Blog 8: T-Cell Therapy

For many years, researchers have been looking for new, more effective ways to treat cancer. One of these new ways is through the use of genetically altered T-lymphocytes. One type of cancer that might possibly be treated with this new therapy is large B-cell non-Hodgkin lymphoma. Another type of lymphatic cancer, lymphoblastic leukemia, can also be potentially treated using this method, but less will be discussed about this type of cancer. B-cell non-Hodgkin lymphomas are tumors that develop in the lymphatic system. As such a characteristic sign of this cancer is the presence of enlarged lymph nodes, where the tumors often develop. Other signs and symptoms may include abdominal pain or swelling, chest pain, persistent fatigue, fever, night sweats, and unexplained weight loss. The cause of this form of cancer remains relatively unknown, but it is thought to be linked to the production of abnormal lymphocytes, in particular B-lymphocytes. There are forms of non-Hodgkin lymphomas that are caused by T-cells, but this form is not currently treated using T-cell therapy. Researchers suggest that a problem occurs in the body that interrupts the normal life cycle of the B-lymphocytes, prohibiting the old ones from dying in a timely manner. As a result, a build-up of lymphocytes occurs, causing a tumor to form. Researchers are not sure why this happens, although they noticed that this form of cancer occurs primarily in immunocompromised or older individuals, so there may be some link.

As mentioned above, T-cell therapy involves the use of genetically altering T-cells to provide enhancing cancer cell killing ability. This is performed by taking a sample of blood from the patient and separating the T-lymphocytes from the blood. The T-lymphocytes are then taken to a laboratory, where they are genetically modified to have chimeric antigen receptors (CAR), which help the T-cells to better recognize the specific cancer cells they are designed to fight. When the T-cells recognize the antigen on the cancer cell (usually CD19), they become activated and release toxins and cytokines to eliminate the cancer cells. However, this poses a few problems in the body. For example, this massive release of cytokines can cause cytokine release syndrome, which is marked by headache; fever; chills; severe nausea, vomiting, diarrhea; severe muscle or joint pain, shortness of breath, low blood pressure, and fast heart rate. These symptoms have shown to be relatively mild, but they can be life-threatening in severe cases. Some neurological events could also take place after treatment. One of the reasons why this treatment is still used is because it is better at preventing the return of cancer after remission than other forms of treatment, such as chemotherapy or radiation. This is because the CAR-T cells remain active in the body for a prolonged period of time, ready to recognize and activate at any given moment. However, this is also one of the reasons why the side effect can be so severe.

Researchers at the Ludwig Institute for Cancer Research might have found a possible solution to this problem. They suggest that the best possible way to prevent cytokine release syndrome is to genetically alter the chimeric antigen receptors so that they can be inactivated by small molecules. There are three main parts to the chimeric antigen receptor. The external part of the receptor recognizes the antigen. The two internal parts are CD3-zeta, which is necessary for activation, and CD28, which supports the proliferation of the cell. To make the CAR-T cell become able to inactivate, researchers found that they could put the CD3-zeta portion of the receptor on one molecule and the antigen-recognizing portion on another, with a chain that could link the two molecules together and make them functional. If a certain molecule was introduced to the system, it would prevent the two molecules from binding, effectively inactivating the T-cells. Due to the potentially dangerous side effects of this therapy, it seems that the best option would be to restrict use until absolutely necessary, meaning when other treatments have failed. If used as a treatment, it would also be beneficial to implement the molecule-inhibiting option of the CAR-T cells.