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Engineering enhanced CAR T-cells for improved cancer therapy.

Chimeric antigen receptor (CAR) T-cell therapies have evolved from a research tool to a paradigm-shifting therapy with impressive responses in B cell malignancies. This review summarizes the current state of the CAR T-cell field, focusing on CD19- and B cell maturation antigen-directed CAR T-cells, the most developed of the CAR T-cell therapies. We discuss the many challenges to CAR-T therapeutic success and innovations in CAR design and T-cell engineering aimed at extending this therapeutic platform beyond hematologic malignancies.

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… Bevan MJ The major histocompatibility complex determines susceptibility to cytotoxic T cells directed against minor histocompatibility antigens. J Exp Med 142, 1349–1364 (1975). 114. Lamberth K et al. …

A concise review on factors influencing the hematopoietic stem cell transplantation main outcomes.

Background and aimsAs a curative procedure, hematopoietic stemcell transplantation (HSCT) is an approved treatment for many malignant orbenign hematologic and non-hematologic diseases. There are different outcomes of HSCT, as well as several parameters influencing these outcomes.MethodsWe had searched scientific sources like Web ofScience and PubMed with a combination of keywords such as HSCT, engraftment,survival, outcomes, etc. Totally, 80 articles were included.ResultsHere we have reviewed the effective factors onmain outcomes of HSCT including engraftment, survival, graft versus hostdiseas

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… Major histocompatibility complex: Antigen processing and presentation. Autoimmunity: From Bench to Bedside [Internet]. Bogota (Colombia): El Rosario University Press; 2013. 7. Bertaina A, Andreani M. … Major histocompatibility complex and hematopoietic stem cell transplantation: Beyond the classical HLA polymorphism. Int J Mol Sci. 2018;19(2):621. 8. Park M, Seo JJ. Role of HLA in hematopoietic stem cell transplantation. Bone Marrow Res. 2012;2012(680841):7. 9. …

Targeting multiple-myeloma-induced immune dysfunction to improve immunotherapy outcomes.

Multiple myeloma (MM) is a plasma cell malignancy associated with high levels of monoclonal (M) protein in the blood and/or serum. MM can occur de novo or evolve from benign monoclonal gammopathy of undetermined significance (MGUS). Current translational research into MM focuses on the development of combination therapies directed against molecularly defined targets and that are aimed at achieving durable clinical responses. MM cells have a unique ability to evade immunosurveillance through several mechanisms including, among others, expansion of regulatory T cells (Treg), reduced T-cell cytot

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… CNX plays a key role in both major histocompatibility complex-class 1 and 2 antigen processing pathways and may also be involved in CD1d lipid antigen presentation [ 82 ]. …

T Cell Based Immunotherapy for Cancer: Approaches and Strategies.

T cells are critical in destroying cancer cells by recognizing antigens presented by MHC molecules on cancer cells or antigen-presenting cells. Identifying and targeting cancer-specific or overexpressed self-antigens is essential for redirecting T cells against tumors, leading to tumor regression. This is achieved through the identification of mutated or overexpressed self-proteins in cancer cells, which guide the recognition of cancer cells by T-cell receptors. There are two main approaches to T cell-based immunotherapy: HLA-restricted and HLA-non-restricted Immunotherapy. Significant progres

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… MAITs are a subset of T cells that recognize antigens presented by a non-classical major histocompatibility complex molecule, MR1. These cells are not HLA-restricted and are not expected to induce GVHD, which gives them huge potential as a source for off-the-shelf immunotherapy. … Treatment of Patients With Metastatic Cancer Using a Major Histocompatibility Complex Class II-Restricted T-Cell Receptor Targeting the Cancer Germline Antigen MAGE-A3. J. Clin. Oncol. 2017;35:3322–3329. doi: 10.1200/JCO.2017.74.5463. 36. …

A new era of cancer immunotherapy: vaccines and miRNAs.

Cancer immunotherapy has transformed the treatment landscape, introducing new strategies to fight various types of cancer. This review examines the important role of vaccines in cancer therapy, focusing on recent advancements such as dendritic cell vaccines, mRNA vaccines, and viral vector-based approaches. The relationship between cancer and the immune system highlights the importance of vaccines as therapeutic tools. The discussion covers tumor cell and dendritic cell vaccines, protein/peptide vaccines, and nucleic acid vaccines (including DNA, RNA, or viral vector-based), with a focus on th

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… Antigen-presenting cells (APCs) process major histocompatibility complex (MHC) and antigens, presenting them on the cell surface and transferring them to lymphoid organs. … TCR-T cells recognize intracellular and surface antigens through major histocompatibility complex (MHC) presentation, broadening their target range compared to CAR-T cells, which primarily bind extracellular antigens. …

Latest developments in MUC1 immunotherapy.

Currently, there is renewed interest in attempting to recruit the host immune system to eliminate cancers, and within this renewed activity, MUC1 continues to arouse interest. MUC1 has been considered a possible therapeutic target for the past 30 years as it is up-regulated, aberrantly glycosylated and its polarization is lost in many adenocarcinomas. Moreover, MUC1 is expressed by some haematopoietic cancers, including acute myeloid leukaemia and myeloma. Although multiple clinical trials have been initiated and immune responses have been documented, effective clinical benefit worthy of appro

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… Immunother . 64 , 1095 – 1108 10.1007/s00262-015-1712-6 25998800 PMC4545381 40 Haurum, J.S. , Arsequell, G. , Lellouch, A.C. , Wong, S.Y. , Dwek, R.A. , McMichael, A.J. et al. ( 1994 ) Recognition of carbohydrate by major histocompatibility complex class I-restricted, glycopeptide-specific cytotoxic … Jr , Hanisch, F.G. et al. ( 2002 ) Complex carbohydrates are not removed during processing of glycoproteins by dendritic cells: processing of tumor antigen MUC1 glycopeptides for presentation to major histocompatibility complex class II-restricted T cells . J. Exp. …

Engineering TCR-directed T-cells for the treatment of multiple myeloma.

Multiple myeloma (MM) is a virtually incurable plasma cell malignancy characterized by malignant cells that expand within the tumor-permissive bone marrow (BM) microenvironment. Novel strategies are urgently needed to improve the outcomes of patients with difficult-to-treat and therapy-refractory disease. The ability to genetically manipulate T-cells and the introduction of adoptive cellular therapies (ACTs) has improved the treatment of relapsed and/or refractory (RR)MM. Emerging evidence supports the efficacy of ACTs as early lines of cancer treatment, potentially even as an alternative to a

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… T-cell receptors (TCRs) mediate anti-tumor responses by recognizing peptides that are derived from specific tumor antigens or neoantigens (NeoAgs) and presented by Major Histocompatibility Complex (MHC) class I molecules on the surface of cancer cells, leading to cytotoxic CD8 + T-cell activation and … Proteasome subtypes and regulators in the processing of antigenic peptides presented by class I molecules of the major histocompatibility complex . …

Systemic amyloidosis: an aggressive evolution in a patient with relapsing polychondritis and monoclonal gammopathy of undetermined significance (MGUS) undergoing peritoneal dialysis.

Herein, we report the case of primary amyloidosis with multi-organ involvement in a female patient in her 50s. The patient had a history of relapsing polychondritis, chronic kidney disease, and monoclonal gammopathy of undetermined significance (MGUS). The clinical manifestations included neuropathic pain, sensorimotor polyneuropathy, intrahepatic cholestatic liver injury, gastrointestinal symptoms, dysautonomia, and myocardial thickening. Initial histologic evaluations of the abdominal fat pad aspirate and bone marrow biopsy were negative for amyloid deposition. However, due to a high index o

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… Other familial amyloidosis include a1-apolipoprotein, gelsolin, among others. 7 , 8 ß2-microglobulin-related amyloidosis, a rare type, is caused by the excessive deposition of a constitutional protein part of major histocompatibility complex (MHC) class I molecules with near total renal clearance but …

Менделийская случайность выявляет белки, связанные с нейродегенеративными заболеваниями.

Протеины участвуют в многочисленных биологических функциях. Технологии высокой производительности позволили измерять тысячи белков в биобанках населения. В этом исследовании мы стремились выявить белки, связанные с болезнью Альцгеймера, болезнью Паркинсона, множественным склерозом и амиотропическим боковым склерозом, используя крупномасштабные генетические и протеомические данные. Мы провели двухвыборное исследование цисов менделий случайности, выбрав инструментальные переменные для изобилия >2700 белков, измеряемых либо Olink, либо SomaScan платформами в плазме из UK Biobank и DeCODE Health S

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… upstream or downstream from the transcription start site of the gene encoding the protein of interest. 27 We used the following criteria to filter the list of statistically significant cis pQTLs in each study: Owing to the complex LD structure of single nucleotide polymorphisms within the human major … histocompatibility complex region, single nucleotide polymorphisms and proteins encoded by genes within the major histocompatibility complex region (Chromosome 6: from 26 to 34 Mb) were excluded. …

Heterogeneous tissue-specific macrophages orchestrate metastatic organotropism of breast cancer: implications for promising therapeutics.

Compelling evidences have manifested that breast cancer cells prefer to metastasize to certain distant organs, including brain, lung, bone and liver. According to the canonical "seed and soil" theory, this prominent biological behavior, termed as metastatic organotropism, involves intricate interactions between breast cancer cells (the "seeds") and specific residents in the tumor microenvironment (the "soil"), initiating from pre-metastatic niche formation to metastatic outgrowth. Recently, multifaceted heterogeneity of tissue-specific macrophages (TSMs) and their roles played in organotropic

Emerging Immunotherapy for Acute Myeloid Leukemia.

Several immune checkpoint molecules and immune targets in leukemic cells have been investigated. Recent studies have suggested the potential clinical benefits of immuno-oncology (IO) therapy against acute myeloid leukemia (AML), especially targeting CD33, CD123, and CLL-1, as well as immune checkpoint inhibitors (e.g., anti-PD (programmed cell death)-1 and anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) antibodies) with or without conventional chemotherapy. Early-phase clinical trials of chimeric antigen receptor (CAR)-T or natural killer (NK) cells for relapsed/refractory AML showed

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… LAG-3 structurally resembles CD4 and binds to major histocompatibility complex (MHC) class II on CD4-positive T cells, resulting in the downregulation of their antigen-mediated activity [ 44 , 45 , 46 ]. … T cell major histocompatibility complex class II molecules down-regulate CD4+ T cell clone responses following LAG-3 binding. Eur. J. Immunol. 1996;26:1180–1186. doi: 10.1002/eji.1830260533. 47. Woo S. …

The Applications of Machine Learning in the Management of Patients Undergoing Stem Cell Transplantation: Are We Ready?

Hematopoietic stem cell transplantation (HSCT) is a life-saving therapy for hematologic malignancies, such as leukemia and lymphoma and other severe conditions but is associated with significant risks, including graft versus host disease (GVHD), relapse, and treatment-related mortality. The increasing complexity of clinical, genomic, and biomarker data has spurred interest in machine learning (ML), which has emerged as a transformative tool to enhance decision-making and optimize outcomes in HSCT. This review examines the applications of ML in HSCT, focusing on donor selection, conditioning re

Paraneoplastic Syndrome After Kidney Transplantation: Frequency, Risk Factors, Differences to Paraneoplastic Occurrence of Glomerulonephritis in the Native Kidney, and Implications on Long-Term Kidney Graft Function.

Posttransplant malignancies are an important complication of solid organ transplantation. Kidney transplant recipients are at particularly high risk of cancer development. The most relevant risk factors of carcinogenesis are the use of immunosuppressive agents and oncogenic viral infections. Additionally, immune dysregulation caused by these factors may predispose to various types of organ damage. Paraneoplastic glomerular diseases are one of the most interesting and understudied cancer manifestations. The appropriate diagnosis of paraneoplastic glomerular damage can be challenging in kidney t

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… The animals showed stronger anti-tumor response when a higher degree of major histocompatibility complex (MHC) mismatch was present in comparison to a well-matched group [ 17 ]. … histocompatibility complex MN | Membranous nephropathy MPGN | Membranoproliferative glomerulonephritis mTOR | Mammalian target of rapamycin NELL-1 | Neural epidermal growth factor-like 1 NK | Natural killer PCDH7 | Protocadherin 7 PD-1 | Programmed cell death 1 PLA2R | Phospholipase A2 receptor sHLA-G …

Anti-PEG Antibodies and Their Biological Impact on PEGylated Drugs: Challenges and Strategies for Optimization.

Polyethylene glycol (PEG) has been widely utilized in optimizing therapeutics due to its excellent biocompatibility and chemical stability. However, multiple dosing of PEGylated drugs may result in toxicity due to PEG accumulation in tissues, leading to the formation of anti-PEG antibodies (APAs), which can accelerate drug clearance, reduce efficacy, and alongside enhanced side effects, such as allergic reactions. Notably, pre-existing APAs have also been detected in individuals with no prior exposure to PEGylated drugs, raising additional clinical concerns. This review summarizes the mechanis

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… B cells take up large quantities of PEGylated drugs and express the major histocompatibility complex (MHC)-bound antigens on their surface, aiding interaction with TFH cells. … Abbreviations The following abbreviations are used in this manuscript: PEG Polyethylene glycol APAs Anti-PEG antibodies MPS Mononuclear phagocyte system RES Reticuloendothelial system ELISA Enzyme-linked immunosorbent assay BCRs B cell receptors TFH Follicular helper T MHC Major histocompatibility complex …

Hematopoietic stem cell transplantation-50 years of evolution and future perspectives.

Hematopoietic stem cell transplantation is a highly specialized and unique medical procedure. Autologous transplantation allows the administration of high-dose chemotherapy without prolonged bone marrow aplasia. In allogeneic transplantation, donor-derived stem cells provide alloimmunity that enables a graft-versus-tumor effect to eradicate residual disease and prevent relapse. The first allogeneic transplantation was performed by E. Donnall Thomas in 1957. Since then the field has evolved and expanded worldwide. New indications beside acute leukemia and aplastic anemia have been constantly ex

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… These lymphocyte subsets are responsible for the occurrence of GVHD. 61 γδ T cells (also termed “innate-like” T cells or “transitional” T cells) belong to the adoptive arm of the immune system. 62 They are capable of recognizing their targets in a major histocompatibility complex-independent manner; …

Тип общей генетической и нейроиммунной архитектуры 1 диабет с нейрокогнитивными признаками.

Тип 1 диабет, особенно в детстве, ассоциируется с изменяющимися нейрокогнитивными признаками, однако основные биологические механизмы неясны. Здесь мы интегрируем результаты общегеномной ассоциации с одноклеточных эпигеномических профилей и показываем этот тип 1 Наследственность диабета обогащается доступным хроматином клеток мозга человека, в первую очередь микроглией, через нейроразвитие до взрослого возраста. Анализ генетической корреляции, скорректированный по методу Bonferroni, показывает отрицательную корреляцию типа 1 диабет с интеллектом, исполнительными функциями и биполярным расстрой

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… Variants with ambiguous strands were removed, and the extended major histocompatibility complex (MHC) region (chr6:25–34 Mb) was excluded from analyzes requiring LD independence due to complex long-range LD. Allele harmonization was performed across all datasets. … SNPs with MAF > 0.05 were retained, while variants in the major histocompatibility complex (MHC, chr6:25–34 Mb) region were excluded due to extensive long-range LD. …

Mechanisms of Cancer Resistance to Immunotherapy.

Over the last decade, based on the extensive development of preclinical animal studies and clinical trials, the efficacy, and mechanisms of immunotherapy have been fully explored. Significant and lasting clinical responses with immunotherapy provide a new breakthrough treatment for a variety of refractory cancer histologies, which gradually change the treatment pattern of tumors. However, although immune checkpoint inhibitor drugs are promising for achieving longer-term efficacy, their benefits in the overall population are still very low, such as low frequency of response in some common tumor

Полиморфизм меланкортина - генезиалы с воспалением и болезнями.

Рецепторы Меланокортина (МКР) выполняют различные функции: от пигментации кожи, регулирования аппетита, реакции на стресс и когниции, синтеза стероидов и энергетического баланса до регенерации клеток и иммуномодуляции. Генетический полиморфизм с распределением тканей от мозга, лимбической системы и адренальной коры до нейтрофилов, моноцитов и макрофазов проявляется в MCR. Мутации в генах MC1R, MC2R, MC3R и MC4R связаны с риском меланомы, семейной глюкокортикоидной недостаточности, ожирения и типа 2 Диафиозный сахар, соответственно. Тем временем, MC1R, MC2R и MC5R связаны с риском серьезного де

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… The activation of these cells has been shown to influence nuclear factor kappa B, which engages in the transcription signaling and modulation of genes for cytokines, chemokines, growth factors, major histocompatibility complex (MHC), anti-apoptotic factors, and inducible nitric oxide synthase [ 15 ]. … Abbreviations MCR Melanocortin receptor MSH Melanocyte stimulating hormone ACTH Adrenocorticotropic hormone POMC Pro-opiomelanocortin PC Prohormone convertase AGRP Agouti-related protein ASIP Agouti-signaling protein NF-kB Nuclear factor kappa B MHC Major histocompatibility complex CLIP Corticotropin-like …

Efficacy and safety of approved cellular therapies and bispecific antibodies in solid tumors: the current state.

Cancer immunotherapy is a broad term including naked antibodies, bispecific antibodies (BsAbs), immune-checkpoint inhibitors (ICIs), chimeric antigen receptor T-cell (CAR-T) therapy, cancer vaccines, activated immune cells, and allogeneic hematopoietic cell transplantation. Recent advances in immune-engaging T-cell therapies have led to significant progress in novel treatments across various cancer types, resulting in prolonged patient survival, mainly in patients with hematologic malignancies. Several CAR T-cell constructs and BsAbs have been approved by regulatory authorities worldwide for r

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… A TCR-based platform bears the ability to recognize tumor-specific epitopes presented by major histocompatibility complex (MHC) class I molecules on the surface of tumor cells. … histocompatibility complex Natural killer Non–small cell lung cancer Overall response rate Overall survival Progression-free survival Tumor-associated macrophages T-cell–engaging T-cell receptor Tumor-infiltrating lymphocytes Tumor microenvironment Triple-negative breast cancer Regulatory …

Приложение А1, калорикулин и коробка с высокой мобильностью 1 увеличены во вторичном прогрессивном множественном склерозе: имеет ли иммуногенная клеточная смерть при множественном склерозе?

ВВЕДЕНИЕ: Множественный склероз (MS) представляет собой хронические нервно-воспалительные заболевания, характеризующиеся обезвоживанием нервных волокон. Иммуногенная смерть клеток (ИКД) представляет собой процесс, в ходе которого поврежденные и напряженные клетки высвобождают связанные с опасностью молекулярные модели (DAMPs), приводящие в действие иммунную реакцию. Цель этого исследования состояла в том, чтобы разъяснить, каким образом НИЗ распространяется на болезни, связанные с НР. МЕТОДЫ: Для достижения этой цели уровень DAMP, включая приложение A1 (ANXA1), кальретикулина и HMGB1, был изме

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… This function of ANXA1 enables the uptake of antigens and their cross-presentation on major histocompatibility complex class I (MHC I), ultimately leading to the activation of immune responses. 27 - 29 ANXA1 level in CSF sample of control group and SPMS patient. …