The Introduction of Chimeric Antigen Receptor T

What is CAR-T?

 

CAR-T refers to chimeric antigen receptor T cell immunotherapy. As a new promising targeted therapy for cancer, CAR-T is precise, fast and efficient. In recent years, it has achieved good results in clinical cancer treatment through continuous optimization and improvement.

T cells, also known as T lymphocyte, are a kind of human white blood cells, derived from bone marrow hematopoietic stem cells. Maturing in the thymus, T cells will migrate to human blood, lymph and surrounding tissues and organs to perform its immune function. They can be regarded as the “warrior” in the human body because they can resist and eliminate “enemies” such as infection, cancer, foreign bodies and so on.

The requirements of target of CAR-T therapy is strict, which are shown as follows:

  1. Being expressed on the cell surface.
  2. This target cannot be found in important organs or cell types (such as hematopoietic stem cells) other than those with tumors. Even low levels of expression may cause serious side effects.
  3. In order to avoid antigen escape, all cancer cells must express the antigen.

The first is easy to understand because of the MHC-independent nature of CAR-T cells. Article 2 is essential for controlling the toxicity of CAR-T cells. Because of the high sensitivity of CAR-T cells, even low levels of antigen expression can trigger T cells to attack the corresponding cells. Article 3 is essential to ensure the effectiveness of CAR-T gene therapy.

It is obvious that CD19 can meet the above three requirements. Besides CD19, some other antigens on the surface of B cells, such as BCMA, can also meet the above characteristics.

BCMA is also an excellent target for CAR-T gene therapy. Although no related products have been approved for market and in clinical trials, CAR-T gene therapy targeting BCMA has achieved great success in the treatment of multiple myeloma.

Controlling toxic reaction

Despite the success of targeted CD19 and BCMA AR-T therapies, toxicity remains a major obstacle.

Severe brain edema is one of the main hazes in the study of CAR-T therapy. Until now, researchers do not have a clear view of the specific mechanism of brain edema. Brain edema is not the only toxic reaction of CAR-T therapy. High-activity reinfusion of CAR-T cells may lead to other serious consequences. CAR-T cells are living drugs, which is different from the traditional drugs. CAR-T cells will expand exponentially when activated by antigens, and cytokines will be released when attacking cancer cells, thus promoting inflammatory response and recruiting more immune cells. If these CAR-T cells attack too quickly, a deadly cytokine release storm will be triggered.

At present, cytokine release storms are generally controllable. In extreme cases, however, severe toxic reactions will be controlled by prompt and rapid removal of CAR-T cells causing toxic reactions..

Suicide switch is a better choice to control CAR-T cells. In the case of severe toxic reaction, the suicide switch on CAR-T cells can be used to induce apoptosis of CAR-T cells quickly and avoid further deterioration of toxic side effects.

Many kinds of suicide switches have been designed by researchers in academic institutions and biotechnology companies. At present, some CAR-T therapies using suicide switches have entered pre-clinical/clinical studies. It is not known whether these suicide switches can effectively control severe toxic reactions, and many people do not think that suicide switches are necessary.

Universal CAR-T

In addition to these biological problems, CAR-T therapy also faces the problem of time and money. Chemotherapy can be widely used in cancer treatment, not only because it can slow down or prevent the progress of cancer, but also because of its high availability, relatively low price, and large-scale preparation, transportation and storage.

Car-T therapy, on the other hand, requires separation of immune cells from blood in the hospital during the preparation of CAR-T cells. After being frozen(some products do not need to be frozen), these separated cells will be transferred to the CAR-T plant. After thawing, viral vectors will be used to transfer genes. Again freeze and transport them to the hospital. Finally, they will be transfused to the patients after thawing.

In addition, it is difficult not only to collect T cells from terminal patients but also to get enough T cells form infants and younger children, which makes it impossible to complete the first step of CAR-T therapy.

In order to make CAR-T therapy into practice, we have to find low-cost ways which are easy to carry out and affordable to patients. A popular way to solve this problem is to use universal CAR-T, that is, to make CAR-T cells from other people rather than patients themselves.

The standard CAR-T treatment process is divided into the following seven steps:

  1. Evaluate whether the patient meets the indications of CAR-T treatment.
  2. Separation of T cells: Mononuclear cells will be isolated from the blood of cancer patients by peripheral blood cell separator, and T cells will be further purified by magnetic beads.
  3. Transforming T cells: Using genetic engineering technology, a viral vector containing chimeric antigen receptors that can recognize and activate T cells is transferred into T cells, i.e. transforming T cells into CAR-T cells.
  4. Expansion of CAR-T cells: A large number of CAR-T cells were cultured in vitro. Generally, a patient needs tens of millions or even hundreds of millions of CAR-T cells. The larger the body weight, the more cells are needed.
  5. CAR-T cells are reintroduced into the human body: Expanded CAR-T cells are reintroduced into the patients via vein, and cancer cell immunotherapy is initiated.
  6. Monitored response: closely monitor the patient’s physical reaction, especially the severe adverse reactions that may occur within one to two weeks after the cell being transported into the body.
  7. Evaluation of therapeutic effect: The therapeutic effect of primary disease will be evaluated on the 15th and 30th day after transfusion of CAR-T cells.