Why CAR-T cell therapy is the new hope for curing cancer?

Posted by beauty33 on June 28th, 2019

What is CAR?

CAR is shorted for Chimeric Antigen Receptor. If you want to know what is CAR, you shall learn from how acquired immunity identify the antigen. Acquired immunity is composed of humoral immunity and cellular immunity. Humoral immunity mainly is the antibody secreted by B cells. The antibody is a "Y" shaped small protein which is like a man opens his arms. The end of the “Y”, which is also the location of the hands, is the site where the antibody specifically binds to the antigen. Cellular immunity is mainly composed of CD4 T cells and CD8 T cells. CD8 T cells are responsible for killing the abnormal cells called Cytotoxic T Lymphocyte. CTL identify the abnormal cells with its MHC I receptor by T Cell Receptor. Almost all cells express MHC I which is like the “Review mechanism” of cells. The cells randomly pick out some proteins in the cell and break them down into 10 amino acid short peptide chains to combine with MHC I receptor to present to the surface of the cell membrane for CTL Review. If the cells are abnormal, for example, being infected with the virus or cancerization occurred, they will generate non - self - contained proteins. Once there were MHC I receptors of non - self - contained proteins recognized by some CTL through TCR recognition，the CTL attack will be triggered.

What is the structure of TCR?

The reason why all the antibody and CTL can recognize abnormal cells is that they can identify by different mechanisms. Antibody may combine with any protein, besides MHC I receptor, in the way of recognizing by the spatial structure of proteins. And CTL identifies them in the way of recognizing by the polypeptide chain transferred by MHC I which is mainly amino acid sequence recognition. Antibody cannot go through the cell membrane, so identify by the antigen on the surface of the cell is the only way. Although MHC I is also on the surface of the cells, the polypeptide chain transferred may be original from any proteins. That’s why CTL can identify the antigen in the cell.

What is CAR T?

Antibodies can bind to proteins on the surface of cancer cells, such as Rituximab and Trotozumab which are all applied on the treatment for cancer successfully. These mAbs inhibit the proliferation of cancer cells by binding to receptors on the surface of cancer cells. However, sometimes we want to go further that not only binding to the receptors of cancer cells but to kill those cancer cells all. But antibodies themselves are not able to kill cells meanwhile the CTL is able to clean off cancer cells in the way of receptor combing with TCR and MHC I.

In order to give antibodies the ability to kill cells，some put up forward with a genius idea that the combining part of TCR and MHC I may be knocked off and transform to be the combining part of antibodies and antigens. So this kind of T cells “chimeric antigen receptor” is called CAR T which can not only identify cancer cells like antibodies but also kill them like CTL. This is really an adventurous idea because antibodies and TCR have two parallel mechanisms of immune system which might be not practicable to “mixed-use”. However, when they actually work out these CAR T cells, a miracle happened. Those CAR T cells really kill cancer cells as they have eyes on the specificity of the antibody instead of the specificity of TCR. Of course, in order to improve the efficacy of medicine, the researchers added some costimulatory units to the original CAR receptor, such as CD28, 41BB and so on. And that’s the original second generation and third generation CAR.

What needs to be explained is that the antigen of cancer cell of target spot of CAR T may not only expressed by cancer cells, for example, the basis that CD19 antigen used for treating acute lymphoblastic leukemia is the B cells expressed. Therefore, the normal B cells of the patients treated with this CAR T are also slaughtered. This kind of side-effect is called “on target, off tumor effect”. As a result, you may be wondering why not target cancer-specific antigens so that side effects are avoided? This is because cancer cells are mutated from normal cells, and most antigens are shared with normal cells so that cancer cells rarely mutate to produce new membrane proteins. As to the question whether the patient will be lacking of B cell aplasia for a long time? The answer is No since human hematopoietic stem cells continue to produce immune cells; B cells can recover as long as CAR T cells die out. Patients can maintain immunity by injecting antibodies, but it is not clear how long this B-cell deficiency will last. So generally speaking, the use of self-antigen has side effects, but this side effect is acceptable.

CAR T is a genius idea, but it is not the only way to kill cancer cells. The binding of antibodies to cancer cells can trigger Antibody Dependent Cellular Cytotoxicity. In addition, the antibody can be transformed into Antibody Drug Conjugate, Bispecific T Cell Engager to improve the lethality. The high cost of CAR T also deterred patients. However, CAR T has unique advantages that make it irreplaceable. CAR T has the greatest advantage of having a very high response rate .CAR T has a response rate of up to 90 % for acute leukemia，compared to BiTE 66% and ADC merely 19%. In addition, CAR T can also be transformed into multiple target cells which is impossible for antibodies. So, CAR T has very broad prospects for cancer treatment.