The possibility of CAR-T therapy for advanced lung cancer

 

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The possibility of CAR-T therapy for advanced lung cancer

In 2017, two CAR-Ts were approved by FDA, which became a breakthrough in cellular immunotherapy. That was the time when many patients began to pay attention to such magical T cell therapy. Recently, we learned that the authoritative doctor of lung cancer at the MD Anderson Cancer Center, the best cancer specialist hospital in the United States, has begun to use T cell therapy clinical trials as a treatment option for patients with advanced lung cancer.

Although the United States has a high degree of acceptance for clinical trials, lung cancer patients generally participate in targeted, immune or combination therapy trials.

According to the registration on Clinical Trial.gov, there are more than 500 relevant clinical trials in the world for CAR-T, but most of them are for hematological malignancies, and solid tumor research accounts for only about 1/4. In recent years, thanks to the rapid development of genetic modification technology and the relatively mature response to the side effects, the feasibility and safety of T-cell therapy has gradually been guaranteed, and the pace of progress to solid tumors has begun to accelerate, including lung cancer, the largest group of cancer patients. So far, 12 clinical trials of CAR-T therapy for lung cancer have begun. Next, let's take a look at the latest clinical trials of T cell therapy in the treatment of lung cancer.

CAR-T treatment for lung cancer

CAR-T, also known as Chimeric Antigen Receptor T-Cell Immunotherapy, first appeared in the 1980s and is similar to other immunotherapies. Its basic principle is to use the patient's own immune cells to clear cancer cells. The difference is that CAR-T technology allows the expression of specific antigen receptors on the surface of T cells by adding a foreign gene, and attacks the target cells under its guidance.

However, the antigen expressed by tumor cells, will also be expressed by some normal tissues. How to effectively combat "destructive molecules", while not injuring the "innocent people", has become the core of research for more than 30 years. After three generations of development, the CAR-T technology is gradually maturing, and the corresponding lung cancer clinical trials have begun to be carried out in an orderly manner. In June 2018, the MD Anderson Cancer Center partnered with Amgen to help the company advance research in two early projects: T cell therapy and small molecule projects. Among them, the clinical trial of CAR-T therapy has been approved by the US institutional ethics review committee, and began recruiting patients on June 30 this year. The therapy used in this test is called AMG 119.

During the treatment, the doctor will separate the T cells from the patient's blood, and genetically modify them in a specialized laboratory, and then return them to the patient by intravenous injection. Unlike other CAR-T therapies, the target of T cell targeting after AMG 119 "modification" is delta-like protein 3 (DLL3). According to previous studies, approximately 80% of small cell lung cancer patients have DLL3 positive expression in tumor tissues, while it is hardly expressed in normal tissues. There are also some drugs under research for this target, such as rovalpituzumab tesirine (Rova-T for short). The AMG 119 trial is expected to recruit 41 patients with small cell lung cancer who have had disease progression or relapse after using at least one platinum-containing chemotherapy regimen. In addition, Amgen also has a Phase I trial of AMG 757 for the treatment of small cell lung cancer. The target is also DLL3, which is recruited in hospitals in the National Medical Center of Hope City. This is just a small step for CAR-T in the field of lung cancer. In addition to DLL3, the researchers have also found other potential lung cancer-specific targets, such asROR1, PD-L1, HER2, MUC1, CEA, GPC3, MAGE-A10, MAGE-A4, NY-ESO-1, WT1 etc. Before CAR-T therapy, some other types of T cell therapy have shown therapeutic potential in the field of solid tumors, such as T-cell receptor engineered T cells (TCR-T). If CAR-T is configured to make T cells indiscriminate and strong, then TCR-T is to make T cells "play a specialty", so that T cells have higher affinity and strong ability to attack tumor cells. Therefore, CAR-T does not have a high requirement for T cells, while TCR-T requires "preferred culture".

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