BACKGROUND: The CD40-CD40L costimulatory pathway regulates adaptive and innate immune responses and has been implicated in the pathogenesis of multiple sclerosis. Frexalimab is a second-generation anti-CD40L monoclonal antibody being evaluated for the treatment of multiple sclerosis. METHODS: In this phase 2, double-blind, randomized trial, we assigned, in a 4:4:1:1 ratio, participants with relapsing multiple sclerosis to receive 1200 mg of frexalimab administered intravenously every 4 weeks (with an 1800-mg loading dose), 300 mg of frexalimab administered subcutaneously every 2 weeks (with a 600-mg loading dose), or the matching placebos for each active treatment. The primary end point was the number of new gadolinium-enhancing T1-weighted lesions seen on magnetic resonance imaging at week 12 relative to week 8. Secondary end points included the number of new or enlarging T2-weighted lesions at week 12 relative to week 8, the total number of gadolinium-enhancing T1-weighted lesions at week 12, and safety. After 12 weeks, all the participants could receive open-label frexalimab. RESULTS: Of 166 participants screened, 129 were assigned to a trial group; 125 participants (97%) completed the 12-week double-blind period. The mean age of the participants was 36.6 years, 66% were women, and 30% had gadolinium-enhancing lesions at baseline. At week 12, the adjusted mean number of new gadolinium-enhancing T1-weighted lesions was 0.2 (95% confidence interval [CI], 0.1 to 0.4) in the group that received 1200 mg of frexalimab intravenously and 0.3 (95% CI, 0.1 to 0.6) in the group that received 300 mg of frexalimab subcutaneously, as compared with 1.4 (95% CI, 0.6 to 3.0) in the pooled placebo group. The rate ratios as compared with placebo were 0.11 (95% CI, 0.03 to 0.38) in the 1200-mg group and 0.21 (95% CI, 0.08 to 0.56) in the 300-mg group. Results for the secondary imaging end points were generally in the same direction as those for the primary analysis. The most common adverse events were coronavirus disease 2019 and headaches. CONCLUSIONS: In a phase 2 trial involving participants with multiple sclerosis, inhibition of CD40L with frexalimab had an effect that generally favored a greater reduction in the number of new gadolinium-enhancing T1-weighted lesions at week 12 as compared with placebo. Larger and longer trials are needed to determine the long-term efficacy and safety of frexalimab in persons with multiple sclerosis. (Funded by Sanofi; ClinicalTrials.gov number, NCT04879628.).

• MeSH
• antigeny CD40 * antagonisté a inhibitory   imunologie   MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• gadolinium MeSH
• injekce subkutánní MeSH
• intravenózní podání MeSH
• lidé MeSH
• ligand CD40 * antagonisté a inhibitory   imunologie   MeSH
• magnetická rezonanční tomografie MeSH
• monoklonální protilátky * imunologie   terapeutické užití   MeSH
• relabující-remitující roztroušená skleróza * diagnostické zobrazování   farmakoterapie   imunologie   MeSH
• roztroušená skleróza diagnostické zobrazování   farmakoterapie   imunologie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH

Multiple myeloma (MM) has witnessed improved patient outcomes through advancements in therapeutic approaches. Notably, allogeneic stem cell transplantation, proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies have contributed to enhanced quality of life. Recently, a promising avenue has emerged with chimeric antigen receptor (CAR) T cells targeting B-cell maturation antigen (BCMA), expressed widely on MM cells. To mitigate risks associated with allogenic T cells, we investigated the potential of BCMA CAR expression in natural killer cells (NKs), known for potent cytotoxicity and minimal side effects. Using the NK-92 cell line, we co-expressed BCMA CAR and soluble tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL) employing the piggyBac transposon system. Engineered NK cells (CAR-NK-92-TRAIL) demonstrated robust cytotoxicity against a panel of MM cell lines and primary patient samples, outperforming unmodified NK-92 cells with a mean difference in viability of 45.1% (±26.1%, depending on the target cell line). Combination therapy was explored with the proteasome inhibitor bortezomib (BZ) and γ-secretase inhibitors (GSIs), leading to a significant synergistic effect in combination with CAR-NK-92-TRAIL cells. This synergy was evident in cytotoxicity assays where a notable decrease in MM cell viability was observed in combinatorial therapy compared to single treatment. In summary, our study demonstrates the therapeutic potential of the CAR-NK-92-TRAIL cells for the treatment of MM. The synergistic impact of combining these engineered NK cells with BZ and GSI supports further development of allogeneic CAR-based products for effective MM therapy.

• MeSH
• bortezomib farmakologie   terapeutické užití   MeSH
• chimerické antigenní receptory * metabolismus   MeSH
• imunoterapie adoptivní MeSH
• kvalita života MeSH
• lidé MeSH
• maturační antigen B-buněk metabolismus   MeSH
• mnohočetný myelom * patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Teklistamab je první bispecifická protilátka proti antigenu zrání B-lymfocytů (BCMA) a proti receptoru CD3 na povrchu T-lymfocytů užívaná v léčbě relabujícího/refrakterního mnohočetného myelomu (RRMM). Nová dlouhodobá data prokazují jeho dlouhodobou účinnost v dosahování hlubokých léčebných odpovědí a jejich udržení v čase, a to i v prodlouženém režimu podávání na 2 týdny

Teklistamab is the fi rst-in-class bispecifi c antibody against B-cell maturation antigen (BCMA) and CD3 receptor on the surface of T-lymphocytes used in the treatment of relapsed/ refractory multiple myeloma (RRMM). New long-term data demonstrate its sustained effi cacy in achieving deep therapeutic responses and maintaining them over time, even with an extended 2-week dosing regimen.

• Klíčová slova
• teklistamab,
• MeSH
• antigeny CD3 imunologie   MeSH
• doba přežití bez progrese choroby MeSH
• lidé MeSH
• maturační antigen B-buněk genetika   imunologie   MeSH
• mnohočetný myelom * farmakoterapie   MeSH
• multicentrické studie jako téma MeSH
• protilátky bispecifické * terapeutické užití   MeSH
• reziduální nádor MeSH
• Check Tag
• lidé MeSH

INTRODUCTION: This study aimed to identify the phytochemical constituents that could target gastric cancer in Kangai injection using a network pharmacology-based approach. METHODS: Protein-protein interactions (PPI), Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were conducted utilizing String and OmicShare tools. In the in vitro experiments, the related mRNA and protein levels were assessed via real-time quantitative polymerase chain reaction and Western blotting, respectively. Cell proliferation was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay. RESULTS: Kangai injection comprises several compounds, which target multiple substrates and pathways related to gastric cancer. The PPI and Gene Ontology analyses revealed that tumor necrosis factor (TNF) was a hub gene. KEGG pathway enrichment analysis indicated that the the TNF pathway was significantly enriched. Kangai injection decreased the mRNA levels of TNFR2, TRAF2, PI3K, AKT, and IκBα and inhibited the phosphorylation of PI3K, AKT, and IκBα phosphorylations. Kangai injection inhibited cell proliferation, while TNFR2 overexpression or treatment with the PI3K activator 740 Y-P partially restored it. CONCLUSION: Kangai injection operates through multiple targets and pathways in gastric cancer, with the TNFR2/PI3K/AKT/NF-κB pathway playing a crucial role in its mechanism against gastric cancer.

• MeSH
• fosfatidylinositol-3-kinasy MeSH
• lidé MeSH
• nádory žaludku * farmakoterapie   genetika   MeSH
• NFKB inhibitor alfa MeSH
• protoonkogenní proteiny c-akt MeSH
• receptory TNF - typ II MeSH
• síťová farmakologie MeSH
• TNF-alfa genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Podávání denosumabu je indikováno pro léčbu osteoporózy u postmenopauzálních žen a u mužů se zvýšeným rizikem zlomenin, dále pro léčbu úbytku kostní hmoty vzniklého následkem hormonální ablace u mužů a pro léčbu úbytku kostní hmoty spojeného s dlouhodobou systémovou léčbou glukokortikoidy. Denosumab inhibuje progresi kostních erozí a zároveň zvyšuje hustotu minerálů v kosti u pacientů s revmatoidní artritidou (RA) léčených methotrexátem a ostatními konvenčními syntetickými chorobu modifikujícími antirevmatickými léky (conventional synthetic disease modifying anti-rheumatic drug, csDMARD). Denosumab potlačuje vznik marginálních kloubních erozí. Denosumab preferenčně redukuje progresi kloubní destrukce u pacientů s RA s autoprotilátkami proti cyklickým citrulinovaným peptidům. Denosumab je prvním lékem, který je účinný v léčbě osteoporózy i v potlačení vzniku kloubních erozí u pacientů s RA léčených csDMARD. Přidání denosumabu do léčby pacientů s RA může být novou terapeutickou možností.

Denosumab is indicated for the treatment of osteoporosis in postmenopausal women and men at an increased risk of fracture, for treating bone loss resulting from hormone ablation in men, and for addressing bone loss associated with long-term systemic glucocorticoid therapy. It inhibits the progression of bone erosions while increasing bone mineral density in patients with rheumatoid arthritis (RA) who are treated with methotrexate and other conventional synthetic disease modifying anti-rheumatic drugs (csDMARD). Denosumab suppresses the development of marginal joint erosions and preferentially reduces the progression of joint destruction in RA patients with autoantibodies to cyclic citrullinated peptides. It is the first drug that is effective both in treating osteoporosis and in suppressing the development of joint erosions in RA patients treated with csDMARD. Therefore, adding denosumab to the treatment of RA patients may represent a new therapeutic option.

• Klíčová slova
• studie FREEDOM,
• MeSH
• denosumab * aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• lidé MeSH
• ligand RANK antagonisté a inhibitory   MeSH
• osteoprotegerin MeSH
• postmenopauzální osteoporóza farmakoterapie   komplikace   MeSH
• randomizované kontrolované studie jako téma MeSH
• revmatoidní artritida farmakoterapie   komplikace   patologie   MeSH
• Check Tag
• lidé MeSH

Rozvoj biotechnologií a genetického inženýrství na konci minulého tisíciletí přinesl přelom v terapii nemocných se zánětlivými revmatickými chorobami, u kterých selhala terapie konvenčními syntetickými chorobu modifikujícími antirevmatickými léky (conventional synthetic disease modifying anti-rheumatic drug csDMARD). Nástup biologické terapie zlepšil prognózu a kvalitu života pacientů, ale přinesl ekonomickou zátěž spojenou s dosud celosvětově vysokou cenou této léčby. Narůstající potřeba biologických chorobu modifikujících antirevmatických léků (biological disease modifying anti-rheumatic drug, bDMARD) a jejich cena vedla po vypršení patentu na originální bDMARD k nástupu biosimilárních léků (biosimilar disease modifying anti-rheumatic drug, bsDMARD). Vzhledem k složité proteinové struktuře nelze bsDMARD považovat za tradiční generika, ale vysoce podobné kopie bDMARD, ze kterých vycházejí. Účinnost, bezpečnost a biosimilarita srovnatelná s originálním bDMARD musí být prokázána prostřednictvím klinických sledování před zavedení bsDMARD do klinické praxe. Předpokládá se, že cenově dostupnější bsDMARD umožní celosvětově širší dostupnost a udržitelnost léčby. Schválení prvního bsDMARD CT-P13 (biosimilární infliximab) se stalo přelomovou událostí, která umožnila rozvoj dalších bsDMARD. Tento článek se zabývá vybranými bsDMARD využívaných v současnosti v terapii zánětlivých revmatických onemocnění v České republice.

The advent of biotechnology and genetic engineering at the close of the last millennium marked a significant advancement in the treatment of patients with inflammatory rheumatic diseases, particularly when conventional disease-modifying drug therapy (csDMARD) had proven ineffective. The introduction of biological therapies (bDMARDs) has improved patient prognosis and quality of life, yet it has also resulted in an economic burden due to the persistently high cost of these treatments globally. The growing demand for bDMARDs and their associated costs have facilitated the emergence of biosimilars (bsDMARDs) following the expiration of the original bDMARDs patents. Given their complex protein structure, bsDMARDs should not be considered as traditional generics but rather as highly similar replicas of the original bDMARDs. Efficacy, safety, and biosimilarity to the original bDMARD must be demonstrated through clinical monitoring before bsDMARDs can be incorporated into clinical practice. The introduction of more affordable bsDMARDs is expected to expand treatment accessibility and sustainability worldwide. The approval of the first bsDMARD, CT-P13 (biosimilar infliximab), was a pivotal event, paving the way for the development of additional bsDMARDs. This article focuses on selected bsDMARDs currently used in the treatment of inflammatory rheumatic diseases in the Czech Republic.

• MeSH
• adalimumab aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• biologická terapie metody   MeSH
• biosimilární léčivé přípravky * farmakologie   MeSH
• etanercept aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• infliximab aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• klinická studie jako téma MeSH
• lidé MeSH
• rituximab aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

BACKGROUND: Autologous tumor cell-based vaccines (ATVs) aim to prevent and treat tumor metastasis by activating patient-specific tumor antigens to induce immune memory. However, their clinical efficacy is limited. Mannan-BAM (MB), a pathogen-associated molecular pattern (PAMP), can coordinate an innate immune response that recognizes and eliminates mannan-BAM-labeled tumor cells. TLR agonists and anti-CD40 antibodies (TA) can enhance the immune response by activating antigen-presenting cells (APCs) to present tumor antigens to the adaptive immune system. In this study, we investigated the efficacy and mechanism of action of rWTC-MBTA, an autologous whole tumor cell vaccine consisting of irradiated tumor cells (rWTC) pulsed with mannan-BAM, TLR agonists, and anti-CD40 antibody (MBTA), in preventing tumor metastasis in multiple animal models. METHODS: The efficacy of the rWTC-MBTA vaccine was evaluated in mice using breast (4T1) and melanoma (B16-F10) tumor models via subcutaneous and intravenous injection of tumor cells to induce metastasis. The vaccine's effect was also assessed in a postoperative breast tumor model (4T1) and tested in autologous and allogeneic syngeneic breast tumor models (4T1 and EMT6). Mechanistic investigations included immunohistochemistry, immunophenotyping analysis, ELISA, tumor-specific cytotoxicity testing, and T-cell depletion experiments. Biochemistry testing and histopathology of major tissues in vaccinated mice were also evaluated for potential systemic toxicity of the vaccine. RESULTS: The rWTC-MBTA vaccine effectively prevented metastasis and inhibited tumor growth in breast tumor and melanoma metastatic animal models. It also prevented tumor metastasis and prolonged survival in the postoperative breast tumor animal model. Cross-vaccination experiments revealed that the rWTC-MBTA vaccine prevented autologous tumor growth, but not allogeneic tumor growth. Mechanistic data demonstrated that the vaccine increased the percentage of antigen-presenting cells, induced effector and central memory cells, and enhanced CD4+ and CD8+ T-cell responses. T-cells obtained from mice that were vaccinated displayed tumor-specific cytotoxicity, as shown by enhanced tumor cell killing in co-culture experiments, accompanied by increased levels of Granzyme B, TNF-α, IFN-γ, and CD107a in T-cells. T-cell depletion experiments showed that the vaccine's antitumor efficacy depended on T-cells, especially CD4+ T-cells. Biochemistry testing and histopathology of major tissues in vaccinated mice revealed negligible systemic toxicity of the vaccine. CONCLUSION: The rWTC-MBTA vaccine demonstrated efficacy in multiple animal models through T-cell mediated cytotoxicity and has potential as a therapeutic option for preventing and treating tumor metastasis with minimal systemic toxicity.

• MeSH
• antigeny CD40 MeSH
• antigeny nádorové MeSH
• imunologická paměť MeSH
• lidé MeSH
• mannany MeSH
• melanom * MeSH
• myši MeSH
• nádory prsu * terapie   MeSH
• protinádorové vakcíny * terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Patients with Sjögren's syndrome, like other patients with autoimmune disorders, display dysregulation in the function of their immune system. Fas and Fas Ligand (FasL) are among the dysregulated proteins. METHODS: We studied Fas and FasL on IL-2Rα+ cells and in serum of patients with Sjögren's syndrome (n = 16) and healthy individuals (n = 16); both from same ethnic and geographical background. We used flow cytometry and enzyme-linked immunosorbent for this purpose. We also measured the expression of Bcl-2 and Bax by reverse transcription quantitative real-time PCR (RT-qPCR) and percentage of apoptotic and dead cells using Annexin V and 7-AAD staining in lymphocytes. RESULTS: FasL was increased in patients' T and B cells while Fas was increased in patients' monocytes, T and B cells. No signs of increased apoptosis were found. sFas and sFasL in patients' serum were increased, although the increase in sFasL was not significant. We suspect an effect of non-steroidal anti-inflammatory therapy on B cells, explaining the decrease of the percentage Fas+ B cells found within our samples. In healthy individuals, there was a noticeable pattern in the expression of FasL which mutually correlated to populations of mononuclear cells; this correlation was absent in the patients with Sjögren's syndrome. CONCLUSIONS: Mononuclear cells expressing IL-2Rα+ had upregulated Fas in Sjögren's syndrome. However, the rate of apoptosis based on Annexin V staining and the Bcl-2/Bax expression was not observed in mononuclear cells. We suspect a functional role of abnormal levels of Fas and FasL which has not been cleared yet.

• MeSH
• annexin A5 MeSH
• antigeny CD95 metabolismus   MeSH
• apoptóza MeSH
• autoimunitní nemoci * MeSH
• lidé MeSH
• protein X asociovaný s bcl-2 metabolismus   MeSH
• receptor interleukinu-2 - alfa-podjednotka metabolismus   MeSH
• Sjögrenův syndrom * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Cancer immunotherapy has shown remarkable clinical progress in recent years. Although age is one of the biggest leading risk factors for cancer development and older adults represent a majority of cancer patients, only a few new cancer immunotherapeutic interventions have been preclinically tested in aged animals. Thus, the lack of preclinical studies focused on age-dependent effect during cancer immunotherapy could lead to different therapeutic outcomes in young and aged animals and future modifications of human clinical trials. Here, we compare the efficacy of previously developed and tested intratumoral immunotherapy, based on the combination of polysaccharide mannan, toll-like receptor ligands, and anti-CD40 antibody (MBTA immunotherapy), in young (6 weeks) and aged (71 weeks) mice bearing experimental pheochromocytoma (PHEO). The presented results point out that despite faster growth of PHEO in aged mice MBTA intratumoral immunotherapy is effective approach without age dependence and could be one of the possible therapeutic interventions to enhance immune response to pheochromocytoma and perhaps other tumor types in aged and young hosts.

• MeSH
• antigeny CD40 MeSH
• feochromocytom * terapie   MeSH
• imunoterapie metody   MeSH
• lidé MeSH
• myši MeSH
• nádory nadledvin * terapie   MeSH
• senioři MeSH
• toll-like receptory MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• senioři MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Intramural MeSH

Periferní T-lymfomy (PTCL) jsou skupinou non-Hodgkinových lymfomů, vyznačující se značnou heterogenitou a ve srovnání s B-lymfomy horší léčebnou odpovědí, limitovanou léčebnými možnostmi a vysokou mortalitou. Statistické údaje týkající se pacientů s PTCL, vč. těch shromážděných na území České republiky, jednoznačně poukazují na nezbytnost pátrání po nových strategiích směrujících ke zlepšení prognózy pacientů s PTCL. Heterogenita T-lymfomů a nedostatečné porozumění jejich patogenezi dosud podmiňují jak jejich nepřesnou a nedokonalou diagnostiku, tak i nedostatečný rozvoj cílených účinných léčebných postupů. V současnosti se významně rozšiřuje spektrum nově identifikovaných genomických defektů ovlivňujících správné fungování T-buněčných signálních drah, které mají klíčovou roli v patogenezi PTCL. Tato skutečnost představuje naději v objevování nových potenciálních léčebných cílů a pro rozvoj nových cílených léčebných strategií, které jsou v současnosti intenzivně testovány na preklinických modelech a v klinických studiích. Nová cílená léčiva, jejich zařazení do standardní klinické praxe a kombinování s již existujícími léčebnými postupy mohou být klíčovým prostředkem ke zlepšení léčebných výsledků u pacientů s PTCL.

Peripheral T-cell lymphomas (PTCL) belong to the group of non-Hodgkin’s lymphomas, characterized by considerable heterogeneity and, compared to B-lymphomas, by poorer treatment response, limited treatment options, and high mortality. Statistical data concerning patients with PTCL, including those collected in the Czech Republic, clearly point to the necessity of searching for new strategies to improve the prognosis of patients with PTCL. The heterogeneity of T-lymphomas and the lack of understanding of their pathogenesis have led to inaccurate and imperfect diagnoses and insufficient development of targeted and effective treatments. The spectrum of newly identified genomic defects affecting the correct function of T-cell signalization, which plays a key role in the pathogenesis of PTCL, is broadening. Thus, there is hope for the potential discovery of new therapeutic agents and the development of new targeted treatment strategies, which are currently intensively tested on preclinical models and in clinical studies. New therapeutic agents, their use in routine clinical practice, and their combination with already-established therapeutic strategies could represent key factors in improving the outcomes of patients with PTCL.

• MeSH
• antigen Ki-1 antagonisté a inhibitory   MeSH
• antitumorózní látky * farmakologie   klasifikace   terapeutické užití   MeSH
• humanizované monoklonální protilátky farmakologie   terapeutické užití   MeSH
• imunoterapie metody   MeSH
• inhibitory histondeacetylas farmakologie   terapeutické užití   MeSH
• klinické zkoušky, fáze III jako téma MeSH
• lidé MeSH
• lymfom T-buněčný * farmakoterapie   klasifikace   patofyziologie   MeSH
• signální transdukce účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH