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A variety of tumor immunotherapies that activate T cells are effective in treating many types of cancer. However, due to the existence of the blood-brain barrier, immune cells cannot effectively infiltrate brain tumors, which is also an important reason why immunotherapy is difficult to effect on glioblastoma.


The blood-brain barrier prevents immune cells from entering the brain. It is a protective mechanism that effectively prevents immune cells from infiltrating the brain and triggers fatal brain inflammation. In general, this protection is beneficial to the human body, but for glioblastoma patients, the presence of the blood-brain barrier prevents T cells from reaching the location of the tumor in the brain, thereby making glioblastoma a We usually call “cold tumors.”


In a paper published this week in Nature, scientists from the Egyptian Children’s Cancer Hospital and Texas, USA, reported a new way to promote the infiltration of T cells into the brain of mice. Will increase the response of glioblastoma to immunotherapy.


The reason why brain inflammation occurs in patients with encephalitis is because immune cells cross the blood-brain barrier and enter the brain, causing inflammation. Migration of T cells into the brain is accomplished through multi-step coordination.


The T cells in the blood must first adhere to the endothelial cells of the blood vessels. The process of adhesion is mediated by the binding of ligands on the surface of T cells to the adhesion molecules of ALCAM and ICAM-1 on the surface of endothelial cells. These adhesion molecules are overexpressed during encephalitis formation, and binding of ALCAM to the T cell ligand CD6 prevents T cells from continuing to migrate forward in the blood vessels, after which ICAM-1 and VCAM-1 are aligned with the surface of the responding T cells. Body combination.


When the binding of the adhesion molecules reaches a certain threshold, the T cells migrate to the gap between the endothelial cells and enter the brain from the blood vessels.


However, in glioblastoma, the expression levels of ICAM-1 and VCAM-17 in endothelial cells are very low due to abnormalities in the vascular structure in the brain. If you can simulate the specific state of patients with encephalitis and strengthen the adhesion of T cells to endothelial cells in patients with glioblastoma, it is possible to cause more T cells to migrate into the brain of patients.


The researchers found that endothelial cells in patients with glioblastoma have ALCAM overexpression, so they believe that by transforming T cells to bind to ALCAM, it is possible to promote T cell migration into the brain.


Next, the researchers designed a synthetic ligand HS-CD6 derived from CD6-based ALCAM and introduced the relevant gene into the genome of T cells using a retroviral vector. They then found that T cells expressing HS-CD6 ligands were able to bind tightly to endothelial cells expressing ALCAM. In vitro experiments have also found that this binding promotes migration of the T cells to endothelial cells.


Next, the researchers introduced a chimeric antigen receptor capable of recognizing HER2 on such T cells, and verified whether such cells can effectively enter the mouse brain and kill tumor cells. They found that the engineered T cells successfully infiltrated glioblastoma and completely cleared glioblastoma in the brain of most mice and maintained long-term remission. As a control, those T cells expressing only the chimeric antigen receptor could not successfully enter the mouse brain.


The study provides a more promising direction for the use of immunotherapy for the treatment of glioblastoma. But there are still many difficulties to overcome before entering clinical trials.


First, ALCAM can be expressed on many types of cell surfaces, including bone marrow cells, so subsequent studies must determine whether such cells can affect the normal function of these cells.

In addition, if T cells produce off-target effects that cause damage to normal tissues, it is possible to cause serious toxic reactions in a direct or indirect manner. Therefore, strategies that limit T cell activation and survival, such as the installation of a safety switch on T cells, may be able to control this toxic response. Although the survival of mice during the experiment is relatively long, it suggests that the method used in this experiment may not cause off-target toxicity, but this experiment did not study the survival time of these CAR-T cells in the brain, so it is now impossible Determine if these cells will have off-target effects.


Finally, it should be noted that crossing the blood-brain barrier is an important step in the systematic application of CAR-T therapy in the treatment of glioblastoma. However, even if this step is completed in the human body, it is not possible to overcome the glioblasts. Barriers to tumor treatment.

CAR-T cells encounter various immunosuppressive factors in the tumor microenvironment after entering the brain. Moreover, this immunosuppressive state is difficult to simulate in experimental animals. Therefore, although this type of cells can effectively eliminate glioblastoma in experimental animals, the predictive value for clinical trials is not very high. Probably later research will rely on combination therapies, such as the combination of PD-1/L1 inhibitors, to allow T cells not only to enter the brain, but also to survive long-term and maintain an effective anti-tumor response over time.

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