The latest research progress of car-t cell therapy (phase 10)

November 30, 2019 / BIOON / -- car-t (chimeric antigen receptor T-cell immunotherapy), 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 and heart disease and other diseases after improvement Based on this, in view of the latest progress of car-t cell therapy, this article makes an inventory for readers 1 Science: glutamine blockers enhance antitumor response and are expected to be used in car-t cell therapy Doi: 10.1126/science.aav2588 in a new study, researchers at Johns Hopkins University in the United States found that a compound they developed to block glutamine metabolism can delay tumor growth, change tumor microenvironment and promote long-term high activity antitumor activity Production of T cells The relevant research results were published online in the journal Science on November 7, 2019 The title of the paper is "glutamine blockade causes diverse metallic programs to achieve more immune evaluation" The chemical structure of glutamine antagonist Don and its precursor drug jhu-083 The picture is from translational oncology, 2019, DOI: 10.1016/j.tranon.2019.05.013 As a "prodrug" of glutamine antagonist don, this compound named jhu083 (also known as jhu-083) produces its active form (Don) after enzymatic reaction in vivo and plays a role in tumors In theory, given the key role of glutamine in the metabolism needed to promote tumor crazy growth, this compound may be able to be used to treat a variety of cancer types, said Jonathan Powell, Ph.D., co-author of the paper and deputy director of cancer immunotherapy Research Institute at Kimmel Cancer Center, Johns Hopkins University These researchers found that in a variety of different mouse cancer models, jhu083 treatment can significantly reduce tumor growth and improve survival rate by destroying tumor cell metabolism and its impact on tumor microenvironment In many mice, treatment with jhu083 alone can lead to a permanent cure This cure is due to the natural antitumor immune response activated by this metabolic therapy When these mice were injected with new tumors to cure cancer free mice, they found that almost all mice had immune rejection of the new tumors, which indicated that jhu083 treatment had a strong immune memory, so that they could recognize and attack new cancer They also treated these mice with jhu083 and anti-PD-1 immunosuppressive checkpoint inhibitors, a class of immunotherapeutic drugs that can relieve the inhibition of cancer cells on T cells "At first, we thought we needed to use the two drugs in turn to avoid any potential effects of metabolic therapy on immunotherapy," Powell said However, it is worth noting that this combination treatment has proved to work best when we give them at the same time " Compared with the use of only anti-PD-1 immunocheckpoint inhibitors, the use of both drugs can enhance their antitumor effect 2 Cell subjournal: label car-t cells with imaging tracer, which can track car-t cells in real time in vivo Doi: 10.1016/j.ymthe.2019.10.007 in car-t cell therapy, T cells extracted from patients themselves are genetically modified and transplanted back to patients to find and kill cancer This type of immunotherapy has led to some cancer treatment changes, but once car-t cells enter patients, where will they go? How do doctors know that they have successfully reached their destination and continue to fight the disease weeks, months or even years later? In a new study, researchers from the University of Pennsylvania found a way to track car-t cells in the body They genetically engineered car-t cells to carry molecular tags so they could monitor them in animal models using positron emission tomography (PET) The relevant research results were recently published in the journal molecular therapy, and the paper title was "imaging car T cell traffic with edhfr as a PET reporter gene" Car-t cells were genetically modified and labeled with bacterial protein edhfr (called PET reporter gene) and then transplanted into mouse models After injecting the mice with trimethoprim, car-t cells lit up, allowing the researchers to track them in real time through PET / CT scans Moreover, since the molecular tags carried by these car-t cells are gene encoded, once they proliferate, the newly generated cells also carry the same PET imaging tag PET / CT images of these animal models show that car-t cells accumulate in the spleen seven days later and begin to accumulate in antigen-positive tumors by thirteen days Sellmyer said the findings suggest that car-t cells may have early and late "harbors" and that they have learned a lot about their location and number in the human body The researchers were also surprised to find that their radiotracer was extremely sensitive to detect car-t cells in tumors - 11000 cells per cubic millimeter 3 Cell: great progress! In a new study, researchers from Glaston Institute and xyphos Biosciences, Inc described a new technology to attack HIV infected cells This new technology is a new and improved version of car-t cell immunotherapy In recent years, this therapy is famous for its success in resisting blood cancer By improving its coverage and versatility, this new technology, called convertiblecar-t, has shown great potential in many therapeutic areas, especially in the fight against HIV, because it can be used to reduce the stock of infected cells that persist in HIV infected people during art The relevant research results were published online in the cell Journal on October 24, 2019 The paper title is "attacking late HIV with convertiblecar-t cells, a highly adaptable killing platform" The corresponding author of the paper is Dr Warner C Greene, director of HIV cure research center, Glaston Institute Picture from cell, 2019, DOI: 10.1016/j.cell.2019.10.002 Traditional car-t cells have been shown to be very successful in inducing remission of blood cancers such as lymphoma and childhood leukemia But as a treatment against HIV infection, traditional car-t cells are not perfect "Some of the disadvantages of traditional car-t cells are that they are genetically engineered to target individual molecules on the surface of cancer cells, and once injected into patients, they cannot be controlled," said Eytan Herzig, the first author of the paper and a scientist at Greene's laboratory Xyphos bioscience has overcome these shortcomings by isolating targeted antibodies from cytotoxic killer cells Dr David W Martin, the company's chief scientist, explained: "we have genetically modified the ccar-t cells so that these T cells can express the human receptor protein NKG2D on their surface, which is slightly modified." This modified NKG2D receptor, when combined with its partner, can turn these T cells into effective killers Its partner is a protein called MIC-A, which has been tailored and modified by scientists from xyphos biosciences to specifically bind to the modified NKG2D receptor on the surface of ccar-t cells The scientists then fused it with the base of the targeted antibody to build a product they call micabody Therefore, this targeting micabody tightly and uniquely binds to ccar-t cells Herzig and Greene have been testing anti HIV antibodies known as broad neutralizing antibodies (bNAb) in the laboratory to remove latent HIV virus libraries In collaboration with scientists from xyphos Biosciences, they built micabody (called mic bNAb) based on bNAb, and tested the combined use of ccar-t cells and Mic bNAb in various laboratory analyses In the laboratory, Herzig tested these combinations with a variety of CD4 T cells (natural targets of HIV) infected with various HIV strains In particular, he used cell preparations derived from the human tonsil; tonsil T cells are known to be a latent HIV virus library in HIV infected people He wants to make sure that the combination of ccar-t / MIC bNAb kills T cell types that represent a latent HIV virus library The results were significant: the combination of ccar-t cells and Mic bNAb specifically killed the infected CD4 T cells, but did not kill the uninfected cells They kill infected cells only when used in combination with MIC bNAb, however, neither when used alone nor in combination with micabody, which does not target HIV They killed CD4 T cells that had been infected with a variety of HIV strains in the laboratory When used in combination with MIC bNAb targeting HIV and micabody targeting cancer cells, ccar-t cells can effectively kill cancer cells mixed in the same cell culture and HIV infected cells In other words, ccar-t cells precisely demonstrate the versatility and specificity it aims to achieve Finally, Herzig and Greene tested whether the ccar-t / MIC bNAb platform could attack the latent HIV virus library in the blood of HIV infected people receiving ART treatment To make these cells visible to ccar-t cells, they first activated the cell cultures with powerful compounds called "latency reversal agents." Within 48 hours after exposure, more than half of the activated HIV target antigen expressing cells were removed Greene concluded, "this platform has a bright future." 4 UCLA uses dual specific car-t cells to conduct human clinical trials news source: UCLA opens car t