CAR-T Therapy as Reborn Chimera to Cure Cancers

In Greek mythology, the Chimera was a fire-breathing she-monster with a lion's head, a goat's body, and a dragon's tail. And nowadays, chimera has been reborn as a healer instead of a killer—chimeric antigen receptor T cell (CAR-T) therapy is saving lives suffering from hard-to-treat cancer.

Antibodies can bind to proteins and recognize foreigners through the spatial structure of the protein on the surface of cancer cells. It has a powerful and efficient capability on recognition, but is not able to kill cancer cells. While T cells have a powerful killing function, however, cancer cells that survive natural selection can "deceive" T cells and avoid being recognized by them. So, wouldn’t it be a perfect plan if the recognition function of antibodies be combined with the killing function of T cells?

CAT-T therapy is such a chimera, which combines antibodies and T cells together. As one of the skeleton staffs in the department of immunotherapy, CAR-T therapy has undergone four great improvements and has made great progress in the treatment of leukocytes and other hematological malignancies.

The First Generation of CAR Technology

The structure of the intracellular segment of the first generation of CAR-T cells is relatively simple, mainly composed of the immunoreceptor tyrosine-based activation motif (ITAM) of the CD3 molecule ζ chain. And it lacks the second signal necessary for T cell activation, that is, the costimulatory signal. Therefore, the first-generation CAR-T cell must interact with costimulatory molecule ligands on the surface of the antigen-presenting cells, thereby obtaining natural costimulatory signals, which makes it less efficient in activation, obtaining very limited curative effect in clinical applications.

The Second Generation of CAR Technology

On the basis of the first generation, the second generation of CAR-T cells adds an ITAM from the costimulatory molecule CD28 or CD137 to the intracellular segment, and after the binding of the extracellular antigen recognition region and target antigen, T cells can obtain antibody stimulation signals and costimulatory signals at the same time. This makes the activation ability of the second generation far stronger than the first, which shows surprising therapeutic effects in clinical treatment. But here is another problem—the activation signal transmitted by CD28 is stronger, which enables T cells to achieve a high killing activity in a shorter period of time; while the activation signal transmitted by CD137 maintains for a longer period of time. Since the second-generation CAR-T cells mostly used retroviruses as vectors, and the gene fragments that can be accommodated and carried are limited, it is difficult to simultaneously transfect the ITAMs of both CD28 and CD137 into T cells. Therefore, researchers have to choose between a stronger activation intensity and longer activation persistence.

The Third Generation of CAR Technology

The third-generation CAR-T cells use lentivirus as a transfection vector, which can carry larger gene fragments into T cells, that’s to say, the intracellular segment can often contain 2 or more ITAMs. However, some studies have shown that the killing activity of the third-generation CAR-T cells has not been significantly improved. This may be because the activation signal generated by an ITAM of a costimulatory molecule in the T cells has already reached the threshold, so simply adding ITAM area in quantity will not further enhance the activation effect of CAR-T cells.

The Fourth Generation of CAR Technology

The fourth-generation CAR-T cells are known for their precision. The design of this generation is mainly considered from the perspective of precise treatment of tumors and other diseases. Another improvement is to control the survival time of CAR-T cells, which usually can survive in patients for more than 10 years and may attack normal cells by recognizing tumor-associated antigens on their surface. Therefore, some researchers have added controllable suicide genes to the structure of CAR, so as to control the survival time of CAR-T cells in human body. What’s more, CAR-T cells were mainly used for the treatment of hematological tumors, and no significant results have been seen in the treatment of solid tumors. This is mainly because CAR-T cells often cannot enter the tumor. Some researchers have added the receptor structure of cytokines or chemokines to the CAR design, thereby increasing the infiltration of T cells in tumor tissues, achieving the effect of enhancing the killing of solid tumors.

CAR-T therapy has been proved to be a potential treatment for tumors and has been a hot topic among global researches. Aiming at accelerating the process of drug or therapy development, Creative Biolabs offers custom service covering the entire CAR-T therapy development steps to best suit any technical, program and budget requirements.