The latest research progress of car-t cell therapy

Source: Biovalley 2018-06-01 May 31, 2018 / bioun / -- car-t (chimeric antigen receptor T-cell immunity), i.e chimeric antigen receptor T-cell immunotherapy It is a new cell therapy which has been used in clinic for many years It has a significant effect on the treatment of acute leukemia and non-Hodgkin's lymphoma, and is considered to be one of the most promising tumor treatment methods Just like all technologies, car-t technology has also experienced a long evolution process It is in this series of evolution process that car-t technology gradually matures The key point of this new treatment strategy is to recognize the artificial receptor called chimeric antigen receptor (car) of the target cell, and after gene modification, the patient's T cell can express the car In human clinical trials, scientists extract some T cells from the diseased human body through a process similar to dialysis, and then genetically modify them in the laboratory to import the gene encoding the car, so that these T cells can express the new receptor These genetically modified T cells proliferate in the laboratory and are then infused back into the diseased body These T cells use their expressed car receptors to bind to molecules on the surface of the target cells, and this binding triggers an internal signal generation, which then activates these T cells so effectively that they quickly destroy the target cells In recent years, car-t immunotherapy is not only used to treat acute leukemia and non Hodgkin's lymphoma, but also used to treat solid tumor, autoimmune disease, HIV infection, transplant rejection and other diseases after improvement, which has a broader application space Based on this, in view of the latest progress of car-t cell therapy, this article makes an inventory for readers 1 New breakthrough of car t therapy! Nat Med back to back published two research teams found a new way to avoid cytokine storm Two research teams from the United States and Italy proposed a new way to avoid the occurrence of cytokine storm (CRS) in the treatment of leukemia patients with car T-cell therapy In the first study, researchers from the memorial Sloan Caitlin cancer center in New York developed a mouse model to simulate the occurrence of CRS They found the key molecules involved in this side effect and successfully found a drug to inhibit CRS The second team found the same molecule using different animal models, but they did not inhibit this molecule, Instead, T cells are genetically modified to prevent this from happening at the source Two research results were recently published back-to-back in nature medicine In order to treat leukemia, scientists have developed a technology to modify the patient's T cells with chimeric antigen receptor (car) and then reinfusion, also known as adoptive cell transfer The whole process is called car T-cell therapy, which has been proved to be very effective in the treatment of leukemia However, there is a major obstacle to the use of CRS - almost one third of patients will have CRS, which requires extremely fine personalized treatment to avoid patient death Some patients also develop neurotoxicity These syndromes limit the use of this technique In the two latest studies, researchers have found new ways to overcome these problems In the first study, after creating animal models, researchers found that IL-1 is a key factor in CRS - and past studies have shown that this molecule is involved in inflammation Further studies have helped researchers find that a drug called anabolin can inhibit this molecule In the second study, the researchers found the same molecule, adding an inhibitory gene to car T cells to prevent CRS production 2 Haematologica: first time! Without pre chemotherapy, the new car t therapy can cure acute myeloid leukemia! Chimeric antigen receptor T cell therapy (car t therapy for short) was rated as the largest research breakthrough in 2017 by the American Society of clinical oncology This personalized gene therapy uses the patient's own immune cells to fight cancer At present, FDA has approved car T-cell therapy products to treat adult patients with diffuse large B-cell lymphoma, as well as children and young adults with acute lymphoblastic leukemia Now researchers at Moffett cancer research center are extending this revolutionary treatment to other cancers One disease that may benefit is acute myeloid leukemia (AML), the most common form of acute leukemia in adults More than half of AML patients will subside after chemotherapy But there are many patients with residual cancer cells that can tolerate chemotherapy and avoid the immune system, so they will relapse A new phase 1 clinical trial (THK) is studying the therapeutic effect of celyad's new car t therapy (cyad-01, genetically modified immune cells to express natural killer cell receptor) on leukemia According to a new case study published in Haematologica, a patient who underwent a bone marrow transplant after receiving cad-01 showed no signs of relapse nine months later 3 Cancer immune res: Car T-cell therapy has successfully eliminated metastatic colorectal cancer in mice In a new study, scientists from Thomas Jefferson University in Philadelphia, Pennsylvania, USA, studied at Adam E Under the leadership of Dr snook, human specific single chain variable region guided by GUCY2C was used as the basis of car targeting human expression of GUCY2C By detecting up regulation of activation markers, cytokine secretion and in vitro killing of cancer cells expressing GUCY2C, rather than GUCY2C deficiency, the researchers showed that rat car T cells targeting human GUCY2C could promote antigen-specific T cell activation In the homologous mouse model, the researchers found that GUCY2C car T cells can protect the lung metastasis of colorectal cancer in mice for a long time GUCY2C car T cells can recognize and kill the human colorectal cancer cells expressing GUCY2C, which makes the immune deficient mice transplanted with human tumor survive for a long time In general, the researchers found a car T-cell therapy specific to human GUCY2C in this study, which may develop into an effective therapy for metastatic colorectal cancer expressing GUCY2C 4 NAT Med: the new progress of car t therapy Carl J leads to find that the tolerance of biomarkers to autoantigens, which determines the efficacy of car T, leads to the failure of the human immune system to remove tumor cells In order to overcome this immune tolerance and make the tumor subside, researchers from the Department of pathology and experimental medicine of the University of Pennsylvania and the center of cell immunotherapy designed a chimeric antigen receptor (cars) to treat patients with chronic lymphocytic leukemia (CLL) They found that some patients' tumors had subsided, but most patients did not respond However, there has not been a comprehensive analysis of car T cells from patients to determine the mechanism of treatment success or failure To this end, the researchers conducted genomics, phenotype and function evaluation and found the decisive factors for the success of the treatment The relevant research results were recently published in nature medicine The research co-author was Professor J Joseph melenhorst, and Carl h June, a pioneer of tumor cell immunotherapy, participated in the study Transcriptome analysis showed that car T cells in fully responsive patients were rich in memory related genes, including IL-6 / STAT3 signal, while car T cells in unresponsive patients were up-regulated in signal related to effector cell differentiation, glycolysis, depletion and apoptosis Continuous tumor regression was associated with an increase in the number of CD27 + CD45RO – CD8 + T cells prior to the production of car T cells, which are memory like cells These highly functional car T cells from patients produce STAT3 related cytokines, while IL-6 in serum is related to car T cell proliferation Inhibition of IL-6 / STAT3 can eliminate the proliferation of car T cells The researchers further studied the mechanism, and found that CD27 + PD-1 – CD8 + car T cells with high expression of IL-6 receptor mean effective treatment, which is responsible for controlling the progress of tumor 5 Cell weighs! Recently, scientists from MIT developed a universal car T cell system for cancer treatment The related research was published in cell The article is entitled "universal childhood antigen receptors for multiple and logical control of T cell responses" This research highlights the development of a separate, universal, and programmable (supra) car system for T cell therapy; supra car can well regulate the activation of T cells to eliminate toxicity; supra car can sense multiple antigens and respond to fight against cancer recurrence; supra car can induce and control cell type specific signals T cells expressing chimeric antigen receptors (cars) are potential therapeutic drugs for cancer In order to expand the potential of car T system for cancer treatment, Professor Wilson W Wong and his colleagues from Boston University have developed a supra car system, which includes various upgrades, such as switching targets without reprogramming T cells, completely controllable activation of T cells, sensing multiple antigens and making logical responses These characteristics can be used to fight tumor recurrence, eliminate over activation and enhance the specificity of car T cell therapy The researchers tested the system in two tumor models and found that the system showed a wide range of anti-cancer capabilities, so they considered humanizing the system to reduce immunogenicity In addition, the researchers have extended an orthogonal supra car system, which can independently regulate different T cell subsets, indicating that this is a dual inducible car system 6 PNAs: a new breakthrough in the mechanism of car-t cancer immunotherapy a recent study shows that car-t immunotherapy can not only be used to treat blood diseases, but also to treat solid tumors One example is intractable brain cancer This study was conducted by Dr misty Jenkins and others from Walter and Eliza Hall Institute The study reveals the key mechanism of car-t therapy for rapid killing cancer cells and why it can cause serious negative effects Car-t therapy is a revolutionary immunotherapy, which uses engineered T cells to induce the immune system to kill cancer Currently, FDA approved this therapy in 2017 for the treatment of blood cancer, such as childhood leukemia and specific types of lymphoma 7 PNAs weighs! Researchers have developed a car-t cell immunotherapy system that can be controlled remotely! A research team has successfully developed a remote immunotherapy system based on ultrasound system, which can control the gene expression of living immune T cells non invasively and remotely, so as to identify and kill cancer cells Researchers believe that non-invasive remote manipulation of cells is essential for clinical transformation in animals and humans Using mechanical genetics, the team developed a new method for remotely controlling gene expression and cell activation