Risk and reward of chimeric antigen receptor T (CAR-T) cellular immunotherapy
For more than half a century, the treatment of cancer has largely relied on radiation therapy, surgery, chemotherapy, and drugs targeted for specific mutations in the tumor genome (increasingly used). Although these conventional therapies are effective in many patients, there is an urgent need to develop new therapies. Using the specific capabilities of the immune system to identify and destroy tumor cells is a new approach to cancer, namely immunotherapy. Chimeric antigen receptor (CAR) T cell therapy is one of cancer immunotherapy. This type of therapy is achieved by extracting the patient's own T cells and providing them with a receptor that targets the cancer cells, mass producing chimeric antigen receptor T cells in specialized equipment, and then injecting them into the patient to destroy the tumor cells. purpose. There are currently more than 100 chimeric antigen receptor CAR-T cell therapies in the world undergoing clinical trials, and the US Food and Drug Administration (FDA) is expected to approve the first CAR-T cell therapy in 2017. Safety issues with CAR-T cell therapy Although some CAR-T therapies have shown gratifying bright prospects, there have been many studies that have significant safety issues. In a recent clinical trial of Juno Therapeutics, five of the 68 treated patients died during the trial: three died of cerebral edema and the other two died of similar neurotoxins. It is not a company of Juno Therapeutics that has had a security incident on CAR-T cell therapy. The death of lymphoma patients who were treated at the Memorial Sloan Kettering Cancer Center in 2014 was also associated with CAR-T cell therapy. However, it is unclear whether CAR-T cell therapy triggers death in patients. The US FDA recently announced plans to establish a trial database to assess CAR-T cell safety and identify specific safety factors associated with clinical trials. There are also many toxic side effects associated with CAR-T cell therapy, the most serious of which is cytokine release syndrome (CRS). CRS, which occurs after activation of immune cells, is a reversible, potentially life-threatening disease mediated by the release of interleukin-6, tumor necrosis factor-alpha and interferon-gamma. CRS seems to exacerbate the condition of patients with high tumor burden, often accompanied by macrophage activation syndrome (uncontrolled proliferation and activation of macrophages), tumor lysis syndrome (sudden release of cell contents into the blood after tumor cell lysis) . Fortunately, the effects of CRS can be alleviated by reducing the amount of CAR-T cells injected and using anti-IL-6 receptor antibodies and steroids. A CAR-T cell therapy specifically targets the B cell-specific marker CD19 to treat hematological tumors, and the associated side effects are B cell hypoplasia or B cell loss, which can be alleviated by injection of gamma globulin. Some patients who receive non-CD19-targeted CAR-T cell therapy may develop fatal non-tumor-targeted toxicity. In addition to the proven side effects in clinical trials of CAR-T cell therapy, long-term persistent injection of CAR-T cells also increases the risk of insertional mutations (CAR insertion into human chromosomes, mutations that may occur over time); B cell aplastic anemia can lead to a decrease in the body's ability to fight infection. Clearly, if CAR-T cell therapy is a necessary treatment, we need to better understand the safety issues it accompanies. Improved CAR-T cell therapy Compared to treating blood tumors, CAR-T cell therapy for solid tumors is not that simple. It is necessary to send modified T cells into specific cells by means of good molecular targets, and suitable molecular targets are currently lacking. In addition, the dense matrix in the interstitial tissue inhibits immune cell infiltration. But we have reason to be optimistic. With the discovery of new antigens produced by tumor-specific mutations and the recognition of a new class of glycosylated Tn/sTN epitopes, there have been encouraging advances in the study of new targets. The Tn/sTN epitope formed by sialylation of the simplest O-glycan structure Tn antigen is widely expressed in tumor cells, and CARs specific for certain epitopes have demonstrated surprising antitumor activity in some studies. Innovative solutions for CAR-T cell therapy are being designed and developed to reduce the likelihood of adverse side effects and improve the timing of CAR-T cell activation. Several different types of suicide genes or safety switches have been incorporated into the design of CAR-T cells, including manipulation of CAR-T cell apoptosis via the induced caspase-9 system, and its safety is being evaluated in clinical trials. Kite's T cell receptor chimeric T cell (TCR-T) therapy MAGE A3/A6 is currently in clinical phase 2, and the indication is solid tumor. The indications for the TCR-T therapy JTCR016 of the US biopharmaceutical Juno Juno include WT1-positive non-small cell lung cancer and mesothelioma, which have also entered the phase 1/2 clinical stage. In addition, companies that use CAR-T cell therapy to treat solid tumors include Houston-based Bellicum Pharmaceuticals, which launched Phase 1 clinical trials for pancreatic cancer at the end of 2016. Researchers are working to assess the safety and efficacy of CAR-T cell therapy in combination with checkpoint inhibitors or other targeted therapies. Initial trial results show that some combination therapies have the potential to significantly improve the patient's treatment. For example, in combination with the CRISPR/Cas9 gene editing technology, CAR-T cell therapy has been greatly improved. Selective deletion of negative regulatory genes using CRISPR/Cas9 gene editing technology can increase CAR-T cell survival and anti-tumor activity, and CRISPR/Cas9 gene editing technology is also used to create CAR-T lacking endogenous T cell receptors. Cells, to reduce the likelihood of graft-versus-host disease, give greater potential to CAR-T cell therapy. More and more companies have joined the ranks of cancer immunotherapy research and development. The results accumulated over the years have witnessed the first wave of CAR-T cell therapy development. CAR-T cell therapy may make even more progress in research and development in the next decade. Especially in the attempt of tumor immunocombination therapy, CAR-T cell therapy volatilizes its unique role. As a hot tumor immunotherapy, the ever-improving CAR-T cell therapy is bound to surprise more and more cancer patients. Shanghai Chuangsai Technology has excellent performance, interleukin cytokines, fetal bovine serum, electrophoresis equipment scientific instruments, raw material drug standards, chemical reagents, cell culture consumables, Shanghai Chuangsai, mass products special promotions, welcome to inquire! DongGuan Lucky Pet Products Co., Ltd. , https://www.dgpetproducts.com