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CAR-T therapy has attracted wide attention due to its bright prospects in the treatment of cancers such as leukemia and lymphoma.

This new type of therapy, which has just entered the market, usually requires the injection of hundreds of millions of genetically engineered T cells into patients.
However, in a paper published today in the journal Nature, researchers from the University of Pennsylvania pointed out that almost one CAR-T cell cures a leukemia patient. This accidental discovery may change the thinking of CAR-T therapy.

In 2013, a 78-year-old man with chronic lymphocytic leukemia (CLL) received a clinical trial of CAR-T therapy at the University of Pennsylvania Abramson Cancer Center. The study, led by Car-T’s pioneer Prof. Carl June and Assistant Professor Joseph Melenhorst, hopes to validate the effect in leukemia treatment.

Joseph Melenhorst (right) and the paper’s first author, Joseph Frayeta (left) (Source: Penn State University)

CAR-T Therapy: New Hope for Cancer Treatment

The full name of CAR-T is the chimeric antigen receptor T cells, which are genetically engineered to specifically destroy tumor cells.

In the human body, as the main force to eliminate tumor cells, T cells are normally in a state of calm. To activate T cells, another type of immune cell, the dendritic cell, extracts a certain protein from the surface or inside of the tumor and hands it to the T cell: “This is the antigen you want to attack.” Signals from dendritic cells activate T cells and they begin to rapidly proliferate and kill tumor cells.

However, it is well known that T cells often fail in the battle with tumor cells because tumor cells have unique skills to avoid attacks. The tumor cells are produced by the normal cell carcinogenesis, so they have many similarities with normal cells.
In order to avoid accidental injury to friendly forces, the immune system has evolved a protective mechanism: after detecting specific antigens, they also need to confirm that the other side of the surface contains two types of molecules (the major histocompatibility complex that binds the antigen, or MHC; the firing signal). – co-stimulatory ligands) will initiate the attack.
This protection mechanism gives tumor cells an opportunity: they can stop producing these two molecules and escape the killing of T cells.

Can T cells be modified to allow researchers to select target antigens for T cells?
For example, let the T cells detect the antigen and launch the attack directly without waiting for the fire command? The idea of ​​genetically engineering T cells was born.
At the end of the 20th century, Zhu et al. began to study the introduction of a gene into T cells that encodes a protein called the chimeric antigen receptor (CAR). The CAR protein binds to specific antigens, allowing the T cells to skip redundant identification steps and directly attack cancer cells.

The standard for antigens is obvious: there are cells on the cancer cells, but normal cells do not, so as to avoid accidentally injuring normal tissues. Currently, researchers have found that the target of attack is a CD19 surface protein carried by some leukemia and lymphoma cells.
In recent years, CAR-T therapy has shown excellent results in these non-solid tumors in clinical trials. In August last year, the FDA approved the first CAR-T therapy for acute lymphoblastic leukemia (ALL). The CAR-T therapy for certain lymphomas was also introduced in May this year.

51 days: a late effect

Although the efficacy of CAR-T therapy is significant, it is accompanied by serious side effects. When too many T cells are activated simultaneously, a side effect called “cytokine release syndrome” can be fatal.
Therefore, researchers need to be cautious about the control of drug use in clinical trials. Patients usually need to receive 3 sequential doses of drug injection in order to minimize side effects.

At the University of Pennsylvania Hospital, the patient in the story is being treated according to this procedure. After the first phase of low-dose drug injection, the patient developed a typical cytokine release syndrome, and his condition continued to develop due to limited doses. After 70 days, the second-stage, moderate-dose injection was performed as scheduled.

However, one month later, the patient’s condition did not develop as expected. He did not have a cytokine release syndrome in his body and his condition did not improve, meaning that CAR-T cells did not function.
In fact, because CAR-T may not be able to proliferate in patients, or tumor cells may have mutations, CAR-T therapy is not effective for all patients. Almost all patients who achieved curative effect had suppressed cancer cells within a month. Therefore, people thought that the treatment of this patient might end in failure.

On the 51st day after the second phase of treatment, the situation changed.
“On the 51st day after treatment, this patient had a cytokine release syndrome, which meant that CAR-T cells became active and anti-cancer effects might begin to appear.” Mehrenhorst reviewed the situation.
Subsequently, the CT image results also confirmed Mehrenhorst’s guess: The tumor in the patient’s body began to become smaller. After confirming the curative effect, the patient continued to receive the third stage, which was the highest dose of injection. Fortunately, his condition was finally completely controlled.
Five years later, the patient’s cancer cells disappeared and his survival was good.

After treatment, the patient’s tumor size changes

Accident: Cancer Killer from a Cell

The old patient recovered after several twists and turns. This cancer-resistant story ended with a perfect ending, but the scientists involved in the trial saw new questions from this particular CLL patient. Why does CAR-T therapy delay his role in him for at least 20 days?
“From every patient, we can learn a lot. We go back to the laboratory from the bedside and hope to understand as much as possible what happened to him,” said Jun.

To this end, researchers at the University of Pennsylvania traced the origin of CAR-T cells in patients. The results were surprising: 94% of CAR-T cells were derived from one CAR-T cell.
In other words, his leukemia was almost defeated by one cell.
It is worth noting that the researchers did not detect them during the one month after the second phase of treatment. But then, it bred for 29 generations in the body and eventually cleared all the cancer cells.

After two months of treatment, there is almost one CAR-T cell left in the patient (red)

As described in the first part of the article, the researchers modified the patient’s T cells to encode a chimeric antigen receptor (CAR) and recognize the CD19 protein.
During the operation, the gene fragment encoding the CAR is randomly inserted into the patient’s DNA through a genetically modified virus.
In this particular case, the researchers discovered that the CAR sequence was accidentally inserted into a gene called TET2.
The main function of TET2 is to regulate the production of blood cells and monitor its proliferation rate.
After this operation, the TET2 structure of this CAR-T cell was destroyed, and the cells began to rapidly proliferate and eliminate leukemia.
After the tumor cells were destroyed, the content of these CAR-T cells dropped back to allow normal T cells. This also explains why the patient is effective only after 51 days: it takes longer to grow from one CAR-T cell to a sufficient number compared to multiple CAR-T cells working at the same time.

Compared to normal CAR-T cells, CAR-T cells proliferate faster after CAR insertion of TET2.

Previously, people’s understanding of TET2 focused on its regulation of the number of blood cells, and its mutations may lead to clonal hematopoiesis, which in turn triggers leukemia.
In this study, Zhu et al., through in vitro experiments, found that TET2 is also associated with many previously unknown functions.
In addition to the rapid proliferation of T cells, TET2 also helps cells maintain a state called central memory. T cells in this state can more accurately locate tumor cells. The deletion of TET2 also reduces the release of cytokines from T cells, mitigating the potentially lethal side effects.

“This finding is truly shocking. It tells us that the minimum dose of CAR-T therapy may only require one cell,” said Joseph Fraietta, the first author of the paper.
There is no doubt that this study has revolutionized the development of CAR-T therapy.
If the role of inhibition of TET2 expression in enhancing the efficacy of CAR-T is finally confirmed, the amount of cells in CAR-T therapy will likely be reduced from the current 50 million to 500 million to several.
This will lead to a reduction in waiting time for treatment and a reduction in costs.
However, the research team also pointed out that because the mutation of TET2 may lead to leukemia, it is necessary to pay attention to potential risks in follow-up studies.

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