chimeric Dotaz Zobrazit nápovědu
Fibrosis is present in an important proportion of myocardial disorders. Injury activates cardiac fibroblasts, which deposit excess extracellular matrix, increasing tissue stiffness, impairing cardiac function, and leading to heart failure. Clinical therapies that directly target excessive fibrosis are limited, and more effective treatments are needed. Immunotherapy based on chimeric antigen receptor (CAR) T cells is a novel technique that redirects T lymphocytes toward specific antigens to eliminate the target cells. It is currently used in haematological cancers but has demonstrated efficacy in mouse models of hypertensive cardiac fibrosis, with activated fibroblasts as the target cells. CAR T cell therapy is associated with significant toxicities, but CAR natural killer cells can overcome efficacy and safety limitations. The use of CAR immunotherapy offers a potential alternative to current therapies for fibrosis reduction and restoration of cardiac function in patients with myocardial fibrosis.
- MeSH
- chimerické antigenní receptory * MeSH
- fibróza MeSH
- imunoterapie adoptivní škodlivé účinky metody MeSH
- imunoterapie metody MeSH
- kardiomyopatie * farmakoterapie MeSH
- myši MeSH
- nádory * farmakoterapie MeSH
- T-lymfocyty MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Rituximab (chimerická anti-CD20 monoklonální protilátka) je první široce dostupnou a efektivníprotilátkou v terapii nehodgkinských lymfomů (NHL). V našem sdělení retrospektivně popisujemezkušenosti s jejím podáváním v terapii CD20 pozitivních B-buněčných, převážně indolentních NHL.Celkově bylo rituximabem léčeno 29 nemocných. Jednotlivá dávka činila 375 mg/m2, standardně bylypomalou intravenózní infuzí aplikovány 4 dávky léku. U 16 nemocných (55 %) byl rituximab podán v 1.nebo 2. parciální remisi choroby (PR), z toho u 7 nemocných (24 %) byla indikací eradikace zbytkovéchoroby po autologní transplantaci periferních kmenových buněk.Odpověďna léčbu rituximabem bylazaznamenána u 23 (79 %) nemocných. U 14 pacientů (48 %) bylo dosaženo kompletní remise choroby(CR). U 5 nemocných s folikulárním lymfomem došlo k vymizení bcl-2/IgH pozitivních buněk z periferníkrve (PCR reakce), u 4 také z kostní dřeně. Do data hodnocení relabovalo nebo progredovalo celkem8 nemocných (35 % z počtu reagujících jedinců), medián doby do relapsu/progrese onemocnění byl 6měsíců (3–20 měsíců). Celkově však mediánu trvání odpovědi u reagujících nemocných zatím nebylodosaženo, medián sledování souboru byl 12 měsíců. Naše výsledky potvrdily vysokou účinnost rituximabua jeho nízký toxický profil. Včasné zařazení do léčby zvyšuje procento léčebných odpovědí a podílCR, zvláště vysoký se jeví jeho potenciál v eradikaci minimální zbytkové nemoci.
Rituximab (chimeric anti-CD20 monoclonal antibody) is the first widely available and effective antibodyin the treatment of non-Hodgkin's lymphomas (NHL). In the submitted paper the authors describeretrospectively their experience with its administration in treatment of CD20 positive B-cell, mainlyindolent NHL.A total of 29 patients were treated with rituximab. Individual doses were 375 mg/m2. Four doses wereadministered slowly by intravenous infusion. In 16 patients (55%) rituximab was administered duringthe first or second partia remission of the disease (PR), incl. 7 patients (24%) where eradication ofresidual disease after autologous transplantation of peripheral stem cells was the indication. Theresponse to treatment with rituximab was recorded in 23 (79%) patients. In 14 patients (48%) completeremission of the disease was achieved (CR). In 5 patients with follicular lymphom bcl-2/IgH positivecells disappeared from the peripheral blood stream (PCR reaction), in 4 also from bone marrow. By thedate of evaluation a total of 8 patients (35% of the responding subjects) relapsed or progressed. Themedian of the period of relapse/progression of the disease was 6 months (3–20 months). In generalhowever the median of persistence of the response in responding patients was not attained so far, themedian of the follow up of the group was 12 months. The results confirmed the great effectiveness ofrituximab and its low toxic profile. Early initiation of treatment increases the percentage of responsesand the ratio of CR, its potential is particularly high in the eradication of minimal residual disease.
- MeSH
- autologní transplantace využití MeSH
- indukce remise metody MeSH
- lidé MeSH
- monoklonální protilátky terapeutické užití MeSH
- nehodgkinský lymfom terapie MeSH
- rituximab MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- kazuistiky MeSH
Léčba T-lymfocyty s chimérickým antigenním receptorem (CAR) představuje významný pokrok v personalizované léčbě zhoubných nádorů. V rámci této koncepce se vlastní pacientovy T-buňky geneticky upraví tak, aby exprimovaly synttický receptor, který váže nádorový atigen. CAR T-lymfocyty jsou pro klinické použtí poté expandovány a navráceny do těla nemocného, aby atakovaly a zničily nádor rezistentní na chemoterapii. Při léčbě B-buněčných malignit CAR T-lymfocyty byly zaznamenány výrazné klinické odpovědi a vysoké podíly kompletní remise. Díky tomu FDA nedávno schválil CAR T-lymfocyty namířené proti proteinu CD19 pro léčbu akutní lymfoblastické leukemie a difuzního velkobuněčného B-lymfomu. CAR T-lymfocyty jsou tedy nepochybně jedním z prvních úspěšných příkladů syntetické biologie a personalizované buněčné léčby zhoubných nádorů, jež se mohou stát komerčně dostupné. V tomto review představujeme koncept použití CAR T-lymfocytů k narušení imunitní tolerance nádorů, upozorňujeme na některé problémy v této oblasti, diskutujeme o využití biomarkerů pro predikci klinických odpovědí a předkládáme možnosti vývoje metod založených na CAR T-lymfocytech, které zlepší výsledky léčby.
- MeSH
- antigeny CD19 MeSH
- biologické markery MeSH
- chimerické antigenní receptory * terapeutické užití MeSH
- genetické vektory terapeutické užití MeSH
- hematologické nádory imunologie terapie MeSH
- imunologická tolerance fyziologie MeSH
- imunoterapie adoptivní * metody MeSH
- lidé MeSH
- poměr CD4 a CD8 lymfocytů MeSH
- Check Tag
- lidé MeSH
Tumor immunotherapy based on the use of chimeric antigen receptor modified T cells (CAR T cells) is a promising approach for the treatment of refractory hematological malignancies. However, a robust response mediated by CAR T cells is observed only in a minority of patients and the expansion and persistence of CAR T cells in vivo is mostly unpredictable.Lenalidomide (LEN) is an immunomodulatory drug currently approved for the treatment of multiple myeloma (MM) and mantle cell lymphoma, while it is clinically tested in the therapy of diffuse large B-cell lymphoma of activated B cell immunophenotype. LEN was shown to increase antitumor immune responses at least partially by modulating the activity of E3 ubiquitin ligase Cereblon, which leads to increased ubiquitinylation of Ikaros and Aiolos transcription factors, which in turn results in changed expression of various receptors on the surface of tumor cells. In order to enhance the effectiveness of CAR-based immunotherapy, we assessed the anti-lymphoma efficacy of LEN in combination with CAR19 T cells or CAR20 T cells in vitro and in vivo using various murine models of aggressive B-cell non-Hodgkin lymphomas (B-NHL).Immunodeficient NSG mice were transplanted with various human B-NHL cells followed by treatment with CAR19 or CAR20 T cells with or without LEN. Next, CAR19 T cells were subjected to series of tests in vitro to evaluate their response and signaling capacity following recognition of B cell in the presence or absence of LEN.Our data shows that LEN significantly enhances antitumor functions of CAR19 and CAR20 T cells in vivo. Additionally, it enhances production of interferon gamma by CAR19 T cells and augments cell signaling via CAR19 protein in T cells in vitro. Our data further suggests that LEN works through direct effects on T cells but not on B-NHL cells. The biochemical events underlying this costimulatory effect of LEN are currently being investigated. In summary, our data supports the use of LEN for augmentation of CAR-based immunotherapy in the clinical grounds.
- MeSH
- chimerické antigenní receptory terapeutické užití MeSH
- imunomodulace MeSH
- imunomodulační látky terapeutické užití MeSH
- lenalidomid * terapeutické užití MeSH
- lidé MeSH
- lymfom terapie MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- protinádorové látky imunologicky aktivní * terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
Congenital adrenal hyperplasia (CAH) comprises a group of autosomal recessive disorders caused by an enzymatic deficiency which impairs the biosynthesis of cortisol and, in the majority of severe cases, also the biosynthesis of aldosterone. Approximately 95% of all CAH cases are caused by mutations in the steroid 21-hydroxylase gene (CYP21A2). The CYP21A2 gene and its inactive pseudogene (CYP21A1P) are located within the HLA class III region of the major histocompatibility complex (MHC) locus on chromosome 6p21.3. In this study, we describe chimeric CYP21A1P/CYP21A2 genes detected in our patients with 21-hydroxylase deficiency (21OHD). Chimeric CYP21A1P/CYP21A2 genes were present in 171 out of 508 mutated CYP21A2 alleles (33.8%). We detected four types of chimeric CYP21A1P/CYP21A2 genes: three of them have been described previously as CH-1, CH-3, CH-4, and one type is novel. The novel chimeric gene, termed CH-7, was detected in 21.4% of the mutant alleles. Possible causes of CYP21A1P/CYP21A2 formation are associated with 1) high recombination rate in the MHC locus, 2) high recombination rate between highly homologous genes and pseudogenes in the CYP21 gene area, and 3) the existence of chi-like sequences and repetitive minisatellite consensus sequences in CYP21A2 and CYP21A1P which play a role in promoting genetic recombination.
- MeSH
- kongenitální adrenální hyperplazie genetika MeSH
- lidé MeSH
- mutační analýza DNA MeSH
- mutantní chimérické proteiny genetika MeSH
- pseudogeny genetika MeSH
- rekombinace genetická MeSH
- steroid-21-hydroxylasa genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Československo MeSH
Cancer immunotherapies utilizing genetically engineered T cells have emerged as powerful personalized therapeutic agents showing dramatic preclinical and clinical results, particularly in hematological malignancies. Ectopically expressed chimeric antigen receptors (CARs) reprogram immune cells to target and eliminate cancer. However, CAR T cell therapy's success depends on the balance between effective anti-tumor activity and minimizing harmful side effects. To improve CAR T cell therapy outcomes and mitigate associated toxicities, scientists from different fields are cooperating in developing next-generation products using the latest molecular cell biology and synthetic biology tools and technologies. The immunotherapy field is rapidly evolving, with new approaches and strategies being reported at a fast pace. This comprehensive literature review aims to provide an up-to-date overview of the latest developments in controlling CAR T cell activity for improved safety, efficacy, and flexibility.
Chimérické antigenní receptory jsou syntetické, geneticky upravené receptory T lymfocytů. Jejich transfer do autologních T lymfocytů pacienta dokáže tyto lymfocyty cíleně naprogramovat proti specifickým antigenům vyskytujícím se na povrchu maligních buněk. Tento princip se v současnosti rozvinul jako potenciálně slibný přístup v terapii nejprve hematologických malignit a později i solidních nádorů. Byly vyvinuty různé strategie v designu chimérických antigenních receptorů a jejich transferu do T lymfocytů a zdá se, že tyto faktory mají velký dopad na aktivitu výsledných modifikovaných T lymfocytů a následně i na úspěšnost léčby. Jednotlivé proměnné v designu se v současnosti intenzivně testují v nespočetných klinických studiích. V tomto přehledu stručně popíši základní princip a strukturu chimérických antigenních receptorů a postup generování T lymfocytů nesoucích chimérický antigenní receptor.
Chimeric antigen receptors are synthetic, genetically modified receptors of T-cells. The introduction of chimeric antigen receptors into autologous patient T-cells can redirect the lymphocytes to specific antigen targets on the surface of malignant cells. This has recently emerged as an intriguing therapy approach in both hematologic malignancies and later also in solid tumors. Various chimeric antigen receptor designs and manufacturing processes were developed and seem to have a strong impact on the activity of chimeric antigen receptor T-lymphocytes and thereby the therapy success. The individual variables are currently being tested in numerous clinical trials. In this review, I will briefly describe the principle, basic structure and construction of chimeric antigen receptor T-lymphocytes. Key words: chimeric antigen receptor – CAR‑T-cells – gene therapy – immunotherapy – neoplasms The author declares he has no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 1. 9. 2015 Accepted: 16. 9. 2015
- Klíčová slova
- chimérický antigenní receptor, genová terapie, CAR-T lymfocyty,
- MeSH
- antigeny nádorové imunologie MeSH
- genetická terapie MeSH
- imunoterapie adoptivní * MeSH
- lidé MeSH
- nádorové buněčné linie imunologie MeSH
- nádory * imunologie terapie MeSH
- receptory antigenů T-buněk * imunologie MeSH
- T-lymfocyty metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
- MeSH
- chiméra genetika imunologie MeSH
- cytotoxické T-lymfocyty fyziologie MeSH
- lidé MeSH
- nádory děložního čípku etiologie prevence a kontrola MeSH
- Papillomaviridae genetika imunologie MeSH
- preventivní lékařství MeSH
- rekombinace genetická MeSH
- virové vakcíny MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- přehledy MeSH
Chagas disease (CD) is a neglected disease caused by Trypanosoma cruzi Chagas, 1909. Causative treatment can be achieved with two drugs: benznidazole or Nifurtimox. There are some gaps that hinder progress in eradicating the disease. There is no test that can efficiently assess cure control after treatment. Currently, the decline in anti-T. cruzi antibody titres is assessed with conventional serological tests, which can take years. However, the search for new markers of cure must continue to fill this gap. The present study aimed to evaluate the decline in serological titres using chimeric proteins after treatment with benznidazole in chronic patients diagnosed with CD. It was a prospective cross-sectional cohort study between 2000 and 2004 of T. cruzi-positive participants from the Añatuya region (Argentina) treated with benznidazole. Serum samples from ten patients were collected before treatment (day zero) and after the end of treatment (2, 3, 6, 12, 24 and 36 months). For the detection of anti-T. cruzi antibodies, an indirect ELISA was performed using two chimeric recombinant proteins (IBMP-8.1 and IBMP-8.4) as antigens. The changes in reactivity index within the groups before and after treatment were evaluated using the Friedman test. All participants experienced a decrease in serological titres after treatment with benznidazole, especially IBMP-8.1. However, due to the small number of samples and the short follow-up period, it is premature to conclude that this molecule serves as a criterion for sustained cure. Further studies are needed to validate tests based on these or other biomarkers to demonstrate parasitological cure.
BACKGROUND: While achieving prolonged remissions in other B cell-derived malignancies, chimeric antigen receptor (CAR) T cells still underperform when injected into patients with chronic lymphocytic leukemia (CLL). We studied the influence of genetics on CLL response to anti-CD19 CAR T-cell therapy. METHODS: First, we studied 32 primary CLL samples composed of 26 immunoglobulin heavy-chain gene variable (IGHV)-unmutated (9 ATM-mutated, 8 TP53-mutated, and 9 without mutations in ATM, TP53, NOTCH1 or SF3B1) and 6 IGHV-mutated samples without mutations in the above-mentioned genes. Then, we mimicked the leukemic microenvironment in the primary cells by '2S stimulation' through interleukin-2 and nuclear factor kappa B. Finally, CRISPR/Cas9-generated ATM-knockout and TP53-knockout clones (four and seven, respectively) from CLL-derived cell lines MEC1 and HG3 were used. All these samples were exposed to CAR T cells. In vivo survival study in NSG mice using HG3 wild-type (WT), ATM-knockout or TP53-knockout cells was also performed. RESULTS: Primary unstimulated CLL cells were specifically eliminated after >24 hours of coculture with CAR T cells. '2S' stimulated cells showed increased survival when exposed to CAR T cells compared with unstimulated ones, confirming the positive effect of this stimulation on CLL cells' in vitro fitness. After 96 hours of coculture, there was no difference in survival among the genetic classes. Finally, CAR T cells were specifically activated in vitro in the presence of target knockout cell lines as shown by the production of interferon-γ when compared with control (CTRL) T cells (p=0.0020), but there was no difference in knockout cells' survival. In vivo, CAR T cells prolonged the survival of mice injected with WT, TP53-knockout and ATM-knockout HG3 tumor cells as compared with CTRL T cells (p=0.0485, 0.0204 and <0.0001, respectively). When compared with ATM-knockout, TP53-knockout disease was associated with an earlier time of onset (p<0.0001), higher tumor burden (p=0.0002) and inefficient T-cell engraftment (p=0.0012). CONCLUSIONS: While in vitro no differences in survival of CLL cells of various genetic backgrounds were observed, CAR T cells showed a different effectiveness at eradicating tumor cells in vivo depending on the driver mutation. Early disease onset, high-tumor burden and inefficient T-cell engraftment, associated with TP53-knockout tumors in our experimental setting, ultimately led to inferior performance of CAR T cells.
- MeSH
- antigeny CD19 terapeutické užití MeSH
- chimerické antigenní receptory imunologie MeSH
- chronická lymfatická leukemie genetika MeSH
- lidé MeSH
- myši MeSH
- T-lymfocyty imunologie MeSH
- zdraví dobrovolníci pro lékařské studie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
