therapy; the safety of this therapy is well protected; researchers have also seen encouraging signs in the treatment of glioblastoma.

After tumor immunotherapy represented by PD-1 pathway inhibitors, CAR-T therapy is setting off a new storm of cancer treatment. We look forward to reading more good news, and we hope that more innovative therapies will come out and completely reduce the threat of cancer to humans.

Source: Academic Jingwei

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