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#CARTcell therapy for #autoimmunediseases Chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy has demonstrated significant success in treating cancers. The potential of CAR-T cells is now being explored in the context of autoimmune diseases. Recent clinical trials have shown sustained and profound elimination of autoreactive B cells by CAR-T cells, leading to promising autoimmune disease control with minimal safety concerns. These encouraging results have inspired further investigation into CAR-T cell applications for a broader range of autoimmune diseases and the development of advanced cell products with improved efficacy and safety CAR-T cell therapy, initially developed for cancer treatment, has shown remarkable success in targeting blood cancers through the use of genetically modified T cells that express synthetic receptors specific to tumor antigens. This approach involves creating chimeric antigen receptors (CARs) that combine antigen recognition domains with signaling domains to direct T cells against cancer cells. Currently, six CAR-T therapies are FDA-approved for treating various types of blood cancer, including diffuse large B cell lymphoma and acute lymphoblastic leukemia, with notable success in achieving high remission rates and long-term progression-free survival. The promising results of CD19-targeting CAR-T cells in treating B cell malignancies have prompted exploration into their potential applications for autoimmune diseases. Autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus, involve the immune system mistakenly attacking the body's own tissues, driven by autoreactive B and T cells. These conditions can be influenced by autoreactive B cells that produce autoantibodies and inflammatory cytokines, or by T cells that attack tissues directly. CAR-T cell therapy is being investigated as a strategy to target and eliminate these autoreactive cells, with ongoing research focusing on CAR-T cells that target specific markers on B cells and T cells. Early clinical trials using CAR-T cells targeting CD19, CD20, BCMA, and other markers have shown effective disease control and favorable safety profiles in autoimmune diseases like systemic lupus erythematosus and multiple sclerosis. Image: Functions of autoreactive B and T cells in autoimmune diseases, and the mechanisms of chimeric antigen receptor (CAR)-T cells in the treatment of autoimmune diseases Source: https://lnkd.in/eVrkB5qN

#CARTcelltherapy as emerging treatment for #autoimmunediseases Safety considerations for CAR-T cell therapy in autoimmune diseases differ markedly from those in cancer treatment due to the lower mortality rates in autoimmune patients. While severe adverse effects like cytokine release syndrome (CRS) and neurotoxicity are major concerns in cancer, most autoimmune patients experience minimal side effects. Strategies to mitigate CRS, such as using glucocorticoids or IL-6 receptor antibodies, need careful evaluation in autoimmune contexts. Additionally, potential infection complications from lymphodepletion pretreatment necessitate prolonged monitoring and preventive measures, like follow-up testing and booster vaccinations. Manufacturing CAR-T cell therapies poses challenges due to their high costs, complex production processes, and the need for sophisticated infrastructure. The personalized approach of extracting, modifying, and expanding a patient’s own T cells contributes to significant expenses and potential delays in treatment. To address these issues, developing allogeneic "off-the-shelf" CAR-T cells could offer a cost-effective and scalable solution, with strategies like gene editing to reduce graft-versus-host disease (GvHD) and enhancing the quality of cells. Utilizing naturally lower-risk cells, such as NK cells or macrophages, may further improve accessibility and reduce costs. CAR-T cell therapy has shown promise for autoimmune diseases by providing sustained B cell depletion and potentially more durable remissions compared to traditional treatments. Future research should focus on comparing CD19 versus BCMA targeting in CAR-T cells, as well as evaluating CAR-Tregs versus conventional CAR-T cells to determine the most effective therapeutic strategy. Further advancements in CAR design, gene editing, and combined therapies are needed to enhance efficacy and safety, while addressing critical questions about target selection and therapy optimization. Image: Comparison of chimeric antigen receptor (CAR)-T cell therapy with monoclonal antibody (mAb) therapy in autoimmune disease treatment Source: https://lnkd.in/e3ajqyNc

#CARTcelltherapy for #autoimmunediseases Chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy has demonstrated significant success in treating cancers. The potential of CAR-T cells is now being explored in the context of autoimmune diseases. Recent clinical trials have shown sustained and profound elimination of autoreactive B cells by CAR-T cells, leading to promising autoimmune disease control with minimal safety concerns. These encouraging results have inspired further investigation into CAR-T cell applications for a broader range of autoimmune diseases and the development of advanced cell products with improved efficacy and safety CAR-T cell therapy, initially developed for cancer treatment, has shown remarkable success in targeting blood cancers through the use of genetically modified T cells that express synthetic receptors specific to tumor antigens. This approach involves creating chimeric antigen receptors (CARs) that combine antigen recognition domains with signaling domains to direct T cells against cancer cells. Currently, six CAR-T therapies are FDA-approved for treating various types of blood cancer, including diffuse large B cell lymphoma and acute lymphoblastic leukemia, with notable success in achieving high remission rates and long-term progression-free survival. The promising results of CD19-targeting CAR-T cells in treating B cell malignancies have prompted exploration into their potential applications for autoimmune diseases. Autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus, involve the immune system mistakenly attacking the body's own tissues, driven by autoreactive B and T cells. These conditions can be influenced by autoreactive B cells that produce autoantibodies and inflammatory cytokines, or by T cells that attack tissues directly. CAR-T cell therapy is being investigated as a strategy to target and eliminate these autoreactive cells, with ongoing research focusing on CAR-T cells that target specific markers on B cells and T cells. Early clinical trials using CAR-T cells targeting CD19, CD20, BCMA, and other markers have shown effective disease control and favorable safety profiles in autoimmune diseases like systemic lupus erythematosus and multiple sclerosis. Image: Functions of autoreactive B and T cells in autoimmune diseases, and the mechanisms of chimeric antigen receptor (CAR)-T cells in the treatment of autoimmune diseases Source: https://lnkd.in/e3ajqyNc

#CARTcelltherapy as emerging treatment for #autoimmunediseases Safety considerations for CAR-T cell therapy in autoimmune diseases differ markedly from those in cancer treatment due to the lower mortality rates in autoimmune patients. While severe adverse effects like cytokine release syndrome (CRS) and neurotoxicity are major concerns in cancer, most autoimmune patients experience minimal side effects. Strategies to mitigate CRS, such as using glucocorticoids or IL-6 receptor antibodies, need careful evaluation in autoimmune contexts. Additionally, potential infection complications from lymphodepletion pretreatment necessitate prolonged monitoring and preventive measures, like follow-up testing and booster vaccinations. Manufacturing CAR-T cell therapies poses challenges due to their high costs, complex production processes, and the need for sophisticated infrastructure. The personalized approach of extracting, modifying, and expanding a patient’s own T cells contributes to significant expenses and potential delays in treatment. To address these issues, developing allogeneic "off-the-shelf" CAR-T cells could offer a cost-effective and scalable solution, with strategies like gene editing to reduce graft-versus-host disease (GvHD) and enhancing the quality of cells. Utilizing naturally lower-risk cells, such as NK cells or macrophages, may further improve accessibility and reduce costs. CAR-T cell therapy has shown promise for autoimmune diseases by providing sustained B cell depletion and potentially more durable remissions compared to traditional treatments. Future research should focus on comparing CD19 versus BCMA targeting in CAR-T cells, as well as evaluating CAR-Tregs versus conventional CAR-T cells to determine the most effective therapeutic strategy. Further advancements in CAR design, gene editing, and combined therapies are needed to enhance efficacy and safety, while addressing critical questions about target selection and therapy optimization. Image: Comparison of chimeric antigen receptor (CAR)-T cell therapy with monoclonal antibody (mAb) therapy in autoimmune disease treatment Source: https://lnkd.in/e3ajqyNc

#Lipidmetabolism in #Bcellbiology An expanding body of scientific literature has unveiled the intricate interplay between energy homeostasis, signalling molecules, and metabolites in relation to fundamental aspects of our immune cells. Emerging evidence, although sometimes fragmented and anecdotal, has highlighted the indispensable role of lipids in modulating the behaviour of immune cells, including B cells. #Lipidmetabolism in #Bcellmalignancies Recent studies have highlighted the critical role of lipid metabolism in B cell malignancies, revealing that lipid uptake and metabolism are essential for the survival and proliferation of malignant B cells. A significant finding is the impact of CD37, a membrane protein, which normally inhibits fatty acid transporter 1 (FATP1) and reduces fatty acid uptake. When CD37 is lost, lymphoma cells increase their lipid uptake and storage, making them more aggressive and vulnerable to fatty acid metabolism inhibition. In EBV-transformed B cell malignancies, lipid metabolism is also significantly altered. EBV-induced expression of latent membrane protein 1 (LMP1) disrupts normal fatty acid metabolism, increasing lipid synthesis and storage, which is critical for cell viability. EBV-infected B cells reroute their mevalonate pathway towards the production of geranylgeranyl pyrophosphate (GGPP), impacting cell signaling and contributing to cancer progression. Conversely, chronic lymphocytic leukemia (CLL) cells rely more on oxidative phosphorylation (OxPhos) and express lipoprotein lipase (LPL) to utilize fatty acids, which is crucial for their survival. Targeting fatty acid metabolism with inhibitors like CPT1 inhibitors has shown promise in treating various B cell malignancies, emphasizing the therapeutic potential of targeting lipid metabolism. Image:  Overview of lipid‐metabolism associated factors in B cell development and malignancies. Throughout the different phases of a B cells life, several proteins and metabolites important for lipid metabolism and homeostasis are involved in maturation, differentiation, and malignant transformation. Initial maturation (Blue segment) of B cells seems to rely mostly on glycolysis and mitochondrial activity, with no major roles for lipids reported. The more innate like MZ‐B and B1 B cells, as well as PCs (Green segment) have been reported to actively take up and process exogenous lipids, which is important for their survival. Activated GC B cells (Yellow segment) seem to require various metabolites including glucose, amino acid and lipids. The exact role for lipids remains ambiguous, yet several reports hint at their importance for GC B cells. Alterations in B cells allowing them to excessively employ lipid metabolism are associated with multiple B cell malignancies (Magenta segment) Source: https://lnkd.in/e4hJ5gib

#CARTcelltherapy for #autoimmunediseases Chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy has demonstrated significant success in treating cancers. The potential of CAR-T cells is now being explored in the context of autoimmune diseases. Recent clinical trials have shown sustained and profound elimination of autoreactive B cells by CAR-T cells, leading to promising autoimmune disease control with minimal safety concerns. These encouraging results have inspired further investigation into CAR-T cell applications for a broader range of autoimmune diseases and the development of advanced cell products with improved efficacy and safety CAR-T cell therapy, initially developed for cancer treatment, has shown remarkable success in targeting blood cancers through the use of genetically modified T cells that express synthetic receptors specific to tumor antigens. This approach involves creating chimeric antigen receptors (CARs) that combine antigen recognition domains with signaling domains to direct T cells against cancer cells. Currently, six CAR-T therapies are FDA-approved for treating various types of blood cancer, including diffuse large B cell lymphoma and acute lymphoblastic leukemia, with notable success in achieving high remission rates and long-term progression-free survival. The promising results of CD19-targeting CAR-T cells in treating B cell malignancies have prompted exploration into their potential applications for autoimmune diseases. Autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus, involve the immune system mistakenly attacking the body's own tissues, driven by autoreactive B and T cells. These conditions can be influenced by autoreactive B cells that produce autoantibodies and inflammatory cytokines, or by T cells that attack tissues directly. CAR-T cell therapy is being investigated as a strategy to target and eliminate these autoreactive cells, with ongoing research focusing on CAR-T cells that target specific markers on B cells and T cells. Early clinical trials using CAR-T cells targeting CD19, CD20, BCMA, and other markers have shown effective disease control and favorable safety profiles in autoimmune diseases like systemic lupus erythematosus and multiple sclerosis. Image: Functions of autoreactive B and T cells in autoimmune diseases, and the mechanisms of chimeric antigen receptor (CAR)-T cells in the treatment of autoimmune diseases Source: https://lnkd.in/e3ajqyNc

#naturalkiller #exosomes #immunotherapy Synergies of engineered natural killer cell-derived exosomes with other tumor therapies Radiotherapy Natural killer (NK) cell-derived exosomes can enhance radiotherapy by increasing tumor sensitivity through the delivery of specific microRNAs, such as miR-146a-5p and miR-99a-5p, which target pathways involved in radioresistance Chemotherapy NK cell-derived exosomes encapsulating chemotherapeutic agents, such as cisplatin or paclitaxel, improve the targeting and effectiveness of these drugs while reducing systemic toxicity Photodynamic therapy Photodynamic therapy (PDT), which uses reactive oxygen species (ROS) to kill tumors, can be enhanced with NK cell-derived exosomes to achieve precision therapy. Exosome-based systems, like the ExoCar/T7@Micelle, enable controlled drug release and improve PDT's ability to target tumor cells Photothermal therapy NK cell-derived exosomes can be combined with nanomaterial-based photothermal therapies (PTT) to enhance tumor ablation while minimizing damage to surrounding tissues Immunotherapy NK cell-derived exosomes enhance immunotherapy by modifying NK cell receptors and stimulating immune cells like T cells and monocytes, overcoming tumor immunosuppression. They can also carry tumor-targeting molecules, boosting their cytotoxicity against tumors, and show great promise in improving immunotherapy for cancers like neuroblastoma Gene therapy Gene therapy using NK cell-derived exosomes enables the delivery of non-coding RNAs, such as miRNAs, to target diseases like cancer by regulating gene expression pathways. These exosomes improve gene therapy efficacy and controllability, making them a promising tool for advancing clinical gene therapies Targeted therapy NK cell-derived exosomes equipped with chimeric antigen receptors (CAR) offer a safer and more effective alternative to CAR-T therapies by targeting tumors more precisely. Their ability to cross the blood-brain barrier and deliver therapeutic molecules specifically at tumor sites makes them a powerful tool for targeted cancer therapy Image:  Synergies of engineered #NKcell-derived exosomes with other tumor therapies a, b) Combined potentiation of natural killer cell-derived engineered exosomes with radiotherapy c) Natural killer cell-derived engineered exosomes facilitate chemotherapeutic drug delivery d) Natural killer cell-derived engineered exosomes are used in combination with photodynamic therapy to promote precise drug release e) Natural killer cell-derived engineered exosomes are used in combination with photothermal therapy treatment to control the release of tumor drugs f) Natural killer cell-derived engineered exosomes deliver immune substances into tumor cells g) Natural killer cell-derived engineered exosomes enter tumor cells and regulate gene expression h) Natural killer cell-derived engineered exosomes for precision therapy Source: https://lnkd.in/eq2h9bu7

#Naturalkiller #exosome #cancertherapy Natural killer cell-derived exosome-based cancer therapy: from biological roles to clinical significance and implications Natural killer (NK) cells are important immune cells in the organism and are the third major type of lymphocytes besides T cells and B cells, which play an important function in cancer therapy. In addition to retaining the tumor cell killing function of natural killer cells, natural killer cell-derived exosomes cells also have the characteristics of high safety, wide source, easy to preserve and transport. At the same time, natural killer cell-derived exosomes are easy to modify, and the engineered exosomes can be used in combination with a variety of current cancer therapies, which not only enhances the therapeutic efficacy, but also significantly reduces the side effects Natural killer (NK) cells originate from common lymphoid progenitors and can be obtained from sources like peripheral blood, cord blood, pluripotent stem cells, and NK cell lines. Over the years, several NK cell lines, such as NK92 and HANK1, have been established for cancer immunotherapy due to their therapeutic potential. NK cells are divided into two main subpopulations based on CD56 expression: CD56bright, which is cytokine-producing, and CD56dim, which is more cytotoxic. These cells develop in the bone marrow and other lymphoid organs, and can be classified into classical or tissue-resident NK cells. NK cell differentiation depends on the expression of receptors such as CD16 and CD57, and their activation relies on ligand/receptor interactions, balancing inhibitory and activating signals. NK cells are activated when tumor cells downregulate MHC I and upregulate NK cell-activating ligands, making them prime targets for cancer immunotherapy. Initially, NK cell-based therapies were used in hematopoietic stem cell transplants (HSCTs), where they provided graft-versus-leukemia effects without causing graft-versus-host disease. Subsequent studies demonstrated NK cell efficacy in non-transplant settings, leading to the development of Chimeric Antigen Receptor (CAR)-NK cells as an alternative to CAR-T therapies. With advancements in genetic engineering and a deeper understanding of NK cell biology, NK-based immunotherapies are becoming increasingly promising. Future innovations may also include NK cell-derived exosomes for cancer treatment Image: Origin of natural killer cell and cancer immunotherapy.  a) The origin of natural killer cells b) Localization of NK cells c) Natural killer cells function selectively d) Four ways natural killer cells fight tumors e) Natural killer cell-based therapies Source: https://lnkd.in/eq2h9bu7

#Naturalkiller #cancerimmunotherapy Natural killer cell memory: challenges and opportunities for cancer immunotherapy Natural killer (NK) cells have been found to acquire immunological memory in a manner akin to T and B cells. The fundamental principles derived from the investigation of NK cell memory offer novel insights into innate immunity and have the potential to pave the way for innovative strategies to enhance therapeutic interventions against multiple diseases including cancer Research into NK cell memory responses has highlighted their potential in cancer treatment, particularly due to their ability to rapidly respond to previously encountered threats without needing antigen-specific receptors. Unlike T and B cells, NK cells utilize ‘innate memory’ for quicker, robust reactions, which can be enhanced when combined with other immunotherapies like CAR-engineered NK cells. These cells show promise in treating hematologic malignancies and, when paired with radiotherapy, could improve immune infiltration in solid tumors. Synergistic approaches, such as using IL-2-activated NK cells with anti-PD-L1 antibodies, have shown potential in reshaping the tumor environment to enhance immunotherapy effectiveness. As NK cell memory research advances, including studies on cytokine-driven NK cells and human CMV adaptive NK cells, it could lead to innovative strategies for cancer treatment. In the image:  The application of memory NK cells in cancer immunotherapy. a. The cytokine IL-12/15/18 induces the generation of memory NK cells, and enhancing the secretion of IFNγ, perforin, and granzymes for effective eradication of cancer cells. b. Memory NK cells induced by IL-12/15/18 can be transduced with CARs, thereby enhancing their antineoplastic activity. c. The administration of antibodies such as cetuximab, rituximab, and AFM13 has been shown to augment the antitumor efficacy in memory NK cells Source: https://lnkd.in/eP_Wip3F

#Bcells present a double-sided effect in #digestivesystemtumors: a review for #tumormicroenvironment Over the past few years, there has been an increasing interest in investigating tumor-infiltrating lymphocytes. B lymphocytes (B cells) are extensively distributed within tertiary lymphoid structure (TLS) as multifaceted subgroups and are intimately linked to the anti-tumor properties of TLS, as well as the survival and prognostication of individuals. While the investigation of T lymphocytes in the TLS has advanced to the level of clinical practice, the study of B cells remains limited B cells in cancer: Esophageal Cancer: In esophageal squamous cell carcinoma (ESCC), B cells are less abundant than T cells but exhibit a diverse range of subtypes that play a role in anti-tumor immunity, particularly through their interaction with T cells. Despite the low infiltration of B cells, their presence, especially in certain subtypes like MBC-ITGAX, is associated with favorable prognoses due to their antitumor effects. Liver Cancer: B cells in hepatocellular carcinoma (HCC) are found primarily at the tumor margin, where their high infiltration correlates with better survival rates and smaller tumor size. However, regulatory B cells (Breg) in advanced stages of HCC can promote tumor growth by suppressing tumor-specific T cell immunity via IL-10 secretion. Colorectal Cancer (CRC): B cells in CRC are typically depleted within tumor tissues, but when present, high levels of memory B cells (MBC) and plasma cells (PC) are linked to better survival outcomes and lower tumor stages. However, intestinal-specific IgA-producing plasma cells may contribute to tumor-promoting inflammation, complicating B cell roles in tumor progression. Gastric Cancer (GC): B cells in gastric cancer are mainly located in tertiary lymphoid structures (TLS) near the tumor, where their infiltration, especially MBC and plasma cells, is associated with longer survival. However, regulatory B cells (Breg) in GC promote tumorigenesis by suppressing T cell responses and are linked to poor prognosis. Pancreatic Cancer: In pancreatic cancer, B cells within TLS promote anti-tumor immunity, contributing to longer survival, whereas B cells outside these structures, particularly regulatory B cells, foster immunosuppression and tumor progression. The presence of immunosuppressive IgG4-producing plasma cells, driven by Breg, is associated with poor outcomes. Image:  The advantages and disadvantages effects of B cells in different cancers. +: positive expression; −: negative expression; hi: high expression; dim: dim expression. NBC, naive B cell; MBC, memory B cell; GCB, germinal center B cell; MALT, mucosa-associated lymphoid tissue; TLS, tertiary lymphoid structures; TIGIT, T-cell immune receptor with immunoglobulin and ITIM domain Source: https://lnkd.in/eQZgbZB3