Inventory: The latest research progress of CAR-T cell therapy

Source: Biology Valley Author: towersimperCAR-T (Chimeric Antigen Receptor T-Cell Immunotherapy), that is, chimeric antigen receptor T-Cell Immunotherapy
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This therapy is a new type of cell therapy that has appeared for many years but has only been improved and used in the clinic in recent years
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It has significant effects in the treatment of acute leukemia and non-Hodgkin's lymphoma, and is considered to be one of the most promising tumor treatment methods
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Like all technologies, CAR-T technology has also undergone a long evolutionary process.
It is during this series of evolutionary processes that CAR-T technology gradually matures
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The key to this new treatment strategy is the artificial receptor called chimeric antigen receptor (CAR) that recognizes target cells, and after genetic modification, the patient’s T cells can express this CAR.

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In human clinical trials, scientists use a process similar to dialysis to extract some T cells from patients, and then genetically modify them in the laboratory to introduce the gene encoding this CAR so that these T cells can express This new receptor
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These genetically modified T cells are proliferated in the laboratory and then infused back into the patient
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These T cells use the CAR receptor they express to bind to molecules on the surface of the target cell, and this binding triggers the generation of an internal signal, which then activates these T cells so strongly that they quickly destroy the target Cell
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In recent years, CAR-T immunotherapy has been used to treat acute leukemia and non-Hodgkin’s lymphoma.
After improvements, it has also been used to treat solid tumors, autoimmune diseases, HIV infection, and heart disease.
A wider application space
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Based on this, the editor will take an inventory of the latest progress made in CAR-T cell therapy for readers
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1.
Nature Sub-Journal: CAR-T cells with controllable heat can destroy solid tumors and prevent cancer recurrence doi:10.
1038/s41551-021-00781-2 A revolutionary immunotherapy called CAR-T cell therapy has been triggered Cancer treatment changes
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Scientists are constantly expanding the accuracy and capabilities of CAR-T cell therapy
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CAR-T cell therapy has been praised by patients, clinical researchers, investors and the media as a viable method for the treatment of certain cancers
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This is a new and vigorous field of immunotherapy.
At present, more than 500 clinical trials are analyzing CAR-T cell cancer treatments around the world
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CAR-T cell therapy involves genetically modifying T cells extracted from patients in the laboratory to express chimeric antigen receptors (CAR) that specifically recognize cancer cells, and then transfusing these customized CAR-T cells.
Injection back into the same patient, where they look for and destroy cancer cells
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This is its mechanism of action
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In a new study, Kwong and his collaborators changed the tumor microenvironment and made some modifications to their own cells to enhance the way CAR-T cells fight cancer
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They added a gene switch to CAR-T cells and developed a remote control system to precisely send these genetically modified T cells into the tumor microenvironment, where they kill the tumor and prevent recurrence
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The relevant research results were published online in the journal Nature Biomedical Engineering on August 12, 2021, with the title of the paper "Enhanced intratumoural activity of CAR T cells engineered to produce immunomodulators under photothermal control"
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The genetically modified Pmel-1 T cells enhance adoptive cell therapy in a high tumor burden environment
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Picture from Nature Biomedical Engineering, 2021, doi:10.
1038/s41551-021-00781-2
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In the early study, these authors did not treat the tumor clinically, but they are now studying this through this new study
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In order to generate heat in the tumors of the mice, they irradiated laser pulses from outside the bodies of these animals to the location of the tumors
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The gold nanorods delivered to the tumor convert light waves into local mild heat, raising the temperature to 40-42 degrees Celsius (104-107.
6 degrees Fahrenheit), which is just enough to activate this gene switch of CAR-T cells, but it will not be too hot.
Damage healthy tissues and these genetically modified T cells
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Once turned on, CAR-T cells begin to work, increasing the expression of anti-cancer proteins
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Kwong said that the real innovation lies in the genetic modification of clinical-grade CAR-T cells, which is what the team has done in the past three years
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Today, in addition to the switch that responds to heat, they have also upgraded CAR-T cells, reconnecting them to produce molecules that stimulate the immune system
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The local production of these powerful, engineered protein molecules (cytokines and bispecific T cell adaptor proteins) must be precisely controlled
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This new study shows that the system cured the cancer in mice, and the team’s method not only shrinks the tumor, but also prevents recurrence, which is essential for long-term survival
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Further research will delve into the additional customization of T cells and how to deposit heat on the tumor site
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A gentle laser is used to heat the tumor site
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When the technology enters human research, this will not be the case
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2.
J Immunother Cancer: CAR-T cells redirected by VEGFR-2 will be functionally impaired due to soluble VEGF-A receptor binding competition doi:10.
1136/jitc-2020-002151 The unprecedented response of CD19 targeting chimeric antigen receptor (CAR)-T cells led to rapid regulatory approval and accelerated cancer immunotherapy efforts in the field of T cell engineering
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However, so far, the clinical benefit of CAR-T cells in the treatment of epithelial-derived solid tumors is limited.
One of the main challenges is to identify solid tumor antigens (TA) that are widely expressed on tumors, and these antigens will not risk target toxicity and tumors.
The risk of external toxicity
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In fact, although CD19 is mainly restricted by B cells, there are also a small amount of solid TAs that have not been found in healthy tissues
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Restricted T cell homing is another obstacle, as well as an obstacle to endothelial migration of T cells across blood vessels into the tumor bed.
In addition, a series of immunosuppressive factors, such as programmed cell death ligand-1 (PD-L1), can be used in tumors.
Up-regulation in the microenvironment (TME), rationally designed combination therapy and collaborative engineering strategies provide the potential to support CAR treatment of solid tumors through TME reprogramming or/and direct enhancement of T cell function
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TA expressed by tumor vascular endothelial cells has clinical significance for CAR therapy because of their genome stability and the accessibility of circulating T cells, as well as their expression in multiple tumor types.
In this study, the researchers tried Explore the limitations of the second-generation (2G) murine CAR-T cell's efficacy on vascular endothelial growth factor receptor-2 (VEGFR-2), which contains the well-characterized single-chain variable fragment DC101
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The study did not involve the relative contribution of blocking the tumor promotion process by anti-VEGF-A antibodies.
However, the development of scFv targeting other domains of VEGFR-2 that are not damaged by soluble ligands requires further exploration of CAR therapy for tumor vasculature.

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This study is the first example of CAR function impaired due to competition with soluble ligands.
The researchers used a combination of promoting CAR-T cell adhesion and reprogramming TME to enhance CAR-T cell adaptability and tumor control.
The therapy provides a theoretical basis
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3.
JCI: Revealing that inhibition of BET protein can reactivate failed CAR-T cells, which is expected to better treat chronic lymphocytic leukemia doi:10.
1172/JCI145459 advanced chronic lymphocytic leukemia (CLL) patients stay after receiving active chemotherapy Too many "depleted" T cells have made it more difficult for chimeric antigen receptor (CAR) T cell (CAR-T) therapy to exert its effect
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Now, in a new study, researchers from the University of Pennsylvania in the United States have shown how to overcome this type of resistance and reactivate these T cells with an experimental small molecule inhibitor
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The relevant research results were published online in the Journal of Clinical Investigation on August 16, 2021, with the title of the paper "BET bromodomain protein inhibition reverses chimeric antigen receptor extinction and reinvigorates exhausted T cells in chronic lymphocytic leukemia"
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Picture from Journal of Clinical Investigation, 2021, doi:10.
1172/JCI145459
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Specifically, these authors revealed that this experimental drug called JQ1 improves the function of CAR-T cells by inhibiting the so-called BET (bromodomain and extra terminal) protein
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They confirmed that BET can disrupt the CAR expression and key acetylated histone functions of T cells in CLL patients
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These authors used small molecule inhibitors and T cells from multiple previously treated patients and CAR-T cells that target CD19 (hereinafter referred to as CD19 CAR-T cells) to prove the role of BET protein in down-regulating CAR expression.
If the BET protein is blocked, CAR-T cell failure can be attenuated, which is manifested by a decrease in inhibitory receptors, an increase in metabolic capacity and an increase in proliferation, and the reactivated CAR-T cells in CLL patients with poor lymphocytes Generate an increase
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BET protein inhibition also reduces the level of TET2 methylcytosine dioxygenase.
The forced expression of the TET2 catalytic domain eliminates the potency-enhancing effect of BET protein targeting in CAR-T cells, thus providing a way to reduce BET protein The mechanism associated with T cell dysfunction
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Based on this, the regulation of BET protein may improve the efficacy of CAR-T cells
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4.
J Immunother Cancer: Application of chimeric non-antigen receptors in T cell-based cancer therapy doi:10.
1136/jitc-2021-002628 The primary goal of T cell bioengineering in cancer immunotherapy is to pro-inflammatory the required T cells And cytotoxicity is directed to tumor cells, while preventing unnecessary off-target effects or misleading inflammation.
Based on these goals, chimeric non-antigen receptors are designed as CAR or T cell receptors (TCR) to provide support for anti-tumor T cell responses.
Common signal transmission
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The domains, smaller motifs and even key residues of innate immune receptors are the basic functional subunits of each receptor.
As long as the structural background is maintained, many domains and motifs show high functional fidelity, making them It can be transplanted into the chimeric protein as a functional module
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This article introduces the functions of various subunits of natural immune receptors related to the regulation of T cell anti-tumor response, and divides these receptors into three categories according to their functions and ligand types: "Conversion receptors, enhanced interactions with biological ligands stimulate receptors and synthetic receptor-ligand pairs
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The four main extracellular domain prototypes are usually integrated into natural receptors on T cells
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First, immunoglobulin (Ig)-like domains are widely shared among immune receptors recognized by ligands, including TCR subunits, co-receptors (such as CD4 and CD8), and CD28 receptor families (such as CD28, ICOS, CTLA) -4 and PD1), CD2 receptor family (such as CD2 and CD150) and interleukin 1 (IL-1) cytokine receptors
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Secondly, the fibronectin type III (FNIII) domain is topologically similar to the Ig-like domain, and the FNIII domain exists in the common gamma chain receptor family (such as IL-2, IL-7, IL-15 and IL-21).
Extracellular part
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The third highly shared extracellular domain is the cysteine-rich domain of the tumor necrosis factor receptor (TNFR) superfamily, which includes costimulatory receptors such as CD27, CD30, CD40, OX40 and 4-1BB, and tumor necrosis Factor (TNF) cytokine receptor
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The extracellular domain of TNFR can be coupled with intracellular TNF receptor-related factors (TRAF) to mediate various pro-inflammatory or proliferative signals (such as CD40 and TNFR2), and the death domain (DD) to mediate cell death (such as Fas or TNFR1) , Or can be non-membrane bound and function independently as a soluble or decoy receptor
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Finally, in adaptive immune cells, the C-type lectin receptor (CLR) domain is less common than the first three types of extracellular domains, but it is thought to be an important part of the chimeric receptor
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NKG2, a CLR family, is expressed on natural killer (NK) and T cells, and regulates pro-inflammatory and anti-inflammatory effects in response to stress-inducing molecules on its own cells (including cancer cells)
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There are two types of transmembrane receptors naturally expressed on T cells: single-channel (two-position) or multi-channel (multi-position)
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Two-position transmembrane domains are very common and contain varying numbers of hydrophobic residues, allowing insertion into hydrophobic lipid membranes; however, selected hydrophilic or charged residues interact with the proximal disulfide bonds and extracellular domains of the membrane to promote polymerization Such as the TCR complex itself with six separate CD3 molecules, two TCR molecules and CD4 or CD8, all of which have separate one-way transmembrane domains
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Multiple receptors, such as the prominent G protein-coupled receptor (GPCR) family, are also common in immune cells.
The GPCR chemokine receptor family, including CXCR1-6 and CCR1-11, is defined as consisting of seven The alpha helix passes through the membrane to form a barrel
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A variety of intracellular domains are used in immune receptors to mediate a variety of activation and inhibitory functions.
In some cases, the entire domain is considered to be activated or inhibited.
For example, in TRAF and DD used by members of the TNFR family, And a specific amino acid sequence or motif can perform a specific function
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Two common opposing motifs are the activation and inhibition motifs based on immunoreceptor tyrosine (ITAM and ITIM, respectively)
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More features of some intracellular domains have well-defined roles.
For example, TIM-3 has no known inhibitory motifs, and its role in T cell regulation depends on the key tyrosine residues 265 and 272 of the phosphoric acid.
And subsequent interaction with human leukocyte antigen (HLA-B)-related transcription factor 3
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Some molecules use a combination of motifs to fine-tune the balance between activation and inhibition.
CD150 has two immunoreceptor tyrosine-based switch motifs (ITSM) that act through SLAM-related proteins to help T cell proliferation and interference.
The production of prime-γ provides an activation signal
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The study classified these receptors into three categories according to their functions and ligand types: (1) "inhibition to stimulation" conversion receptors that bind to natural ligands, (2) enhanced stimulation receptors that interact with biological ligands, (3) Synthesis of receptor-ligand pairs
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5.
Sub-Journal of Nature: Using focused ultrasound to control the activity of CAR-T cells in solid tumors can reduce off-target effects doi:10.
1038/s41551-021-00779-w In a new study, from the University of California, San Diego Researchers at Developed a cancer immunotherapy that combines ultrasound with cancer-killing immune cells to destroy malignant tumors while preserving normal tissues
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This new experimental therapy significantly slowed the growth of solid cancer tumors in mice
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The relevant research results were published online in the journal Nature Biomedical Engineering on August 12, 2021.
The title of the paper is "Control of the activity of CAR-T cells within tumours via focused ultrasound"
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The corresponding authors of the paper are Yingxiao Wang, Professor of Bioengineering at the University of California, San Diego, and Shu Chien, Honorary Professor of Bioengineering
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The first author of the paper, Wang Lab project scientist Yiqian Wu said, “CAR-T cells are so powerful that they may also attack normal tissues that express target antigens at low levels
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The problem with standard CAR-T cells is that they are always active.
Status-They always express CAR protein, so you can't control their activation
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"FUS series ultrasound-induced in vitro function of CAR-T cells targeting prostate-specific membrane antigen (PSMA)
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Picture from Nature Biomedical Engineering, 2021, doi:10.
1038/s41551-021-00779-w
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To solve this problem, these authors used standard CAR-T cells and redesigned them so that they only express CAR protein when ultrasonic energy is applied
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This allows them to choose where and when the CAR-T cell genes are turned on
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Wang said, “We have successfully used ultrasound to directly control CAR-T cells in the body for cancer immunotherapy
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"Wang pointed out that the exciting thing about using ultrasound is that it can penetrate tens of centimeters under the skin, so this type of therapy has the potential to treat tumors buried deep in the body non-invasively
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This cancer immunotherapy developed by these authors This involves injecting redesigned CAR-T cells into the tumors of mice, and then placing a small ultrasound transducer on the skin area above the tumor to activate the CAR-T cells
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This ultrasound transducer uses the so-called Focusing the ultrasound beam focuses or concentrates short pulses of ultrasound energy on the tumor
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This causes the tumor to warm up moderately-in this case, the temperature reaches 43 degrees Celsius (109 degrees Fahrenheit)-without affecting the surrounding tissues
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This The CAR-T cells under study are equipped with a gene that expresses CAR protein only when heated
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Therefore, CAR-T cells express CAR protein only where ultrasound is applied
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These authors compared their CAR-T cells with standard CARs.
-T cells were tested
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In the mice that received this new type of CAR-T cell treatment, only the tumors exposed to ultrasound were attacked, while other tissues of the body were not affected
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But after receiving standard CAR-T cells In the treated mice, all tumors and tissues expressing the target antigen were attacked
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6.
NEJM: A case report study shows that CAR-T cells targeting CD19 are expected to treat systemic lupus erythematosus doi:10.
1056/NEJMc2107725 in a new article In the study, researchers from the University of Erlangen-Nuremberg in Germany tested the genetically modified CAR-T cell therapy on a 20-year-old woman with severe systemic lupus erythematosus (SLE) for the first time, and found that it can make Her severe lupus was quickly resolved, and there were no obvious side effects after six weeks
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The relevant research results were published in the NEJM journal on August 5, 2021, with the title of the paper "CD19-Targeted CAR T Cells in Refractory Systemic Lupus Erythematosus"
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The 20-year-old female patient in this case report has arthritis, kidney damage, and inflammation of the lungs and heart
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All the standard medications for systemic lupus erythematosus did not work for her
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Some existing lupus drugs work by depleting B cells, but they also did not help this female patient
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Therefore, Schett and his team turned to CAR-T cells
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They genetically modified the patient's T cells so that the CAR expressed by them can recognize CD19, which is a protein on B cells
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Under normal circumstances, these B cells produce antibodies to help fight infection; but in systemic lupus erythematosus, dysfunctional B cells produce autoantibodies
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Schett's team found that within 44 days after receiving CAR-T cell therapy targeting CD19, the patient's autoantibodies disappeared and her disease was relieved
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Systemic lupus erythematosus is an autoimmune disease that can cause organ damage throughout the body
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The corresponding author of the paper and Dr.
Georg Schett of Erlangen-Nuremberg University said that this woman is the world's first lupus patient treated with CAR-T cells
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This means that more research is needed before this therapy is widely used
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7.
Nat Med: The new study predicts which blood cancer patients may benefit from CAR-T cell therapy doi:10.
1038/s41591-021-01436-0 In a new study, researchers from the Stanford University School of Medicine pointed out that many people The envisaged method of improving the treatment of certain blood cancers with one stone may be more challenging to implement than previously anticipated
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The relevant research results were published online in the journal Nature Medicine on July 26, 2021.
The title of the paper is "CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial"
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The corresponding authors of the paper are Dr.
Crystal Mackall, Professor of Pediatrics at Stanford University School of Medicine, and Dr.
David Miklos, Professor of Medicine and Director of Bone Marrow Transplant and Cell Therapy at Stanford University School of Medicine
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The first authors of the paper are Dr.
Jay Spiegel, a researcher in hematology at Stanford University School of Medicine, Dr.
Shabnum Patel, Associate Director of Process Development and Manufacturing at Stanford University Cancer Cell Therapy Center, and Dr.
Lori Muffly, Assistant Professor of Medicine at Stanford University School of Medicine
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The picture is from Nature Medicine, 2021, doi:10.
1038/s41591-021-01436-0
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Studies of leukemia patients have shown that cancer cells gain the upper hand by reducing the density of CD19 on their surface, making it more difficult for genetically modified T cells to recognize them
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Although it is unclear whether this is the case in lymphoma patients, many scientists speculate that targeting two or more cancer-related molecules - such as CD19 and CD22 or CD20, or all three molecules - may It will make it more difficult for cancer cells to escape treatment
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Miklos, Mackall and their colleagues examined 44 patients with large B-cell lymphoma who had received standard CAR-T cell therapy that only targeted CD19
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Among these 44 people, the current standard clinical test judged that 39 people (89%) expressed significant levels of CD19 on the surface of cancer cells before treatment and were considered CD19 positive
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About half of these large B-cell lymphoma patients experienced disease deterioration after CAR-T cell therapy
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Among these relapsed patients, 60% of patients who were initially CD19-positive had converted to CD19-negative or low CD19 levels at the time of relapse, indicating that these lymphoma cells evade treatment in the form of leukemia cells
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In further investigation, these authors used a technology developed by Stanford University called flow cytometry to quantify the number of CD19 molecules on the surface of a single cancer cell, and found that there was obvious treatment between patients who later relapsed and patients who were successfully treated.
Before the difference
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They found that patients with more than about 3000 CD19 molecules on the surface of each cancer cell are more likely to respond well to CAR-T cell therapy, while those with fewer CD19 molecules are more likely to relapse after seemingly successful treatment.

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8.
Nat Immunol: Two transcription factors may cooperate with each other to inhibit the depletion of tumor infiltrating CAR-T cells, which is expected to improve the treatment of a variety of cancers doi: 10.
1038/s41590-021-00964-8 transcription factor—nuclear factor of activated T cells (NFAT) , Nuclear factor of activated T cells) and activated protein 1 (AP-1) can cooperate with each other to promote the effector function of T cells, but NFAT will impose a negative effect of T cell hyporesponsiveness (exhaustion) when AP-1 is absent.
Feedback procedure
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The fight against tumor seems to be a marathon, not a sprint.
For anti-cancer T cells, the time of the race is sometimes so long that they will give up the race in the middle.
Researchers call this phenomenon "T cell exhaustion".
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Recently, in a research report titled "BATF and IRF4 cooperate to counter exhaustion in tumor-infiltrating CAR T cells" published in the international journal Nature Immunology, scientists from La Jolla Institute of Immunology and other institutions found through research that T Cells may be engineered to clean up tumors without succumbing to the process of T cell depletion
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T cell depletion occurs in both therapies.
Many scientists have tried to use CAR-T cells to kill solid tumors, but this seems unlikely because T cells will be depleted
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In this study, the researchers may hope to solve this problem by giving T cells a capability to resist exhaustion
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In the article, the researchers screened T cells to discover which transcription factors can enhance the effector subprograms of T cells.
This program is a key step in preparing T cells to kill cancer cells
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This screening helped researchers discover the BATF transcription factor, which can cooperate with the IRF4 transcription factor to combat the T cell depletion program
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In mouse melanoma and colorectal cancer tumor models, changing CAR-T cells to overexpress BATF may clear the tumor, but it will not promote T cell exhaustion; in this way, CAR-T cells can effectively resist entities It's a tumor
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Therefore, BATF can work well with IRF4 to make T cells better
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After further research, the researchers found that although IRF4 is very important, it should not be overexpressed to the same extent as BATF.
In order to achieve the maximum effect, the overexpression of BATF is 20 times that of normal cells
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What makes researchers very exciting is that some altered T cells will persist and become memory T cells.
This is very important, because the exhaustion of T cells usually prevents T cells from having a strong memory response to recurrent cancer; Researcher Edahi Gonzalez-Avalos said that we not only increase the ability of T cells to resist exhaustion, but also increase the ability of cells to resist tumors.
We believe that overexpression of BATF may be used as a strategy to improve the efficiency of CAR-T therapy.
, And can help solve some difficult-to-treat cancer types, such as pancreatic ductal adenocarcinoma; these types of cancers are called immunological "cold tumors" because they do not trigger a strong anti-cancer response in the body’s immune system.
That is, T cells will not fight against it
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9.
iScience: Compared with CAR-T cells, CAR-NK cells are expected to treat solid tumors more safely doi:10.
1016/j.
isci.
2021.
102619 In a new study, researchers from McMaster University in Canada Developed a promising new type of cancer immunotherapy, which uses natural killer cells (NK cells) genetically modified in vitro to find and destroy malignant tumors
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These genetically modified NK cells can distinguish cancer cells from healthy cells.
Although healthy cells are usually mixed in and around tumors, they only destroy cancer cells, even in the presence of healthy cells carrying similar markers
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Related research results were recently published in the journal iScience, with the title of the paper "Expanded human NK cells armed with CAR uncouple potent anti-tumor activity from off-tumor toxicity against solid tumors"
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The picture is from iScience, 2021, doi:10.
1016/j.
isci.
2021.
102619
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This experimental therapy is an alternative to chimeric antigen receptor (CAR) T cell therapy (CAR-T), which was approved by the U.
S.
Food and Drug Administration (FDA) in 2017
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In CAR-T cell therapy, T cells genetically modified in vitro are very effective against some blood-borne cancers, but cannot effectively distinguish cancer cells from non-cancer cells.
Therefore, although they provide important benefits, they are not applicable For all forms of cancer
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In patients with solid tumors, these T cells can cause devastating and even fatal side effects
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In this study, these authors hope to have a treatment method that has the same power as CAR-T but can be safely used to treat solid tumors
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They first proliferated NK cells extracted from the blood of breast cancer patients
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The function of NK cells is similar to that of T cells in the immune system
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They then genetically modified NK cells to express a specific CAR receptor that recognizes the tumor antigen HER2 on the cell surface, thereby obtaining CAR-expressing NK cells (hereafter referred to as HER2 CAR-NK), and target them in the laboratory against breast cancer cells.
Tumor cells from cancer patients successfully tested HER2 CAR-NK cells
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Ana Portillo, the first author of the paper and a doctoral student in the Department of Medicine at McMaster University, said, "We hope to be able to attack these malignant tumors that are extremely resistant to other treatments
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The HER2 CAR-NK cells we observed in the laboratory The curative effect is very promising, and it is very important to see that this technology is feasible
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Today, we have a better and safer choice for solid tumors
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"10.
Lancet: Developed a treatment for multiple bone marrow New CAR-T cell therapy for tumors! doi:10.
1016/S0140-6736(21)00933-8AR-T cell therapy, that is, chimeric antigen receptor T cell therapy, is a new technology developed by scientists in recent years for precise targeted therapy of tumor cells
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Recently, an article was published in the international journal The Lancet entitled "Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/ In the "open-label study" report, scientists from the Sarah Cannon Institute in the United States and other institutions have developed a new CAR-T therapy for the treatment of multiple myeloma through research
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Yi Lin, MD, said that CAR-T cell therapy is a special type of immunotherapy, which mainly involves the identification and destruction of cancer cells by engineering the host's T cells, thereby using the patient's own immunity to achieve cancer treatment
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The FDA approved the first CAR-T cell therapy for the treatment of multiple myeloma—Abecma (idecabtagene vicleucel) in March of this year.
Now researchers are exploring another CAR-T cell therapy for the treatment of multiple myeloma
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The researchers stated that the CARTITUDE-1 research plan is a registration phase 1B/II clinical trial.
In the trial, the researchers tested the B-cell maturation antigen-targeted CAR-T cell therapy ciltacabtagene autoleucel (cilta-cel).
The therapy is suitable for patients with multiple myeloma who have previously received at least three first-line standard drug treatments, including proteasome inhibitors, immunomodulatory drugs, and CD38 antibodies
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Cilta-cel is modified by the patient's own T cells, which are genetically modified and infused into the patient in a single dose
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The researchers found that the overall response rate of the therapy was 97%, while the complete response rate and progression-free survival rate were 67% and 77%, respectively, and the overall survival rate was 89%
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11.
Nat Cancer: A new study reveals whether CAR-T cell therapy is effective in treating childhood leukemia doi:10.
1038/s43018-021-00207-7 In a new study, researchers from University College London in the United Kingdom are studying the use of CAR- In the effectiveness of T cell therapy in treating children with leukemia, it was discovered that a small number of T cells called stem cell memory T-cells may play a key role in the success of this treatment
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They pointed out that stem cell memory T cells seem to be critical to destroying cancer in the first place and long-term immune surveillance.
Using this feature may improve the design and performance of CAR-T cell therapy
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Related research results were recently published in the journal Nature Cancer, with the title of the paper "Clonal expansion of T memory stem cells determines early anti-leukemic responses and long-term CAR T cell persistence in patients"
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Immune phenotype analysis of CD3+ cells in Pt4 and Pt6.
The picture is from Nature Cancer, 2021, doi:10.
1038/s43018-021-00207-7
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These authors evaluated CAR-T cells in patients participating in the CARPALL phase I study, which used a type developed by the Cancer Institute of University College London and the University College London’s Great Ormond Street Children’s Health Institute called CAT- 19 new CAR molecules for the treatment of children with acute lymphoblastic leukemia (ALL)
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These authors compared CAR-T cells in patients whose CAR-T cells were still detectable in the blood after more than two years of treatment with those who lost CAR-T cells within 1 to 2 months after treatment
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Using a technology called "insertion site barcoding", they were able to study the fate of different types of CAR-T cells in patients
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The corresponding author of the paper and Professor Persis Amrolia of the University College London’s Great Ormond Street Children’s Health Institute said, “Using this barcode technology, we can observe stem cell memory T cells in the early anti-leukemia response and late immune surveillance (the body recognizes and destroys Cancer cells) play a central role
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This shows that this small part of T cells is critical to the long-term success of CAR-T cell therapy
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12.
Clin Transl Immunol: New EGFRvIII-specific CAR-T cells can effectively eliminate human glioblastoma doi:10.
1002/cti2.
1283 glioblastoma is an aggressive brain cancer
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There are more than 1,800 Australians every year .
who was diagnosed with brain cancer
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brain cancer is a major cause of cancer death in adults 40 years of age children
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is only 5% of adults diagnosed with glioblastoma of the five-year survival rate
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in a In the new study, researchers from the Walter Eliza Hall Institute of Medical Research in Australia can use chimeric antigen receptor (CAR) T cells (CAR-T) in preclinical models by using specially designed receptors.
The therapy completely eliminates brain cancer
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This new immunotherapy may pave the way for the development of new methods for the treatment of patients with glioblastoma
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The
results of the related research were recently published in the journal Clinical & Translational Immunology with the title of the paper "Novel high-affinity EGFRvIII-specific chimeric antigen receptor T cells effectively eliminate human glioblastoma"
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Specifically, her team used the Human Retained Display (ReD) antibody platform (Myrio Therapeutics) to identify a new type that can recognize epidermal growth factor receptors.
The single-chain variable region fragment (scFv) of body mutant III (EGFRvIII), which they called GCT02, where EGFRvIII is a common tumor-specific mutation in glioblastoma
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They used in vitro functional assays and in vivo orthotopic xenograft models of glioblastoma to study the function of this new CAR called GCT02
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They found that the EGFRvIII-specific scFv they developed had a higher affinity than the reported contrast that was reverse-engineered by monoclonal antibodies
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Although the affinity is higher, the lethality of GCT02 CAR-T cells is comparable to that of this counterpart, but the number of cytokines secreted is smaller
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In addition, GCT02 CAR-T cells can also mediate rapid and complete tumor elimination in vivo
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