Immune monitoring of cell therapies is a complex and evolving topic, particularly in the rapid expanding field of chimeric antigen receptor T (CAR-T) cell applications. Defining essential, recommended, and optional immune monitoring data post-CAR-T cell infusion is crucial to improve patient outcomes and inform post-treatment decisions. To address this gap, we conducted a survey-based study across centers affiliated with the European Society for Blood and Marrow Transplantation (EBMT), focusing on patients treated with European Medicines Agency (EMA)-approved CAR-T products. Building on a thorough review of the literature, we mapped the current landscape of immune monitoring practices and assessed their impact on clinical management. By defining the state of the art in the field, this work marks an initial step towards a structured harmonization process potentially able to enhance the management and outcomes of patients undergoing these immune cell therapies.

• Klíčová slova
• B cell aplasia, CAR-T cell expansion, CAR-T cells, CRS, ICANS, Immune monitoring, Immune reconstitution, Lentiviral integration, Transduction,
• MeSH
• chimerické antigenní receptory * imunologie   MeSH
• imunoterapie adoptivní * metody   škodlivé účinky   MeSH
• lidé MeSH
• monitorování imunologické metody   MeSH
• průzkumy a dotazníky MeSH
• T-lymfocyty imunologie   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• chimerické antigenní receptory * MeSH

Initiation of newborn screening (NBS) programs in Europe dates back to the 1960s. One of the most recent expansions of NBS programs was the addition of severe combined immunodeficiency (SCID) based on detection of T-cell receptor excision circles (TRECs). In this review, we present an overview of the current situation in Europe. To avoid a biased overview based on only published results, a 37-item survey on TREC-based NBS was sent to representatives of 46 European countries. With a response rate of 83%, we collected data of 38 countries. Seventeen of the 38 European countries that have completed the survey have nationally or regionally implemented TREC-based NBS. The survey results emphasize similarities and differences as well as common practices and challenges in TREC-based NBS. Because TRECs are a general surrogate marker for severe T lymphocytopenia, conditions other than SCID are also identified. Therefore, the initial definition of the target disease as "SCID" might need to be reconsidered and extended to "SCID and severe T lymphocytopenia." Even though complete harmonization of TREC-based NBS programs across Europe will remain challenging, collaboration and close partnerships will help in the move toward universal TREC-based screening for all newborns, resulting in more infants with SCID and severe T lymphocytopenia being detected each year.

• Klíčová slova
• Europe, IEI, NBS, Newborn screening, SCID, TREC, inborn errors of immunity, severe T lymphocytopenia, severe combined immunodeficiency,
• MeSH
• lidé MeSH
• lymfopenie * diagnóza   epidemiologie   MeSH
• novorozenec MeSH
• novorozenecký screening * metody   MeSH
• receptory antigenů T-buněk genetika   MeSH
• T-lymfocyty * imunologie   MeSH
• těžká kombinovaná imunodeficience * diagnóza   epidemiologie   genetika   MeSH
• Check Tag
• lidé MeSH
• novorozenec MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Geografické názvy
• Evropa epidemiologie   MeSH
• Názvy látek
• receptory antigenů T-buněk MeSH

IMPORTANCE: Advancements in molecular engineering have facilitated the creation of engineered T cells that express synthetic receptors, termed chimeric antigen receptors (CARs). This is promising not only in cancer treatment but also in addressing a spectrum of other conditions. This review provides a comprehensive overview of the current approaches and future potential of CAR T-cell therapy in the field of neurology, particularly for primary brain tumors and autoimmune neurological disorders. OBSERVATIONS: CAR T-cell therapy for glioblastoma is promising; however, first-in-human trials did not yield significant success or showed only limited success in a subset of patients. To date, the efficacy of CAR T-cell therapies has been demonstrated in animal models of multiple sclerosis, but larger human studies to corroborate the efficacy remain pending. CAR T cells showed efficacy in treatment of patients with relapsed or refractory aquaporin 4-immunoglobulin G-seropositive neuromyelitis optica spectrum disorders. Further studies with larger patient populations are needed to confirm these results. Success was reported also for treatment of cases with generalized myasthenia gravis using CAR T cells. Chimeric autoantibody receptor T cells, representing a modified form of CAR T cells directed against autoreactive B cells secreting autoantibodies, were used to selectively target autoreactive anti-N-methyl-d-aspartate B cells under in vitro and in vivo conditions, providing the basis for human studies and application to other types of autoimmune encephalitis associated with neuronal or glial antibodies. CONCLUSIONS AND RELEVANCE: CAR T cells herald a new era in the therapeutic landscape of neurological disorders. While their application in solid tumors, such as glioblastoma, has not universally yielded robust success, emerging innovative strategies show promise, and there is optimism for their effectiveness in certain autoimmune neurological disorders.

• MeSH
• chimerické antigenní receptory * imunologie   terapeutické užití   MeSH
• imunoterapie adoptivní * metody   trendy   MeSH
• lidé MeSH
• nádory mozku * terapie   imunologie   MeSH
• nemoci nervového systému * terapie   imunologie   MeSH
• neurologie * trendy   metody   MeSH
• T-lymfocyty * imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• chimerické antigenní receptory * MeSH

The adaptive immune response critically hinges on the functionality of T cell receptors, governed by complex molecular mechanisms, including ubiquitination. In this study, we delved into the role of in T cell immunity, focusing on T cell-B cell conjugate formation and T cell activation. Using a CRISPR-Cas9 screening approach targeting deubiquitinases genes in Jurkat T cells, we identified BAP1 as a key positive regulator of T cell-B cell conjugate formation. Subsequent investigations into BAP1 knockout cells revealed impaired T cell activation, evidenced by decreased MAPK and NF-kB signaling pathways and reduced CD69 expression upon T cell receptor stimulation. Flow cytometry and qPCR analyses demonstrated that BAP1 deficiency leads to decreased surface expression of T cell receptor complex components and reduced mRNA levels of the co-stimulatory molecule CD28. Notably, the observed phenotypes associated with BAP1 knockout are specific to T cells and fully dependent on BAP1 catalytic activity. In-depth RNA-seq and mass spectrometry analyses further revealed that BAP1 deficiency induces broad mRNA and protein expression changes. Overall, our findings elucidate the vital role of BAP1 in T cell biology, especially in T cell-B cell conjugate formation and T cell activation, offering new insights and directions for future research in immune regulation.

• Klíčová slova
• BAP1, CRISPR-Cas9 screening, T cell activation, T cell receptor (TCR), T cell-B cell conjugates,
• MeSH
• aktivace lymfocytů * imunologie   MeSH
• B-lymfocyty * imunologie   metabolismus   MeSH
• Jurkat buňky MeSH
• lidé MeSH
• nádorové supresorové proteiny * metabolismus   genetika   MeSH
• receptory antigenů T-buněk * metabolismus   MeSH
• signální transdukce MeSH
• T-lymfocyty * imunologie   metabolismus   MeSH
• thiolesterasa ubikvitinu * genetika   metabolismus   nedostatek   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• BAP1 protein, human MeSH Prohlížeč
• nádorové supresorové proteiny * MeSH
• receptory antigenů T-buněk * MeSH
• thiolesterasa ubikvitinu * MeSH

Allelic variability in the adaptive immune receptor loci, which harbor the gene segments that encode B cell and T cell receptors (BCR/TCR), is of critical importance for immune responses to pathogens and vaccines. Adaptive immune receptor repertoire sequencing (AIRR-seq) has become widespread in immunology research making it the most readily available source of information about allelic diversity in immunoglobulin (IG) and T cell receptor (TR) loci. Here, we present a novel algorithm for extrasensitive and specific variable (V) and joining (J) gene allele inference, allowing the reconstruction of individual high-quality gene segment libraries. The approach can be applied for inferring allelic variants from peripheral blood lymphocyte BCR and TCR repertoire sequencing data, including hypermutated isotype-switched BCR sequences, thus allowing high-throughput novel allele discovery from a wide variety of existing data sets. The developed algorithm is a part of the MiXCR software. We demonstrate the accuracy of this approach using AIRR-seq paired with long-read genomic sequencing data, comparing it to a widely used algorithm, TIgGER. We applied the algorithm to a large set of IG heavy chain (IGH) AIRR-seq data from 450 donors of ancestrally diverse population groups, and to the largest reported full-length TCR alpha and beta chain (TRA and TRB) AIRR-seq data set, representing 134 individuals. This allowed us to assess the genetic diversity within the IGH, TRA, and TRB loci in different populations and to establish a database of alleles of V and J genes inferred from AIRR-seq data and their population frequencies with free public access through VDJ.online database.

• MeSH
• alely * MeSH
• algoritmy * MeSH
• genetická variace MeSH
• lidé MeSH
• receptory antigenů B-buněk genetika   imunologie   MeSH
• receptory antigenů T-buněk genetika   imunologie   MeSH
• sekvenční analýza DNA metody   MeSH
• software * MeSH
• vysoce účinné nukleotidové sekvenování metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• receptory antigenů B-buněk MeSH
• receptory antigenů T-buněk MeSH

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment paradigms for hematological malignancies. However, more than half of these patients cannot achieve sustainable tumor control, partially due to the inadequate potency of CAR-T cells in eradicating tumor cells. T cells are crucial components of the anti-tumor immune response, and multiple intrinsic T-cell features significantly influence the outcomes of CAR-T cell therapy. Herein, we review progressing research on T-cell characteristics that impact the effectiveness of CAR-T cells, including T-cell exhaustion, memory subsets, senescence, regulatory T-cells, the CD4+ to CD8+ T-cell ratio, metabolism, and the T-cell receptor repertoire. With comprehensive insight into the biological processes underlying successful CAR-T cell therapy, we will further refine the applications of these novel therapeutic modalities, and enhance their efficacy and safety for patients.

• MeSH
• chimerické antigenní receptory * imunologie   MeSH
• hematologické nádory * terapie   imunologie   MeSH
• imunoterapie adoptivní * metody   MeSH
• lidé MeSH
• T-lymfocyty imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• chimerické antigenní receptory * MeSH

Besides many other mutations in known cancer driver genes, mantle cell lymphoma (MCL) is characterized by recurrent genetic alterations of important regulators of the phosphoinositol-3-kinase (PI3K) cascade including PIK3CA gains and PTEN losses. To evaluate the biological and functional consequences of these aberrations in MCL, we have introduced transgenic expression of PIK3CA (PIK3CA UP) and performed knockout/knockdown of PTEN gene (PTEN KO/KD) in 5 MCL cell lines. The modified cell lines were tested for associated phenotypes including dependence on upstream B-cell receptor (BCR) signaling (by an additional BCR knockout). PIK3CA overexpression decreased the dependence of the tested MCL on prosurvival signaling from BCR, decreased levels of oxidative phosphorylation, and increased resistance to 2-deoxy-glucose, a glycolysis inhibitor. Unchanged protein kinase B (AKT) phosphorylation status and unchanged sensitivity to a battery of PI3K inhibitors suggested that PIK3CA gain might affect MCL cells in AKT-independent manner. PTEN KO was associated with a more distinct phenotype: AKT hyperphosphorylation and overactivation, increased resistance to multiple inhibitors (most of the tested PI3K inhibitors, Bruton tyrosine kinase inhibitor ibrutinib, and BCL2 inhibitor venetoclax), increased glycolytic rates with resistance to 2-deoxy-glucose, and significantly decreased dependence on prosurvival BCR signaling. Our results suggest that the frequent aberrations of the PI3K pathway may rewire associated signaling with lower dependence on BCR signaling, better metabolic and hypoxic adaptation, and targeted therapy resistance in MCL.

• MeSH
• chemorezistence genetika   MeSH
• cílená molekulární terapie MeSH
• fosfatidylinositol-3-kinasy třídy I * genetika   metabolismus   MeSH
• fosfatidylinositol-3-kinasy metabolismus   MeSH
• fosfohydroláza PTEN * metabolismus   genetika   MeSH
• lidé MeSH
• lymfom z plášťových buněk * farmakoterapie   genetika   metabolismus   MeSH
• nádorové buněčné linie MeSH
• protoonkogenní proteiny c-akt metabolismus   MeSH
• receptory antigenů B-buněk metabolismus   MeSH
• signální transdukce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fosfatidylinositol-3-kinasy třídy I * MeSH
• fosfatidylinositol-3-kinasy MeSH
• fosfohydroláza PTEN * MeSH
• PIK3CA protein, human MeSH Prohlížeč
• protoonkogenní proteiny c-akt MeSH
• PTEN protein, human MeSH Prohlížeč
• receptory antigenů B-buněk MeSH

The mammalian body possesses remarkable adaptability to cold exposure, involving intricate adjustments in cellular metabolism, ultimately leading to thermogenesis. However, cold-induced stress can impact immune response, primarily through noradrenaline-mediated pathways. In our study, we utilized a rat model subjected to short-term or long-term mild cold exposure to investigate systemic immune response during the cold acclimation. To provide human relevance, we included a group of regular cold swimmers in our study. Our research revealed complex relationship between cold exposure, neural signaling, immune response, and thermogenic regulation. One-day cold exposure triggered stress response, including cytokine production in white adipose tissue, subsequently activating brown adipose tissue, and inducing thermogenesis. We further studied systemic immune response, including the proportion of leukocytes and cytokines production. Interestingly, γδ T cells emerged as possible regulators in the broader systemic response, suggesting their possible contribution in the dynamic process of cold adaptation. We employed RNA-seq to gain further insights into the mechanisms by which γδ T cells participate in the response to cold. Additionally, we challenged rats exposed to cold with the Toll-like receptor 2 agonist, showing significant modulation of immune response. These findings significantly contribute to understanding of the physiological acclimation that occur in response to cold exposure.

• Klíčová slova
• Cold exposure, Cytokines, Immune response, TLR2, γδ T cells,
• MeSH
• aklimatizace imunologie   MeSH
• cytokiny metabolismus   MeSH
• hnědá tuková tkáň imunologie   metabolismus   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• nízká teplota * MeSH
• receptory antigenů T-buněk gama-delta imunologie   metabolismus   MeSH
• T-lymfocyty imunologie   MeSH
• termogeneze imunologie   MeSH
• toll-like receptor 2 * metabolismus   genetika   imunologie   MeSH
• zánět * imunologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cytokiny MeSH
• receptory antigenů T-buněk gama-delta MeSH
• Tlr2 protein, rat MeSH Prohlížeč
• toll-like receptor 2 * MeSH

AIM: The aim of this study was to analyse the outcomes of patients with large B-cell lymphoma (LBCL) treated with chimeric antigen receptor T-cell therapy (CAR-Tx), with a focus on outcomes after CAR T-cell failure, and to define the risk factors for rapid progression and further treatment. METHODS: We analysed 107 patients with LBCL from the Czech Republic and Slovakia who were treated in ≥3rd-line with tisagenlecleucel or axicabtagene ciloleucel between 2019 and 2022. RESULTS: The overall response rate (ORR) was 60%, with a 50% complete response (CR) rate. The median progression-free survival (PFS) and overall survival (OS) were 4.3 and 26.4 months, respectively. Sixty-three patients (59%) were refractory or relapsed after CAR-Tx. Of these patients, 39 received radiotherapy or systemic therapy, with an ORR of 22% (CR 8%). The median follow-up of surviving patients in whom treatment failed was 10.6 months. Several factors predicting further treatment administration and outcomes were present even before CAR-Tx. Risk factors for not receiving further therapy after CAR-Tx failure were high lactate dehydrogenase (LDH) levels before apheresis, extranodal involvement (EN), high ferritin levels before lymphodepletion (LD) and ECOG PS >1 at R/P. The median OS-2 (from R/P after CAR-Tx) was 6.7 months (6-month 57.9%) for treated patients and 0.4 months (6-month 4.2%) for untreated patients (p < 0.001). The median PFS-2 (from R/P after CAR-Tx) was 3.2 months (6-month 28.5%) for treated patients. The risk factors for a shorter PFS-2 (n = 39) included: CRP > limit of the normal range (LNR) before LD, albumin < LNR and ECOG PS > 1 at R/P. All these factors, together with LDH > LNR before LD and EN involvement at R/P, predicted OS-2 for treated patients. CONCLUSION: Our findings allow better stratification of CAR-Tx candidates and stress the need for a proactive approach (earlier restaging, intervention after partial remission achievement).

• Klíčová slova
• CAR T‐cell failure, outcomes of patients after CAR T‐cell therapy failure, relapsed/refractory large B‐cell lymphoma, risk factors for CAR T‐cell therapy failure,
• MeSH
• antigeny CD19 imunologie   MeSH
• biologické přípravky terapeutické užití   MeSH
• chimerické antigenní receptory imunologie   MeSH
• difúzní velkobuněčný B-lymfom * terapie   mortalita   imunologie   MeSH
• doba přežití bez progrese choroby MeSH
• dospělí MeSH
• imunoterapie adoptivní * metody   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokální recidiva nádoru MeSH
• mladý dospělý MeSH
• progrese nemoci MeSH
• receptory antigenů T-buněk genetika   metabolismus   MeSH
• rizikové faktory MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH
• Slovenská republika MeSH
• Názvy látek
• antigeny CD19 MeSH
• axicabtagene ciloleucel MeSH Prohlížeč
• biologické přípravky MeSH
• chimerické antigenní receptory MeSH
• receptory antigenů T-buněk MeSH
• tisagenlecleucel MeSH Prohlížeč

COVID-19 has been associated with high mortality in patients treated with Chimeric Antigen Receptor (CAR) T-cell therapy for hematologic malignancies. Here, we investigated whether the outcome has improved over time with the primary objective of assessing COVID-19-attributable mortality in the Omicron period of 2022 compared to previous years. Data for this multicenter study were collected using the MED-A and COVID-19 report forms developed by the EBMT. One-hundred-eighty patients were included in the analysis, 39 diagnosed in 2020, 35 in 2021 and 106 in 2022. The median age was 58.9 years (min-max: 5.2-78.4). There was a successive decrease in COVID-19-related mortality over time (2020: 43.6%, 2021: 22.9%, 2022: 7.5%) and in multivariate analysis year of infection was the strongest predictor of survival (p = 0.0001). Comparing 2022 with 2020-2021, significantly fewer patients had lower respiratory symptoms (21.7% vs 37.8%, p = 0.01), needed oxygen support (25.5% vs 43.2%, p = 0.01), or were admitted to ICU (5.7% vs 33.8%, p = 0.0001). Although COVID-19-related mortality has decreased over time, CAR T-cell recipients remain at higher risk for complications than the general population. Consequently, vigilant monitoring for COVID-19 in patients undergoing B-cell-targeting CAR T-cell treatment is continuously recommended ensuring optimal prevention of infection and advanced state-of-the art treatment when needed.

• MeSH
• chimerické antigenní receptory imunologie   MeSH
• COVID-19 * terapie   imunologie   mortalita   MeSH
• dítě MeSH
• dospělí MeSH
• hematologické nádory * terapie   mortalita   imunologie   MeSH
• imunoterapie adoptivní * metody   škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• míra přežití MeSH
• mladiství MeSH
• mladý dospělý MeSH
• předškolní dítě MeSH
• SARS-CoV-2 * imunologie   MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• Geografické názvy
• Evropa epidemiologie   MeSH
• Názvy látek
• chimerické antigenní receptory MeSH