What will happen when CAR-T combine with gene therapy or stem cell therapy?

Posted by alexboc on January 2nd, 2020

The key to CAR-T strategy is the recognition of target cells by artificial receptors called chimeric antigen receptors (CAR), and after genetic modification, patient T cells can express this CAR. In human clinical trials, scientists extract a number of T cells from a patient's body through a dialysis-like process, and then genetically modify them in the laboratory to introduce the gene that encodes the CAR so that these T cells can express this new receptor. These genetically modified T cells proliferate in the laboratory and are then perfused back into the patient, binding to molecules on the surface of target cells using the CAR receptors they express, and this binding triggers an internal signal generation, which then activates these T cells so strongly that they rapidly destroy the target cell.

No refractory blood cancer can escape when gene therapy combines with CAR T therapy.

A new preliminary trial suggests that a gene therapy that modulates the immune system may give hope to patients with blood cancer who are resistant to standard treatment. This type of cancer is called multiple myeloma and originates from certain white blood cells.

The disease is currently incurable, but there are some treatments that can help people live with the disease for many years. However, most people's condition will eventually get worse, while some people simply do not respond to any existing treatments. The new study involved 33 such patients who usually received 7 to 8 different treatments and ended up having no choice.

Therefore, the researchers tried a recently developed method to exploit the anti-cancer potential of the immune system: CAR T cell therapy. It involves extracting T cells from the immune system from the patient and then genetically engineering them to have a chimeric antigen receptor, CAR. Dr. James Kochenderfer, a senior researcher at the study, said that this allows T cells that are re-injected into the blood to recognize and attack cancer cells in a more powerful manner. CAR T cell therapy has been approved for the treatment of leukemias and lymphomas - two other types of blood cancer. But this method is not universal.

Kochenderfer, a scientist at the National Cancer Institute, explains that CAR must target specific proteins on cancer cells. In this study, his team used CARs to identify a protein called BCMA on multiple myeloma cells. The researchers found that the treatment seems to be safe. However, it has short-term side effects for all patients, but luckily, these side effects are controllable, and there are early indications that the therapy is effective. Most patients (85%) found that their tumors had shrunk or disappeared.

According to Kochenderfer, this treatment is completely different from other myeloma treatments. Myeloma, which is resistant to other therapies, may respond to BCMA CAR T cells.

Incredible effects achieved when CAR technology meets stem cells.

Human pluripotent stem cells include embryonic stem cells and induced pluripotent stem cells. In recent years, immune cells derived from human pluripotent stem cells have become hotspots in the field of regenerative medicine research. The pluripotent stem cell-derived immune cells include natural killer cells and phagocytic and lymphoid cells, especially T cells, which are often used as immune cell therapies to treat cancers that are difficult to treat.

In addition, due to the emergence of chimeric antigen receptor (CAR) technology, the clinical use of CAR-T cells has successfully stimulated its new therapeutic potential, so future researchers are expected to use CAR technology to generate CAR engineered immune cells through pluripotent stem cells. Recently, a review article published in the International Journal of Molecular Sciences, scientists from Handong Global University summarized the pluripotent stem cell-derived immune cells and CAR technology through research, and the researchers provides new ideas and ways to develop a new generation of immune cell therapy.

Immune cell therapy is a new type of therapy that is expected to treat cancer types that are difficult to treat with conventional therapies. Now scientists have developed a variety of immune cell therapies. In addition to developing immune cells that can be used as a therapy, making immune cells even more safe, promising, and efficient in use is also critical for clinical applications. To achieve this, researchers are now using CRISPR and CAR technology to transform immune cells. The CRISPR/Cas9 tool provides a simple method of generating a variety of genetic modifications. So far, 11 gene-edited CAR-T cell clinical trials have been registered, while CAR technology enables immune cells to detect tumor-specific antigens. There are currently 10 CAR-NK and 220 CAR-T cell clinical trials registered. 

Scientists are developing CAR-T cells with even more potentials.

Recently, scientists from Japan and the United States did a joint research to develop new and efficient CAR-T cells, which can carry herpes simplex virus into the mediation and sub-co-stimulatory signal domain. Moreover, these novel CAR-T cells exhibit even higher potentials. As we mentioned above, chimeric antigen receptor (CAR) is a hybrid molecule composed of an antigen binding protein and a signal transduction domain. CAR (CAR-T cells) expressed by artificial T cells is expected to be a kind of useful tool to treat a variety of diseases including cancer. Adding a co-stimulatory signal domain (CSSD) to the CAR is critical for regulating the activity of CAR-T cells. However, current research still haven’t specified the interaction between different types of CSSDs, effector functions, and CAR-T cell characteristics. 

To elucidate the interactions, the researchers analyzed the function of effectors, the differentiation of memory T cell subsets, depletion, and the energy metabolism mechanisms of CAR-T cells carrying different CSSDs, compared to CSSD-derived CSSD or in the case of 4-1BB-derived CSSD (which is used for CAR-T cell development). The results of this study indicate that CSSD in CAR is a key determinant of the function and characteristics of CAR-T cell effectors. CSSD is very important for later scientists to design high-potential CAR-T cells. The new CAR-T cells developed by the researchers have high-efficiency HVEM-derived CSSD, which may help develop more potent CAR-T cells.

Conclusion

Generally speaking, to enhance the therapeutic effects and the response rate of CAR-T therapy, stem cell molecules and inhibitors are used in combination. Currently, these popular inhibitors being intensively researched and applied are wide-ranged, including pkd inhibitor, lpxc inhibitor, eribulin, and dubs inhibitor.

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