On Sep. Food and Drug Administration FDA approved Keytruda pembrolizum ab for the treatment of terminal or unrespectable melanoma patients who do not respond to other drugs, and Keytruda became the first drug approved by FDA to block the PD-1 cell pathway.
PD-L1 is abnormally expressed in different malignant tumors, such as squamous cell carcinoma in lung, esophagus, head and neck, and in other types of malignant tumors, for example, ovarian cancer, bladder cancer, malignant melanoma, and glioma. Structurally, PD-L2 is similar to PD-L1, both being type I transmembrane proteins which include a signal peptide, an IgV-like region, an IgC-like region, a stem region, a transmembrane region, and a cytoplasmic region.
Tumor cells in solid tumors can up-regulate the expression of PD-L1, and then provide an inhibitory signal which down-regulates the activated T cells, ultimately turning off immune response and inducing immune tolerance. The survival rate of patients with high PD-L1 expression level was significantly decreased, which was associated to and consistent with most reports describing the association of high expression level of PD-L1 on most tumor with poor prognosis. In addition to expression in malignant melanoma, PD-L1 also was expressed in other different tumors, including glioblastoma, pancreatic cancer, ovarian cancer, breast cancer, renal cell carcinoma, head and neck and esophageal squamous cell carcinoma, and non-small cell lung cancer, and high expression of PD-L1 on tumor cells is associated with poor prognosis.
The theory of chimeric antigen receptor T lymphocyte technology CAR-T is that T cells modified by a chimeric antigen receptor can specifically recognize tumor-associated antigens, which makes targeting ability, killing activity and persistence of effector T cells higher than that of the conventionally used immune cells, and can overcome the local immunosuppressive microenvironment of the tumor and break the host immune tolerance state.
Normally, the body's T lymphocytes recognize the target cells through the T cell receptors on their surface. This recognition is specific. That is, a T lymphocyte only recognizes target cells with specific antigens, and these specific antigens are presented to T lymphocytes under the action of special molecules after being processed in cells.
These antigen-presenting molecules are either present on the surface of antigen presenting-cells or on the surface of target cells, which means that the activation of the T cell requires not only specific recognition antigen but also costimulatory signals. In tumors: 1 Tumor cells must be presented by antigens before they are recognized by T cell receptors specific signals ; 2 There's a second signal involved As shown in the diagram, CD28 participates , and CD28 must also be activated.
After the first and second signals are both activated, T cells can only kill the tumor.
STEM OF ASCLEPIUS Original (PDF)
However, tumors realize immune escape mainly from two aspects: 1 The antigen presentation mechanism of tumor cell is down-regulated or even lost HLA-negative , which causes T cells to fail to recognize tumor cells; 2 Many tumor cells are abnormally highly expressed PD-L1 molecules, which activates PD-1 molecules on the surface of T cells, and leads to the depletion of T cells function and even death of T cells.
Based on this situation, scientists have proposed the concept of constructing a chimeric T cell receptor now commonly referred to as a Chimeric Antigen Receptor.
Chimeric Antigen Receptor CAR is mainly composed of two parts, one end of which is located outside the cell that can specifically recognize an antigen on the surface of cancer cells, the other end of which is located in the cell that contains a signal activation element such as a T cell receptor, Zeta chain , which plays a role in transmitting signals and activating T cells. Therefore, the T-lymphocytes CAR-T cells expressing CAR can prevent the T cell receptor from recognizing the restriction of target cells, and play a killing role in targeting cancer cells.
Construction of CAR-T can make T cells recognize and kill cancer cells without restriction, and bring the inherent killing function of T cells into full play. However, most of these CAR-T cells are still in the research stage, and their the clinical effects need to be confirmed. Therefore, it is necessary to design and construct novel CAR-T cells to achieve breakthroughs in the treatment of solid tumors. The main technical problem to be solved by the present invention is to provide a PD-1 CAR-T cell and preparation method and application thereof, wherein the obtained PD-1 CAR-T cells can specifically recognize and bind to tumor cells with high expression of PDL-1 protein and can be used in the preparation of drugs for the prevention and treatment of tumor diseases.
In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings used in the description of the embodiments will be briefly described below.https://cessformeltrab.tk
Asclepius Medical Research and Reviews
It is obvious that the figures in the following description are only some embodiments of the present invention. For a person of ordinary skilled in the art, other drawings can be obtained based on these figures without any creative work. The figures include:. The technical solutions in the embodiments of the present invention are clearly and completely described below.
It is obvious that the described embodiments are only a part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by a person skilled in the art without any creative work is within the scope of the protection of the present invention. The vector was transformed into Stbl3 Escherichia coli strain, and screened by ampicillin to obtain positive clones, then the plasmids were extracted and identified by restriction enzyme digestion, and PRRLSIN-PD-1 lentiviral transfection vector was obtained, the structure of which is as shown in FIG.
Solution B: adding the following plasmids, respectively, and mixing: Total volume of solution A: 6. But Asclepius, who grew up to be the Greek god of medicine, was born into an all-too-human story of domestic violence and could have used his staff before birth to protect his mortal mother, Coronis, from his divine father, Apollo, the sun god.
Even after Asclepius acquired his staff and single serpentine assistant, mayhem followed him most of his life. The birth story goes like this: Apollo went on a trip. Coronis, already pregnant, fell in love with another man. The two became a duo so dynamic that not enough people were dying to satisfy Pluto, the god of the underworld. Eventually, he complained to Zeus, who threw a thunderbolt at Asclepius to kill him.
Apollo, again enraged, slew the Cyclopes who made the thunderbolt.
STEM OF ASCLEPIUS PDF Original - Free E-Book Download
Though officially dead and hanging in the sky as star art, Asclepius visited his temples all over Greece. In a kind moment, Apollo urged them to accept help from his son. The senate took two years to call Asclepius sound familiar? It has been the symbol of healthcare providers for 2, years.
In the mid-nineteenth century, Americans got a little confused between medicine and trade somewhat characteristic of us, huh?
The confusion actually started in the fifteenth century when the German publisher Johann Froben, not erroneously read on Hermes above , used the caduceus on his books, only some of which were on medicine. It went to China to become part of the Chinese horoscope and rule over the year actually or , depending.
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