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Лобода, Андрій Миколайович, Андрей Николаевич Лобода, and Andrii Mykolaiovych Loboda. "Liposomal Nanoparticles for Pediatric Leukemia Therapy." Thesis, University of Latvia, 2019. http://essuir.sumdu.edu.ua/handle/123456789/73975.
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Селективна доставка протиракових агентів до ракових клітин без шкоди для здорових клітин є основною метою нової терапії лейкемії у дітей на основі наночасток. Низка досліджень показують, що рецептори ліпопротеїдів (особливо рецептор до ліпопротеїдів високої щільності) дуже активні на поверхні злоякісних лейкозних клітин, тому можуть використовуватися в якості каналів для доставки протиракових агентів. Ліпосомальний сульфат вінкристину був першою наноформацією, що отримала схвалення FDA для лікування Ph+ гострої лімфобластної лейкемії у дорослих. Діти переносять тижневу дозу 2,25 мг/м2 ліпосомального сульфату вінкристину з доказом клінічної активності, але без нейротоксичности, що обмежує дозу. Ліпосомальний доксорубіцин і пегільований (покритий поліетиленгліколем) інкапсульований в ліпосоми доксорубіцин володіють вражаючим профілем безпеки, особливо щодо гострої серцевої токсичності, при лейкозі у дітей. Пегільована формула L-аспарагінази знижує імуногенність, збільшує період напіввиведення з кровотоку і може використовуватися у пацієнтів з гіперчутливістю до непегільованих продуктів.<br>Селективная доставка противораковых агентов к раковым клеткам без вреда для здоровых клеток является основной целью новой терапии лейкемии у детей на основе наночастиц. Ряд исследований показывают, что рецепторы липопротеидов (особенно рецептор к липопротеидам высокой плотности) очень активны на поверхности злокачественных лейкозных клеток, поэтому могут использоваться в качестве каналов для доставки противораковых агентов. Липосомальный сульфат винкристина был первой наноформацией, получившей одобрение FDA для лечения Ph+ острой лимфобластной лейкемии у взрослых. Дети переносят недельную дозу 2,25 мг/м2 липосомального сульфата винкристина с доказательством клинической активности, но без нейротоксичности, ограничивающей дозу. Липосомальный доксорубицин и пегилированный (покрытый полиэтиленгликолем) инкапсулированный в липосомы доксорубицин обладают впечатляющим профилем безопасности, особенно в отношении острой сердечной токсичности, при лейкозе у детей. Пегилированная формула L-аспарагиназы снижает иммуногенность, увеличивает период полувыведения из кровотока и может использоваться у пациентов с гиперчувствительностью к непегилированным продуктам.<br>Selective delivery of anti-cancer agents to cancer cells without harming the healthy cells is a major goal of novel nanoparticle-based pediatric leukemia therapy. Some studies are show that lipoprotein receptors (especially the HDL receptor) are highly active on the surface of malignant leukemic cells, that’s why may be used as conduits for the delivery of anti-cancer agents. Liposomal vincristine sulfate was the first nanoformulation to get approval by the FDA to treat Ph+ ALL in adults. Children tolerate 2.25 mg/m2/dose of weekly liposomal vincristine sulfate with evidence for clinical activity without dose‐limiting neurotoxicity. Liposomal doxorubicin and pegylated (polyethylene glycol coated) liposome-encapsulated doxorubicin has an impressive safety profile, particularly regarding acute cardiac toxicity, in childhood leukemia. Pegylated formula of L-asparaginase decreases immunogenicity, increases circulating half-life and can be used in patients with hypersensitive to un-pegylated products.
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Naoe, Tomoki. "Mechanism-based Therapy for Leukemia: A Lesson from Atra Therapy." Nagoya University School of Medicine, 2001. http://hdl.handle.net/2237/5372.
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Suck, Garnet, Yeh Ching Linn, and Torsten Tonn. "Natural Killer Cells for Therapy of Leukemia." Karger, 2016. https://tud.qucosa.de/id/qucosa%3A71644.
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Clinical application of natural killer (NK) cells against leukemia is an area of intense investigation. In human leukocyte antigen-mismatched allogeneic hematopoietic stem cell transplantations (HSCT), alloreactive NK cells exert powerful anti-leukemic activity in preventing relapse in the absence of graft-versus-host disease, particularly in acute myeloid leukemia patients. Adoptive transfer of donor NK cells post-HSCT or in non-transplant scenarios may be superior to the currently widely used unmanipulated donor lymphocyte infusion. This concept could be further improved through transfusion of activated NK cells. Significant progress has been made in good manufacturing practice (GMP)-compliant large-scale production of stimulated effectors. However, inherent limitations remain. These include differing yields and compositions of the end-product due to donor variability and inefficient means for cryopreservation. Moreover, the impact of the various novel activation strategies on NK cell biology and in vivo behavior are barely understood. In contrast, reproduction of the thirdparty NK-92 drug from a cryostored GMP-compliant master cell bank is straightforward and efficient. Safety for the application of this highly cytotoxic cell line was demonstrated in first clinical trials. This novel ‘off-theshelf’ product could become a treatment option for a broad patient population. For specific tumor targeting chimeric-antigen-receptor-engineered NK-92 cells have been designed.
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Adamson, Penelope Jane. "Engineering antibodies for use in leukemia and lymphoma therapy /." Title page, contents and summary only, 2000. http://web4.library.adelaide.edu.au/theses/09PH/09pha221.pdf.
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Yu, Bo. "Oligonucleotide Based Liposomal Nanoparticles for Leukemia and Liver Cancer Therapy." The Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1275490450.
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Lundin, Jeanette. "Targeted CD52 therapy in lymphoid malignancies : a clinical and immunological study /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-441-0/.
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Ahmed, Tamer. "HIGH DOSE SIMVASTATIN AS A POTENTIAL ANTICANCER THERAPY IN LEUKEMIA PATIENTS." UKnowledge, 2013. http://uknowledge.uky.edu/pharmacy_etds/13.
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Simvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor that is used for the treatment of hyperlipidemia. Simvastatin has recently been studied for its potential use in cancer therapy. In-vitro studies have shown that simvastatin displays anticancer activity, but at concentrations unlikely to be achieved in patients being receiving typical antihyperlipidemic treatment doses. Thus, several clinical trials were conducted to study the tolerability of high dose statins in cancer patients. The maximum tolerated dose of simvastatin was determined to be 15 mg/kg/day, 25-fold higher than a typical dose. However, it is not known if simvastatin plasma concentrations can reach those found to be effective in-vitro. In this context, we initiated a clinical study to determine the pharmacokinetics of high dose simvastatin in patients with chronic lymphocytic leukemia. For this purpose, an LC-MS/MS method was developed and validated for the quantitation of simvastatin and its acid form in plasma and peripheral blood mononuclear cells obtained from CLL patients. Results show that simvastatin concentrations were dose proportional relative to the antihyperlipidemic doses, but lower than those required for in-vitro cytotoxicity against cancer cells. These findings demonstrate that the in-vitro effective concentrations of simvastatin are not achievable clinically, which might explain the limited effectiveness of high dose simvastatin in this study and in previous clinical trials. In view of these data, the use of simvastatin as a sole therapy in cancer treatment was not encouraging and led us to examine the use in combination with other anticancer drugs.
After screening several chemotherapeutic agents in combination with simvastatin, we showed that tipifarnib (a farnesyltransferase inhibitor) interacts synergistically in several leukemia cell lines. Mechanistically we showed that simvastatin augments the cytotoxicity of tipifarnib by disrupting the localization of RAS in the cell membrane and by subsequent deactivation of the ERK pathway. Consistent with this observation, drug treatment led to the induction of apoptosis through the caspase cascade activation and the cleaved PARP upregulation. Notably, this synergistic effect
was observed at clinically achievable concentrations of simvastatin and tipifarnib. Thus, the effectiveness of this combination should be explored further in future clinical studies.
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Chen, Liying Michelle. "Targeting the Epigenetic Lesion in MLL-Rearranged Leukemia." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10663.
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It has become increasingly apparent that the misregulation of histone modification actively contributes to cancer. The histone H3 lysine 79 (H3K79) methyltransferase Dot1l has been implicated in the development of leukemias bearing translocations of the Mixed Lineage Leukemia (MLL) gene. We studied the global epigenetic profile for H3K79 dimethylation and found abnormal H3K79 dimethylation profiles exist not only in leukemias driven by MLL-fusion proteins with nuclear partners like AF9, but also in leukemia with MLL-fusions containing cytoplasmic partners like AF6. Genetic inactivation of Dot1l led to downregulation of fusion target genes and impaired both in vitro bone marrow transformation and in vivo leukemia development by MLL-AF10, CALM-AF10 as well as MLL-AF6, suggesting that aberrant H3K79 methylation by DOT1L sustains fusion-target gene expression in MLL rearranged leukemias and CALM-AF10 rearranged leukemias. Pharmacological inhibition of DOT1L selectively killed MLL-AF10 and MLL-AF6 transformed cells but not Hox9/Meis1 transformed cells, pointing to DOT1L as a potential therapeutic target in MLL-rearranged leukemia. We further characterized the DOT1L complex under physiological conditions from human leukemia cells and identified AF10 as a key DOT1L complex component. Given the importance of H3K79 methylation in MLL-rearranged leukemia, we sought to study the role of DOT1L complex component AF10 in H3K79 methylation and MLL leukemia. We generated conditional knockout mice in which the Dot1l-interacting octapeptide-motif leucine-zipper (OM-LZ) domain of Af10 was flanked by LoxP sites. Cre induced deletion of \(Af10^{OM-LZ}\) is predicted to abrogate the Af10-Dot1l interaction. Our histone mass spectrometry data demonstrated that deletion of the endogenous \(Af10^{OM-LZ}\) domain abrogated global H3K79 dimethylation but retained H3K79 monomethylation. Interestingly, bone marrow transformation by MLLAF6 and MLL-AF9 is abrogated by induced deletion of endogenous \(Af10^{OM-LZ}\), while bone marrow transformation by MLL-AF10 and CALM-AF10 is not affected by deletion of endogenous \(Af10^{OM-LZ}\), confirming the importance of Af10-Dot1l interaction in MLL- or CALM fusion-leukemias. Moreover, we showed \(Af10^{OM-LZ}\) deletion prolonged survival of MLL-AF9 leukemia in vivo and led to chromotin compaction and downregulation of MLL fusion targets in MLL-AF9 leukemia. Therefore our results demonstrate a role for Af10 in the conversion of H3K79 monomethylation to dimethylation and reveal the AF10-DOT1L interaction as an attractive therapeutic target in MLL-rearranged leukemias.
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Chan, Onyee, Abdur Rehman Jamil, Rebecca Millius, Ramandeep Kaur, and Faiz Anwer. "Mixed phenotype acute leukemia with t(9;22): success with nonacute myeloid leukemia-type intensive induction therapy and stem cell transplantation." WILEY, 2017. http://hdl.handle.net/10150/624353.
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Cameron, Eleanor Ruth. "An in vivo RNAi therapy screen identifies novel mediators of leukemia-microenvironment interaction." Thesis, Massachusetts Institute of Technology, 2016. http://hdl.handle.net/1721.1/103236.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2016.<br>Cataloged from PDF version of thesis.<br>Includes bibliographical references.<br>Minimal residual disease refers to those cancer cells that persist following initial therapy. In precursor B-cell acute lymphoblastic leukemia (BCP-ALL), the presence of minimal residual disease is a strong prognostic indicator of relapse. The establishment of minimal residual disease fundamentally arises from leukemia cells that are resistant to drug-mediated killing due to alterations in a myriad of both cell-intrinsic and cell-extrinsic pathways. Understanding mechanisms by which leukemia cells can survive therapy is vital to our ability to target and eradicate minimal residual disease. BCR-ABL1+ BCP-ALL is an aggressive subtype of BCP-ALL, and despite the use of tyrosine kinase inhibitors (TKIs) as additional therapeutics that directly inhibit BCR-ABLI, more than half of BCR-ABLI+ BCP-ALL patients will experience a relapse. We have adapted an in vivo RNAi screening approach to perform novel longitudinal studies both in mice and in cultured cells to identify genetic mediators of response to the TKI dasatinib in a transplantable syngeneic mouse model of BCR-ABLI+ BCP-ALL. The unique combination of a longitudinal screen design and independent component analysis of screening data allowed for identification of hairpins that have distinct behavior in different therapeutic contexts as well as in the in vivo versus in vitro settings. From the set of hairpins found to have distinct behavior before versus after therapy, we identified AB13 as a potential biomarker of therapeutic response in BCRABLI+ BCP-ALL cells. Knockdown of AB13 promoted resistance to dasatinib in vivo, potentially due to alterations in the invasive capabilities of leukemic cells. We also found that loss of PAFAH1B3 sensitizes cells to dasatinib specifically in the in vivo setting. Changes in Pafah1b3 levels alter the distribution of leukemic cells in vivo, and cells that express higher levels of Pafah1b3 are enriched in the bone marrow after dasatinib treatment. Therefore, sensitization after loss of PAFAHIB3 may result from decreased ability of leukemia cells to migrate to or remain in the bone marrow, an established site of MRD in BCP-ALL. Pafah1b3 is a druggable enzyme and thus represents a potential target for combination therapy with TKIs for BCR-ABLI+ BCP-ALL.<br>by Eleanor Ruth Cameron.<br>Ph. D.
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Gonzalez, Paola. "Chronic Myeloid Leukemia: from Therapy Monitoring to Personalized Medicine. Assessment of Industrial Process." Doctoral thesis, Università degli studi di Padova, 2017. http://hdl.handle.net/11577/3422302.
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Introduction: Chronic myeloid leukemia (CML) is a white blood cells cancer, which is characterized by a BCR-ABL fusion gene. The disease it is caused by a reciprocal translocation between chromosome 9 and 22, t(9; 22)(q34; 11) commonly known as the Philadelphia chromosome (Ph), resulting in an abnormally BCR-ABL tyrosine kinase, which is responsible for the pathogenesis of CML. The high efficacy of the tyrosine kinase inhibitors (TKIs) in the treatment of CML has caused the need for sensitive methods to monitor the course of therapy. Quantification of BCR-ABL transcripts with qRT-PCR Real-Time has demonstrated to be the most accurate method available. Following the European LeukemiaNet recommendations, the lack of initial response can be detected only after 3-6 months from the diagnosis. The ability to understand how patients respond to the different TKIs available as first-line treatment at the moment of diagnosis would help clinicians to prescribe more patient-tailored therapy, decreasing the onset of future drug resistance and decreasing treatment cost.
Materials and Methods: We have developed and validated two devices (RQ-BCR-ABL p210 One-Step and RQ-BCR- ABL p190 One-Step) for monitoring therapy of CML. The RQ-BCR-ABL p210 One-Step kit has undergone a further external validation in three reference laboratories, belonging to LabNet network.?For what concern the prevision of therapy’s response the University of Verona has developed LeukoPredict, an in-vitro device to screen the inhibitory potential of several BCR- ABL-targeting drugs and to obtain the percentage of inhibition compared to the same non- treated samples. We took part to this project in the framework of industrial planning, performing a Freedom to Operate analysis and a Cost-Effectiveness analysis.
Results: Both kits based in qRT-PCR Real-Time One-Step have showed high reproducibility and high sensitivity in quantification of BCR-ABL transcripts, proving to be suitable for CE-IVD mark. Moreover, RQ-BCR-ABL p210 One-Step kit has been verified by the LabNet network as a suitable device for the monitoring of CML, improving the reproducibility regarding the current system used in routine.?The Freedom to Operate analysis of LeukoPredict has found some close prior patents documents, but none could hinder entry into the market. The Cost-Effectiveness analysis has demonstrated that LeukoPredict is either cost saving or very cost-effective, depending on the scenario analyzed, generating significant savings for health systems.
Conclusions: This project is able to connect actual principal issues in CML. On one side we have developed and validated two devices that completely satisfy actual request of therapeutic monitoring in pharmaceutical market making a complete panel to track CML. The develop of devices as LeukoPredict helps to decrease the risk of disease’s progression to more aggressive phase, personalizing the therapy and obtaining the maximum effectiveness of therapeutical choices. This can help physicians in an evidence based decisional therapeutic process, avoiding potential conflict of interest and giving a rational explanation to other kind of treatment when the risk of failure is too high. Finally, it has been considered as a technology that can be affordable and that could contain the cost of healthcare.<br>Introduzione: La Leucemia Mieloide Cronica (LMC) è un disordine mieloproliferativo delle cellule staminali pluripotenti caratterizzato per la presenza del gene di fusione BCR-ABL. Questo disturbo è causato da una traslocazione reciproca di materiale genetico tra il cromosoma 9 e 22 t(9; 22)(q34; 11) comunemente riconosciuta come cromosoma Philadelphia (Ph), che porta alla formazione di una proteina tirosinchinasica con un’attività alterata, causante della patogenesi della LMC. L’elevata efficacia degli inibitori della tirosinchinasa (TKIs) nel trattamento della LMC ha originato la necessità di metodi molto sensibili per monitorare il corso terapeutico. La quantificazione dei trascritti BCR-ABL con qRT-PCR Real Time si è dimostrato il metodo disponibile più accurato al giorno di oggi. Secondo le raccomandazioni degli esperti appartenenti alla European LeukemiaNet, la mancanza di risposta iniziale può essere rilevata solo dopo 3-6 mesi dal momento della diagnosi. La capacità di comprendere come i pazienti rispondono ai diversi TKIs disponibili nel momento della diagnosi aiuterebbe ai medici a prescrivere la terapia di prima linea più conveniente in ogni caso, riducendo l’insorgere di una futura resistenza ai farmaci e riducendo così i costi del trattamento.
Materiali e Metodi: Abbiamo sviluppato e validato due dispositivi (RQ-BCR-ABL p210 One-Step e RQ-BCR- ABL p190 One-Step) per il monitoraggio terapeutico della LMC. Il kit RQ-BCR-ABL p210 One-Step ha subito un’ulteriore validazione esterna in tre diversi centri di riferimento per la LMC appartenenti alla rete italiana LabNet. Per quanto riguarda alla previsione della risposta terapeutica, l’Università degli Studi di Verona ha sviluppato LeukoPredict, un dispositivo in-vitro per individuare il potenziale inibitorio di diversi farmaci che hanno BCR-ABL come bersaglio, ottenendo il percentile d’inibizione rispetto agli stessi campioni non trattati. Abbiamo partecipato a questo progetto nell’ambito della pianificazione industriale, eseguendo un’analisi Freedom to Operate e un’analisi costo-efficacia sul prodotto.
Risultati: Entrambi I kit basati sulla tecnologia qRT-PCR Real-Time One-Step hanno mostrato una elevata riproducibilità e un’alta sensibilità nella quantificazione dei trascritti BCR-ABL, dimostrando di essere adatti alla marcatura CE-IVD. Inoltre, il kit RQ-BCR-ABL p210 One-Step è stato certificato dalla rete LabNet come un dispositivo adatto per il monitoraggio della LMC, migliorando notevolmente la riproducibilità dei sistemi attuali utilizzati nella routine.
L’analisi Freedom to Operate di LeukoPredict ha rilevato alcuni brevetti relazionati con la tecnologia presente nel dispositivo, ma nessuno potrebbe ostacolare la sua uscita nel mercato in questo momento. L’analisi costo-efficacia ha dimostrato che LeukoPredict ha un costo ridotto ed è molto conveniente a livello economico secondo lo scenario analizzato, generando rilevanti risparmi per i sistemi sanitari.
Conclusioni: Questo progetto è in grado di collegare le problematiche attuali della LMC. Da un lato abbiamo sviluppato e validato due dispositivi che soddisfano completamente le richieste del mercato farmaceutico per il monitoraggio terapeutico, proporzionando un panello completo per la gestione della LMC. Lo sviluppo di dispositivi come LeukoPredict aiuta a diminuire il rischio di progressione della malattia verso fasi più aggressive, personalizzando la terapia e ottenendo la massima efficacia delle diverse scelte terapeutiche. Ciò aiuterebbe ai medici nella decisione della miglior terapia basandosi sull’evidenza, evitando potenziali conflitti d’interesse e fornendo una spiegazione razionale ad altri tipi di trattamento quando il rischio di fallimento terapeutico è troppo alto. Infine, la sua tecnologia è stata definita come molto conveniente potendo contribuire a contenere il costo dell’assistenza sanitaria.
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Yazdanparast, Haniyeh [Verfasser], and Viktor [Akademischer Betreuer] Umansky. "Myeloid cells and therapy resistance in Chronic Lymphocytic Leukemia / Haniyeh Yazdanparast ; Betreuer: Viktor Umansky." Heidelberg : Universitätsbibliothek Heidelberg, 2018. http://d-nb.info/1177385988/34.
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Robustelli, Valentina <1986>. "Molecular characterization of unresponsiveness to BiTE CD19-CD3 therapy in adult acute lymphoblastic leukemia." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2020. http://amsdottorato.unibo.it/9471/1/Molecular%20characterization%20of%20unresponsiveness%20to%20BiTE%20CD19-CD3%20therapy%20in%20adult%20acute%20lymphoblastic%20leukemia.pdf.
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Acute lymphoblastic leukemia is a heterogeneous disease characterized by the sequential acquisition of genetic aberrations driving the leukemic clone’s onset and maintenance. The introduction of monoclonal antibodies has both increased over all survival rates and reduced the need of intensive and prolonged chemotherapy in relapsed/refractory (R/R) ALL. Blinatumomab is a BiTE (T-cell engaging bi-specific) antibody that redirects CD3-expressing T-cells to CD19-expressing leukemic cells. To identify predictive biomarkers of response/no-response and mechanisms underlying unresponsiveness to Blinatumomab, 26 B-ALL adult patients both responder and non-responder have been molecularly characterized by gene expression profiling.
A bioinformatic analysis was performed employing the linear mixed model (LMM) in order to consider all the possible bias interfering with the results.
The LMM output allows to classify training set patients (R or NR); the following LOPO (Leave One (Patient) Out) cross validation have been performed to avoid artifacts, determined by dataset structure. 649 genes pass the LOPO filter and the genes that contribute to less than the 1% to the total variance in the first PCA component have been discarded in order to obtain a small set of significant genes (MS4A1, CSRP2, MY05C, SEMA6A, CD200, CDR1, NEGR1, SCN3A, MME, DNTT, MIR1206).
Moreover, the LMM capability of classify patients as responder or non-responder has been confirmed through its output blind application in validation set at baseline; only 1/8 patients is misclassified and additional data are needed to clarify if causes of only one patient misclassification are patient-related or structure dataset-related.
Thus, the gene signature composed by 11 genes is capable of classify as responder or non-responder to Blinatumomab treatment adult B-ALL patients at baseline and easy to use for routine diagnostics.
However, the dataset increase and deep molecular characterization (e.g. single-cell sequencing) are required to improve statistical significance and define strict associations between genomic characteristics and phenotypic features.
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Ismail, Said. "Development of novel MoMLV gene transfer systems by exploiting retroviral RNA processing." Thesis, University of Oxford, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.365806.
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HASAN, SYED K. "Investigation on the mechanisms underlying the chromosomal translocations in therapy-related acute myeloid leukemias." Doctoral thesis, Università degli Studi di Roma "Tor Vergata", 2010. http://hdl.handle.net/2108/1428.
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La leucemia acuta promielocitica (APL) è caratterizzata dalla traslocazione t(15;17) con la formazione del gene chimerico PML-RARa. La APL secondaria a trattamento con inibitori della topoisomerasi II (t-APL) rappresenta una nota complicanza del trattamento chemioterapico in pazienti affetti da cancro. Tuttavia negli ultimi anni sono stati descritti parecchi casi di t-APL in pazienti affetti da sclerosi multipla (SM) e trattati con mitoxantrone. In 12 pazienti affetti da MS con t-APL secondaria all’uso di mitoxantrone, l’analisi genomica ha mostrato un’alterata distribuzione all’interno dell’introne 6 del gene PML dei punti di rottura sul cromosoma 15 rispetto alle APL de novo (11/12, 92% vs 622/1022, 61%: p=0.035). Infatti, nonostante l’introne 6 abbia una dimenzione di circa 1kb, in 5 pazienti con t-apl secondaria a MS il punto di rottura nel cromosoma 15 cade in una regione di 8 paia di basi (hotspot) precedentemente desritta in pazienti affetti da t-APL secondaria a carcinoma della mammella (KM). Inoltre, all’interno del gene RARa , che si estende per circa 17 kb abbiamo identificato un altro punto di rottura comune a due pazienti con t-APL secondaria a trattamento con mitoxantrone per MS e KM. In 4 casi, l’utilizzo di saggi funzionali ci ha permesso di confermare sia in PML che in RARa la presenza di loci che sono risultati essere siti preferenziali di taglio da parte della topoisomerasi IIa in presenza di mitoxantrone. Questo studio conferma ulteriormente la presenza nei geni PML e RARa di porzioni di DNA particolarmente sensibili al danno indotto da mitoxantrone che possono spiegare la propensione a sviluppare questo la t-APL in pazienti trattati con questo chemioterapico. Abbiamo esteso l’analisi genomica anche in un caso con leucemia acuta mieloide con traslocazione t(16;21) (RUNX1-ETO”) secondaria a sclerosi multipla trattata con mitoxantrone. Ancora una volta abbiamo identificato una regione di 9 paia di basi (ATGCCCCAG) che mostrava una omologia del 90% con la sequenza ATGCCCTAG presente nell’introne 6 di PML evidenziata nei pazienti con t-APL secondarie a trattamento con mitoxantrone.
In questo contesto è da notare che l’Accademia Americana di Neurologia nel 2000 ha approvato il mitoxantrone per il trattamento della sclerosi multipla. Following the response to post-marketing findings such as potential risk of therapy related leukemia, decreased systolic function and heart failure, the US Food and Drug administration (FDA) has added a “black box” warning to the prescribing information for the mitoxantrone.<br>Therapy-related acute promyelocytic leukemia (t-APL) with the t(15;17) translocation is a well-recognized complication of cancer treatment with agents targeting topoisomerase II. However, cases are emerging following mitoxantrone therapy for multiple sclerosis (MS). Analysis of 12 cases of mitoxantrone-related t-APL in MS patients revealed an altered distribution of chromosome 15 breakpoints compared to de novo APL, biased towards disruption within PML intron 6 (11/12, 92% vs 622/1022, 61%: p=0.035). Despite this intron spanning ~1kb, the breakpoint in five mitoxantrone-treated patients fell within an 8bp region (1482-9) corresponding to the “hotspot” previously reported in t-APL complicating mitoxantrone-containing breast cancer therapy. Another shared breakpoint was identified within the ~17kb RARA intron 2 involving two t-APL cases arising after mitoxantrone treatment for MS and breast cancer, respectively. Analysis of PML and RARA genomic breakpoints in functional assays in 4 cases, including the shared RARA intron 2 breakpoint at 14446-49, confirmed each to be preferential sites of topoisomerase IIa-mediated DNA cleavage in the presence of mitoxantrone. This study further supports the presence of preferential sites of DNA damage induced by mitoxantrone in PML and RARA genes that may underlie the propensity to develop this particular subtype of leukemia following exposure to this agent. On extending our genomic analysis on therapy-related acute myeloid leukemia associated with t(16;21) (RUNX1-ETO2) arising after treatment of multiple sclerosis with mitoxantrone t-AML. We identified that genomic breakpoint region of RUNX1 contained a ATGCCCCAG nucleotide sequence showing ~90% homology to a “hotspot” DNA region ATGCCCTAG present in intron 6 of PML which was identified in therapy-related acute promyelocytic leukemia cases arising following treatment with mitoxantrone.
Of note, in year 2000 Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology had approved mitoxantrone for progressive multiple sclerosis. Following the response to post-marketing findings such as potential risk of therapy related leukemia, decreased systolic function and heart failure, the US Food and Drug administration (FDA) has added a “black box” warning to the prescribing information for the mitoxantrone.
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Bishop, Michael W. M. D. "Therapy-Related Events and Health-Related Quality of Life for Children with Leukemia and Lymphoma." University of Cincinnati / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1342544150.
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PIZZITOLA, IRENE. "Chimeric antigen receptor: a cell therapy based approach for the treatment of acute myeloid leukemia." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2013. http://hdl.handle.net/10281/40113.
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Despite the progress in the treatment of acute myeloid leukemia (AML) achieved in the last decades, a significant number of patients are still refractory to or relapse after standard cures. Hence, to improve cure rates of AML, it is crucial to develop novel therapeutic strategies.
Immunotherapy with T cells genetically modified to express chimeric antigen receptors (CARs) represent a valid option in this sense. CARs are artificial molecules constituted by an extracellular-antigen-binding domain derived from a monoclonal antibody and an intracellular-signalling region that is immediately triggered after antigen recognition. Therefore, CARs combine the antigen binding properties of mononoclonal antibodies to T cell mediated effector functions, including the killing mechanism -that might be active against antibody resistant targets-, cytokine secretion- that might boost the anti-tumoral immune response- and capacity to efficiently home and infiltrate tumor sites.
Different CARs have been generated so far, against a wide range of surface molecules expressed by many tumors and, currently, several phase I clinical trials are undergoing and the results obtained so far are very encouraging.
The CARs approach can be employed to selectively target AML cells due to the overexpression of myeloid antigens, like CD33 and CD123.
We recently demonstrated that expression of CD33-specific CARs in a population of ex-vivo activated T cells, called “cytokine induced killer” (CIK) cells, confers them potent in vitro anti-leukemic functions.
However, since CD33 antigen is also expressed on normal haematopoietic stem/progenitors cells (HSPCs) resulting in a potential severe impairment of normal myelopoiesis, CD123 has recently been proposed as a new potential attractive molecule based on its differential expression pattern, being widely overexpressed by AML population and at the same time less expressed on HSPCs.
In order to improve the safety profile against these cells we develop and test a novel CAR specific for the CD123 antigens.
Here we describe the in vitro and the in vivo efficacy and the safety of this approach based on CIK cells genetically modified to express CAR molecules specific for the CD33 or CD123 antigen.
The development and the optimization of the proposed strategy could be a good potential therapeutic tool in the context of minimal residual disease in high-risk transplanted AML patients. Moreover, CAR approach could be potentially used to treat patients resistant to conventional chemotherapeutic approaches or for whom high dose chemotherapy treatment could not be proposed.
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Samuel, Sara. "Vesicular stomatitis virus and BCL-2 inhibitor combination therapy for the treatment of chronic lymphocytic leukemia." Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=119339.
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Chronic lymphocytic leukemia (CLL) is a cancer of the white blood cells (B cell lymphocytes). It is an indolent disorder that results in the accumulation of CD5+ B cells. In CLL, resistance to cell death is attributed to the overexpression of several key pro-survival proteins (i.e. B-cell lymphoma 2 (Bcl-2) and myeloid cell leukemia- 1 (Mcl-1)) that belong to the apoptotic Bcl-2 family of proteins. Bcl-2 and Mcl-1 overexpression deregulates both the apoptotic and autophagic signaling pathways and contributes to tumorigenesis. Oncolytic virotherapy has emerged as a novel anti-cancer therapy for the treatment of a variety of malignant disorders. Oncolytic virus (OV) Vesicular stomatitis virus (VSV)-AV1 takes advantage of genetic defects present within cancerous cells and preferentially targets and kills them. Normal cells are spared the cytotoxic effects of viral lysis and are left unharmed. CLL cells are largely resistant to VSV oncolysis due to an elevated protein expression level of Bcl-2 and Mcl-1 as well as the inhibitory interactions Bcl-2 and Mcl-1 form with pro-apoptotic and pro-autophagic proteins. It is a common approach to use combination therapy to overcome limitations with single agent treatment. In the studies presented within, VSV-AV1 treatment was combined with small-molecule Bcl-2 inhibitors as a means to overcome resistance to oncolytic virtotherapy observed in CLL patients.In the first strategic approach, we combined low-dose amounts of the pan–Bcl-2 inhibitor, Obatoclax, with VSV-AV1 and examined the effect on the apoptotic signaling pathway. Obatoclax and VSV-AV1 synergistically enhanced cell death in primary CLL cells. The combination therapy induced intrinsic apoptotic signaling through the activation of caspases-3 and -9 cleavage. Inhibitory complexes between Bcl-2:Bax and Mcl-1:Bak were disrupted as well. Pro-death protein, Noxa, was upregulated following VSV-AV1 infection and as identified as a critical mediator of apoptotic cell death..In the second approach, we examined VSV-AV1 virotherapy in combination with Bcl-2 inhibitors (Obatolcax or ABT-737) to elucidate the role of the autophagic pathway on cell death in primary CLL cells. We also investigated the crosstalk between the autophagic and apoptotic pathways following combination treatment. Bcl-2 inhibitor/VSV-AV1 therapy led to increased LC3-II and reduced p62 proteins levels, which signify the activation of autophagy. Inhibition of autophagy, with 3-methyladenine, significantly increased apoptotic cell death induced by Bcl-2 inhibitor/VSV-AV1 treatment. The combination therapy also abrogated Bcl-2:Beclin interactions thus stimulating the induction of autophagy.Altogether, our therapeutic strategies indicate that Bcl-2 inhibitors improve VSV-AV1 oncolysis in treatment-resistant hematological malignancies, such as CLL, with characterized defects in apoptotic and autophagic responses.<br>La leucémie lymphoïde chronique (LLC) est un cancer qui affecte les globules blancs et provient de l'accumulation des lymphocytes B CD5+. La résistance à la mort cellulaire est attribuée à la surexpression de plusieurs protéines de pro-survie tel que « B-cell lymphoma 2 » (Bcl-2) et « myeloid cell leukemia (Mcl-1) » qui appartiennent à la famille de protéines apoptotiques Bcl-2. La surexpression de Bcl-2 et Mcl-1 dérégule les voies de signalisations apoptotiques et autophagiques et contribue au développement de la tumeur. La virothérapie oncolytique a démontré son efficacité comme nouvelle thérapie anticancéreuse pour le traitement de plusieurs types de tumeur. Le virus de la stomatite vésiculaire (VSV)-AV1 est un virus oncolytique qui prend avantage des anomalies génétiques présentes dans les cellules cancéreuses pour préférentiellement infecter et détruire ces dernières tandis que les cellules normales sont épargnées de la lyse virale. Cependant, les cellules affectées par LLC sont tout de même résistante à l'oncolyse par VSV à cause d'un niveau d'expression élevé des protéines Bcl-2 et Mcl-1, et de leur effet inhibiteur sur les protéines pro-apoptotiques et pro-autophagiques. Les thérapies combinées permettent de dépasser les limites imposées par les traitements utilisant un seul agent anticancéreux. Dans la présente étude, le traitement oncolytique VSV-AV1 a été combiné avec un autre agent anticancéreux, une molécule inhibitrice de Bcl-2, pour surpasser la résistance au traitement oncolytique par VSV-AV1. Dans une première stratégie, nous avons combiné une faible dose d'Obatoclax, un inhibiteur de Bcl-2, avec VSV-AV1 et examiné l'effet sur la voie de signalisation apoptotique. Obatoclax et VSV-AV1 ont augmenté de façon synergique la mort cellulaire des cellules primaires isolées de patients atteints de LLC. La thérapie combinée a induit la signalisation apoptotique intrinsèque en activant la caspase-3 et caspase-9 ainsi qu'en séparant les complexes inhibiteurs Bcl-2:Bax et Mcl-1:Bax. De plus, l'expression de la protéine pro-apoptotique Noxa a augmenté suite à l'infection avec VSV-AV1 et il a été démontré que cet événement est critique pour enclencher la mort cellulaire par apoptose. Dans une deuxième stratégie, nous avons examiné le rôle de la voie de signalisation de l'autophagie dans la mort cellulaire des cellules primaire LLC suite à la thérapie oncolytique avec VSV-AV1 en combinaison avec Obatoclax ou ABT-737, deux inhibiteurs de Bcl-2. Nous avons étudié l'interaction entre l'autophagie et l'apoptose suite au traitement combiné et démontré que le traitement a augmenté le niveau de LC3-II et a réduit le niveau de la protéine p62, ce qui indique une activation de l'autophagie. En contrepartie, l'inhibition de l'autophagie avec le 3-methyladénine a augmenté de façon significative la voie apoptotique. La thérapie combinée a également bloqué l'interaction entre Bcl-2 et Bectin et par conséquent stimulé l'induction de l'autophagie. Les stratégies thérapeutiques examinées dans cette étude indiquent que les inhibiteurs de Bcl-2 améliorent l'oncolyse virale dans les leucémies résistantes aux traitements simples et qui sont caractérisées par des anomalies dans la réponse apoptotique et autophagique, tel qu'observé chez les patients atteints de LLC.
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Delviks, Krista Anda. "Development of murine leukemia virus-based vectors for more effective gene therapy genetic analysis of direct repeat deletions /." Morgantown, W. Va. : [West Virginia University Libraries], 1999. http://etd.wvu.edu/templates/showETD.cfm?recnum=642.
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Thesis (Ph. D.)--West Virginia University, 1999.<br>Title from document title page. Document formatted into pages; contains vi, 119 p. : ill. Vita. Includes abstract. Includes bibliographical references.
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Bento, Rui Pedro Garcia de Oliveira. "CAR-modified T cells targeted to CD19 antigen for lymphocytic leukemia." Master's thesis, Universidade de Aveiro, 2014. http://hdl.handle.net/10773/13445.
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Mestrado em Biomedicina Farmacêutica<br>Cellular immunotherapies, or Advanced Therapy Medicinal Products (ATMPs), are emerging as novel and specific therapeutic approaches to treat diseases, such as certain types of leukemias, which are difficult or impossible to treat with today’s biopharmaceutical products. Breakthroughs in basic, preclinical, and clinical science spanning cellular immunology, and cellprocessing technologies has allowed clinical applications of chimeric antigen receptor–based therapies. A recent example is CTL019, a lentivirus-based gene therapy for autologous T cells, acquired by Novartis in 2012 through a global alliance with the University of Pennsylvania. Although this technology is still in its infancy, clinical trials have already shown clinically significant antitumor activity in chronic lymphocytic leukemia and acute lymphocytic leukemia. Trials targeting a variety of other adult and pediatric malignancies are under way. The potential to target
essentially any tumor-associated cell-surface antigen for which a monoclonal antibody can be made opens up an entirely new arena for targeted therapy of cancer. The regulatory environment for these Advanced Therapies Medicinal Products is complex and in constant evolution. Many challenges lie ahead in terms of manufacturing process, non-conventional supply chain logistics, business models, intellectual property, funding and patient access.
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Tsang, Jovian. "The Biology and Interplay of Immunotherapy by Leukemia-Oncolytic Virus (iLOV) Immune Responses." Thesis, Université d'Ottawa / University of Ottawa, 2014. http://hdl.handle.net/10393/31873.
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Oncolytic viruses (OVs) are novel biological agents that selectively infect and kill malignant cells. OVs can also generate anti-cancer immunity. Our lab exploited this phenomenon and developed an in vitro vaccine with infected leukemia cells with oncolytic virus vaccine – and named immunotherapy by leukemia-oncolytic virus (iLOV) – that provided in vivo protection in a murine model for acute lymphoblastic leukemia. This work further characterizes iLOV biology and the interaction of its immune responses. An in vitro immune response assay was optimized to detect and quantify the in vivo anti-leukemia immunity generated by iLOV. Anti-viral immunity is an obstacle for OV therapy. Although iLOV created anti-viral antibodies towards itself, these neutralizing antibodies did not hinder the vaccine’s ability to initiate complement or dendritic cell activation. We envision personalized versions of iLOV for leukemia patients in remission to prevent the possibility of relapse. This work highlights new advantages for infected cell vaccines and supports the progress of iLOV toward clinical testing.
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Imawan, Jensen. "Early and risk adapted therapy with Fludarabine in high risk binet stage a chronic lymphocytic leukemia patients." Diss., lmu, 2009. http://nbn-resolving.de/urn:nbn:de:bvb:19-112034.
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Chiodin, Giorgia. "Chronic Lymphocytic Leukemia: analysis of microenvironmental influence on neoplastic clone survival and IgM signaling during Ibrutinib therapy." Doctoral thesis, Università degli studi di Padova, 2017. http://hdl.handle.net/11577/3422771.
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Chronic Lymphocytic Leukemia (CLL) is characterized by the monoclonal expansion of mature CD19+/CD5+/CD23+ B lymphocytes in peripheral blood, bone marrow and lymphoid tissues. Surface IgM (sIgM) signaling is key to CLL behavior and is a therapeutic target of the BTK-inhibitor Ibrutinib. SIgM levels and signaling capacity are variable in CLL and correlate with the behavior of the disease. In CLL, the microenvironment also plays an important role in disease support and progression. In this thesis two projects are presented: the analysis of the microenvironmental influence on neoplastic clone survival in different in vitro culture conditions, and the study of the effects that Ibrutinib in vivo therapy exerts on sIgM in CLL patients.
Mesenchymal Stromal Cells (MSCs), which represent the major component of the stromal microenvironment, were isolated from the marrow aspirate of CLL patients and co-cultured with leukemic cells. After 7 days, we observed a relevant extended survival of leukemic cells in respect to the B cells cultured alone, and the behavior of the neoplastic clones could be differently dependent on the signals coming from the stromal cells. MSCs were able to counteract the cytotoxic effect of Fludarabine/Cyclophosphamide in vivo administration, confirming the important role played by the microenvironment during therapy. However, the kinase inhibitors Ibrutinib and Bafetinib could induce apoptosis of leukemic cells co-cultured with MSCs, and inhibited CLL B cell CD49d-mediated adhesion and pseudoemperipolesis, suggesting that the new kinase inhibitors are effective in targeting the pro-survival cross-talk between leukemic lymphocytes and stromal cells.
In patients, Ibrutinib treatment induces a rapid redistribution of CLL cells into the blood. In this study, the expression and function of sIgM was analyzed in 12 CLL patients after 1 week of Ibrutinib therapy. At this time point, the expression of sIgM increased significantly (P=0.001), accompanied by full N-glycan maturation of sIgM heavy-chain, indicating recovery from antigen engagement. In addition, the sIgM levels correlated with increased sIgM-mediated SYK phosphorylation. The data suggest that Ibrutinib could prevent antigen encounter, thus favoring sIgM expression and maturation.<br>La leucemia linfatica cronica (LLC) e’ caratterizzata dall’accumulo di linfociti B maturi con fenotipo CD19+/CD5+/CD23+ nel sangue periferico, nel midollo osseo e nei tessuti linfatici. I segnali mediati dalle immunoglobuline M di superficie (sIgM) sono fondamentali per il comportamento dei linfociti di LLC, e sono divenuti target di inibitori chinasici come Ibrutinib. I livelli di sIgM e la capacita’ di mediare segnali intracellulari sono variabili nei cloni tumorali e si associano al comportamento della malattia. Inoltre, anche il microambiente tumorale ricopre un ruolo importante nel supporto e nella progressione della LLC. In questa tesi sono presentati due progetti: l’analisi dell’influenza del microambiente sulla sopravvivenza del clone neoplastico in diverse condizioni di coltura in vitro, e lo studio degli effetti della terapia con Ibrutinib su signalling e funzionalita’ delle sIgM in pazienti di LLC.
Nella prima parte dello studio, le cellule mesenchimali stromali (MSCs) sono state isolate da aspirati midollari da pazienti affetti da LLC e sono state poste in co-coltura con cellule B neoplastiche. Dopo 7 giorni di incubazione, abbiamo osservato un rilevante incremento della sopravvivenza delle cellule leucemiche poste in co-coltura con MSCs rispetto alle cellule poste in coltura singola; abbiamo osservato che cloni diversi mostrano comportamento diverso in termini di sopravvivenza, in base alle caratteristiche intrinseche dei cloni stessi. Le MSCs, inoltre, sono in grado di contrastare l’effetto citotossico della terapia Fludarabina/Ciclofosfamide quando somministrata in vivo in pazienti con LLC, a conferma dell’importante ruolo svolto dal microambiente. Tuttavia, i risultati ottenuti hanno mostrato che gli inibitori chinasici Ibrutinib e Bafetinib sono invece in grado di indurre apoptosi nelle cellule tumorali anche in presenza di MSCs e di inibirne l’adesione mediata da CD49d e la pseudemperipolesi, suggerendo che gli inibitori del signalling del BCR sono efficaci nel bloccare il cross-talk tra linfociti neoplastici e cellule stromali.
Nei pazienti affetti da LLC il trattamento con Ibrutinib induce una rapida ridistribuzione delle cellule tumorali nel sangue. In questo studio, l’espressione e la funzione delle sIgM e’ stata analizzata in 12 pazienti con LLC dopo 1 settimana di terapia con Ibrutinib. A questo time point, l’espressione di IgM sulla superficie delle cellule neoplastiche e’ risultata significativamente aumentata (P=0.001); allo stesso tempo abbiamo anche osservato un aumento della forma matura della catena pesante delle sIgM, indicativa di un mancato incontro con l’antigene. Inoltre, i risultati ottenuti hanno mostrato una correlazione tra l’incremento dei livelli di sIgM e l’aumentata fosforilazione di SYK mediata da IgM. I dati suggeriscono che Ibrutinib potrebbe prevenire l’incontro con l’antigene, favorendo quindi espressione e maturazione delle sIgM nelle cellule di LLC.
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Melgar, Katelyn M. "A polypharmacologic strategy for overcoming adaptive therapy resistance in AML by targeting immune stress response pathways." University of Cincinnati / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1571061798761171.
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Vasser, Geneva M. "Manipulation of the moloney murine leukemia virus envelope protein in an effort to develop directly and indirectly targeted retroviral vectors for use in human gene therapy." View the abstract Download the full-text PDF version, 2008. http://etd.utmem.edu/ABSTRACTS/2008-031-Vasser-Index.html.
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Thesis (M.S. )--University of Tennessee Health Science Center, 2008<br>Title from title page screen (viewed on Sept. 17, 2008). Research advisor: Lorraine M. Albritton, Ph.D. Document formatted into pages (x, 138 p. : ill.). Vita. Abstract. Includes bibliographical references (p. 40-48).
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Agnusdei, Valentina. "Selective targeting of NOTCH-1 for therapeutic purposes in xenograft models of T-acute lymphoblastic leukemia." Doctoral thesis, Università degli studi di Padova, 2013. http://hdl.handle.net/11577/3423012.
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T-cell acute lymphoblastic leukemia (T-ALL) is an heterogeneous disease, characterized by several genetic alterations and polymorphic clinical features both in children and adults. The Notch pathway, an evolutionary conserved pathway involved in many biological processes including T cell differentiation, has been implicated in the pathogenesis of this disease. Notably, about 50-55% of T-ALL samples show increased Notch1 activity, due to mutations in NOTCH1 or FBW7 genes. Among T-ALL patients, only 70-80% of children and 40% of adults reach long-term remission, therefore new therapeutic approaches are required. Here, we investigated the biologic and therapeutic effects of a human Notch1-specific neutralizing antibody in xenograft models of pediatric T-ALL, obtained from patients with different clinical features and NOTCH1/FBW7 mutational status. We demonstrated that anti-Notch1 treatment greatly delayed engraftment of T-ALL cells bearing NOTCH1/FBW7 mutations, including samples derived from relapsed and clinically difficult-to-treat patients. In these xenografts we observed increased levels of apoptosis, decreased proliferation of leukemic cells and a marked inhibitory effects on Notch transcriptional profile. Moreover, modulation of T-ALL cells metabolism was detected following anti-Notch1 therapy. Serial transplantation experiments suggested that anti-Notch1 therapy could compromise leukemia initiating cell functions and a preliminary experiment showed that resistance may arise in a regimen of continuous administration of anti-Notch1 mAb. Finally, we demonstrated that combination of anti-Notch1 and dexamethasone – a leading drug in T-ALL treatment - could further improve therapeutic effect.
Altogether these results indicate that NOTCH1/FBW7 mutations identify suitable candidates for Notch targeted therapy and highlight the potential of Notch target genes and CD7 expression as candidate predictive markers of response to anti-Notch1 therapy.<br>La leucemia linfoblastica acuta a cellule T (T-ALL) è una malattia eterogenea caratterizzata da diverse alterazioni genetiche e caratteristiche cliniche, sia in età pediatrica che adulta. Un ruolo importante in questo tipo di neoplasia è ricoperto dal pathway di Notch, meccanismo evolutivamente conservato coinvolto in numerosi processi biologici tra cui il differenziamento dei linfociti T; difatti in circa il 50-55% dei pazienti affetti da T-ALL si riscontra una mutazione attivante nel gene NOTCH1 o a carico di FBW7. Dal momento che solo il 70-80% dei bambini e il 40% degli adulti affetti da questo tipo di leucemia riesce a raggiungere la remissione a lungo termine, e’ necessario sviluppare ed adottare nuove strategie terapeutiche per poter curare anche i pazienti refrattari alle terapie convenzionali. A questo scopo abbiamo analizzato gli effetti biologici e terapeutici di un anticorpo neutralizzante specifico per il recettore Notch1 umano, avvalendoci di un modello di xenotrapianto di T-ALL. Tale modello è stato generato nel nostro laboratorio utilizzando campioni ottenuti da pazienti pediatrici con caratteristiche cliniche differenti e presentanti diverso stato mutazionale di NOTCH1/FBW7. Il trattamento con anti-Notch1 si è rivelato efficace nel contrastare la crescita della leucemia dei campioni con mutazione di NOTCH1/FBW7, compresi campioni derivati da pazienti in ricaduta o poco responsivi alle terapie convenzionali. In seguito alla somministrazione di anti-Notch1, in questi xenotrapianti abbiamo osservato un aumento dei livelli di apoptosi, una riduzione della proliferazione, un effetto inibitorio molto marcato sui profili trascrizionali dei geni target di Notch e inoltre una modulazione del metabolismo cellulare delle cellule leucemiche. Gli esperimenti di inoculo seriale indicano che la terapia con anti-Notch1 può compromettere la capacità di dare origine a leucemia delle cellule di T-ALL residue dopo il trattamento. Inoltre un esperimento preliminare ha rivelato che la somministrazione continua dell’anticorpo anti-Notch1 può causare l’insorgenza di fenomeni di resistenza alla terapia. Infine abbiamo dimostrato che la combinazione di anti-Notch1 e desametasone, un farmaco comunemente utilizzato nel trattamento delle T-ALL, può ulteriormente migliorare l’efficacia terapeutica.
Nel complesso, i nostri risultati indicano che la presenza di mutazioni in NOTCH1/FBW7 identifica dei candidati che potrebbero beneficiare di una terapia mirata contro Notch1 e sottolinea la potenzialità del valutare l’espressione dei geni target di Notch e del CD7 come marcatori predittivi della risposta terapeutica all’anti-Notch1.
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Salvatico, Jose. "The Expression of MKRN1, an E3 Ubiquitin Ligase for Telomerase Reverse Transcriptase, Is Induced with Differentiation Therapy in Leukemia." Master's thesis, University of Central Florida, 2009. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/3744.
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Telomeres are important structural and functional components of chromosomes, serving to provide stability and enabling full replication of the chromosomes. However, a shortening of the telomeres occurs with each cell division that can be fixed by a polymerase activity provided by telomerase, preventing this loss which would otherwise eventually lead to chromosome end-to-end fusions, senescence and cell death. The telomerase activity is present in stem cells and germ line cells, but absent or barely noticeable in adult somatic cells. However, in approximately 80-90% of transformed somatic cells the telomerase activity is recovered, resulting in a "telomerase positive phenotype". This phenotype has been a prime target in cancer research, and recently a novel mechanism for regulating telomerase levels has been uncovered. Makorin 1 RING finger protein (MKRN1) was found to be an E3 ubiquitin ligase for hTERT, the rate-limiting catalytic component of telomerase, leading to the ubiqutin-mediated 26s proteasomal degradation of hTERT and reduced telomerase activity. So, MKRN1 plays a role in telomere homeostasis. In this study we looked at the expression of MKRN1 in numerous tumor cell lines (Hela, HCT116, HL60) and the normal diploid fibroblasts (WI-38). In the latter cell line, basal levels of MKRN1 were found to increase 6-fold when the cells were serum starved and arrested in G1/G0. In contrast, the cancer cell lines expressed MKRN1 at low levels or undetectable. This would indicate that MKRN1 is up-regulated in resting or G1 arrested cells.In one cell line the promyelocytic leukemia, HL-60, showed no protein levels of MKRN1. This cell line is able to be terminally differentiated upon ATRA treatment, when cells are arrested at G1. In this model system of cellular differentiation hTERT mRNA levels and telomerase activity decrease drastically and quickly. We hypothesized that the differentiation of HL-60 induced by ATRA would be accompanied by an increase in MKRN1 levels. MKRN1 mRNA and protein levels were strongly up-regulated during the ATRA-mediated differentiation of HL-60 cells. Although, a decrease in hTERT mRNA is a contributor to telomerase inhibition during cellular differentiation; our data indicate that the up-regulation of MKRN1 ensures the effective removal of residual telomerase activity by the ubiquitin-mediated degradation pathway at the proteasome.<br>M.S.<br>Department of Molecular Biology and Microbiology<br>Burnett College of Biomedical Sciences<br>Molecular and Microbiology MS
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Habringer, Stefan [Verfasser], Ulrich [Akademischer Betreuer] Keller, Wolfgang [Gutachter] Weber, Dieter [Gutachter] Saur, and Ulrich [Gutachter] Keller. "CXCR4-directed Imaging and Therapy in Acute Leukemia / Stefan Habringer ; Gutachter: Wolfgang Weber, Dieter Saur, Ulrich Keller ; Betreuer: Ulrich Keller." München : Universitätsbibliothek der TU München, 2019. http://d-nb.info/1190285150/34.
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Ibach, Tabea [Verfasser]. "Adoptive T-cell Therapy via Chimeric Antigen Receptors (CARs) against Leukemia in Combination with a human Suicide Gene / Tabea Ibach." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2020. http://d-nb.info/1209354136/34.
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Hallböök, Helene. "Acute lymphoblastic leukaemia in adult patients : studies of prognostic factors, treatment results and in vitro cellular drug resistance /." Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-5768.
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Sentís, Carreras Inés 1990. "The Evolution of T-cell acute lymphoblastic leukemia in adult patients under treatment." Doctoral thesis, TDX (Tesis Doctorals en Xarxa), 2021. http://hdl.handle.net/10803/670544.
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Acute lymphoblastic leukemia (ALL) is a blood cancer characterized by a high proliferation and maturation arrest of the lymphoid precursors which can either be from B or T-cell lineage. In adult patients, this type of cancer is considered a rare disease and the outcome is worse than children, especially for those presenting the T-Cell ALL (T-ALL) type. In order to get insights on the evolution of adult T-ALL under therapy, we have whole genome sequenced leukemic samples at diagnosis and relapse of 19 adult patients with T-ALL who relapsed after standard treatment. We report the somatic driver alterations and active mutational process and compared them to other ALL cohorts. We pinpoint candidates of therapy resistance by looking at relapse-enriched alterations (e.g. genes NT5C2, ABCB1 and SMARCA4). In most cases, the relapse clone is estimated to diverge from the primary the previous year to the diagnosis, by which time, the relapse-fated subpopulation size ranges from few to millions of cells. We have also simulated different scenarios of primary and relapse leukemias and concluded that the relapsed leukemias of the sequenced cohort are driven by genetic resistance. In this project we provide an integrated vision of the mutational evolution of T-ALL adult cases and highlight the relevance of finding cancer driver genes of resistance. In line with that, we have also generated a compendium of mutational cancer driver genes across different cancer types through the analysis of thousands of tumors with a whole new framework for driver gene discovery (IntOGen).<br>La leucèmia limfoblàstica aguda (LLA) és un càncer de sang que es caracteritza per una altra proliferació i arrest en la maduració dels precursors limfoblàstics que poden ser del llinatge B o T. En pacients adults, aquest tipus de càncer és considerat una malaltia rara i presenten pitjor pronòstic que els pacients pediàtrics en especial en aquells adults del tipus T-LLA. Per tal de conèixer millor l'evolució de la T-LLA en adults en tractament, hem seqüenciat el genoma sencer de mostres a diagnòstic i recaiguda de 19 pacients adults amb T-LLA que van recaure després de rebre el tractament estàndard. Reportem les alteracions somàtiques driver i els processos mutationals actius en comparació amb d’altres cohorts de LLA. També assenyalem candidats de resistència al tractament tot mirant les alteracions abundants en recaiguda (per exemple als gens NT5C2, ABCB1 i SMARCA4). En la majoria dels casos, el clon de recaiguda s’estima que va divergir del clon primari l’any previ a la diagnosi, moment pel qual, les cèl·lules destinades a fer la recurrència constitueixen una subpoblació cel·lular que va de poques a milions de cèl·lules. Mitjançant simulacions de diferents escenaris de leucèmies primàries i de recaiguda, concloem que les leucèmies de recaiguda d’aquesta cohort seqüenciada es deuen a una resistència genètica. En aquest projecte donem una visió integrada de l’ evolució mutacional de les T-LLA en casos adults i resaltem la rellevància de trobar gens driver de resistència. En aquesta línia, també hem generat un compendi de gens driver mutacionals de diferents tipus càncer a través de l'anàlisi de milers de tumors amb una nova plataforma de detecció de gens driver (IntOGen).
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Küpper, Maja Kim [Verfasser], Wolfgang [Akademischer Betreuer] Wagner, and Gerhard [Akademischer Betreuer] Müller-Newen. "STAT3-mediated therapy resistance of malignant stem cells in chronic myeloid leukemia (CML) / Maja Kim Küpper ; Wolfgang Wagner, Gerhard Müller-Newen." Aachen : Universitätsbibliothek der RWTH Aachen, 2019. http://d-nb.info/1194067107/34.
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Ghelli, Luserna di Rorà Andrea <1987>. "The Inhibition of Chk1/Chk2 and Wee-1 Kinases as a Promising Therapy for the Treatment of Adult Acute Lymphoblastic Leukemia." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2016. http://amsdottorato.unibo.it/7529/1/Ghelli_Luserna_di_Rora%27_Andrea_Tesi.pdf.
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Due to inadequate treatments, the survival rate of adult patients with acute lymphoblastic leukemia (ALL) is still very poor. Thus there is a need to improve the efficacy of conventional therapy. In this study we evaluated the effectiveness of checkpoint kinase inhibitors (Chk-i) in single agent and in combination with different compounds conventionally used for the treatment of B-/T-ALL. We showed that Chk1 and Chk2 kinases are highly expressed and hyper-activated in tumor samples in comparison to normal tissue. On these bases we speculate that the inhibition of these kinases could mine the genetic stability and enhance cell death in ALL cells. We firstly evaluate the efficacy in single agent of the Chk1/Chk2 (PF-0477736 and LY2606368) and of the Wee1 (MK-1775) inhibitors on different cell lines and on primary cells isolated from adult B-ALL patients. We demonstrated that the inhibition of Chk1/Chk2 kinases reduces of the cell viability, activates the apoptosis and modify the expression of different elements of the G2/M checkpoint. To assess the chemo-sensitizer activity of different checkpoint kinase inhibitors, several combination studies were performed. To this purpose, LY2606368 and MK-1775 were combined with different tyrosine kinase inhibitors (imatinb, dasatinib and bosutinib) and with the purine nucleoside analogue, clofarabine. The efficacy of the combinations was not only evaluated in term of reduction of the cell viability but also in term of induction of apoptosis and induction of DNA damages. The results found were then confirmed on primary cells of B-ALL patients. Finally different class of checkpoint kinase inhibitors were combined together in order to evaluate their interaction. In our opinion the preclinical data presented in this study are the basis for a future evaluation of this class of compound in clinical trials in the treatment of adult ALL patients.
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Ghelli, Luserna di Rorà Andrea <1987>. "The Inhibition of Chk1/Chk2 and Wee-1 Kinases as a Promising Therapy for the Treatment of Adult Acute Lymphoblastic Leukemia." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2016. http://amsdottorato.unibo.it/7529/.
Full textAbstract:
Due to inadequate treatments, the survival rate of adult patients with acute lymphoblastic leukemia (ALL) is still very poor. Thus there is a need to improve the efficacy of conventional therapy. In this study we evaluated the effectiveness of checkpoint kinase inhibitors (Chk-i) in single agent and in combination with different compounds conventionally used for the treatment of B-/T-ALL. We showed that Chk1 and Chk2 kinases are highly expressed and hyper-activated in tumor samples in comparison to normal tissue. On these bases we speculate that the inhibition of these kinases could mine the genetic stability and enhance cell death in ALL cells. We firstly evaluate the efficacy in single agent of the Chk1/Chk2 (PF-0477736 and LY2606368) and of the Wee1 (MK-1775) inhibitors on different cell lines and on primary cells isolated from adult B-ALL patients. We demonstrated that the inhibition of Chk1/Chk2 kinases reduces of the cell viability, activates the apoptosis and modify the expression of different elements of the G2/M checkpoint. To assess the chemo-sensitizer activity of different checkpoint kinase inhibitors, several combination studies were performed. To this purpose, LY2606368 and MK-1775 were combined with different tyrosine kinase inhibitors (imatinb, dasatinib and bosutinib) and with the purine nucleoside analogue, clofarabine. The efficacy of the combinations was not only evaluated in term of reduction of the cell viability but also in term of induction of apoptosis and induction of DNA damages. The results found were then confirmed on primary cells of B-ALL patients. Finally different class of checkpoint kinase inhibitors were combined together in order to evaluate their interaction. In our opinion the preclinical data presented in this study are the basis for a future evaluation of this class of compound in clinical trials in the treatment of adult ALL patients.
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ARCANGELI, SILVIA. "Optimization of Chimeric Antigen Receptor (CAR) design strategy for a specific anti-CD123 targeted therapy in pediatric Acute Myeloid Leukemia (AML)." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2016. http://hdl.handle.net/10281/114569.
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Chimeric Antigen Receptors (CARs)-redirected T lymphocytes are a promising novel immunotherapeutic approach, nowadays object of accurate preclinical evaluation also for the treatment of Acute Myeloid Leukemia (AML). In this context, we recently developed a CAR against CD123, over-expressed on AML blasts and leukemic stem cells. However, the potential recognition of low CD123-positive healthy tissues, through the "on-target-off-organ" effect, limits the safe clinical employment of CAR-redirected T cells. Therefore, in search for a CAR design optimization, we here evaluated the effect of variables capable to modulate CAR T-cell functional profiles in a context-dependent manner, such as CAR binding affinity for the target antigen, CAR expression and target antigen density.
To study these variables in the absence of other interfering elements we exploited computational structural biology tools to design rational mutations in the anti-CD123 CAR antigen binding domain that altered CAR expression and CAR binding affinity, without affecting the overall CAR design. We were able to define both “lytic” and “activation” antigen thresholds, showing that whereas the early T-cell cytotoxic activity is not affected either by CAR expression or CAR affinity tuning, later effector functions are impaired by low CAR expression. Moreover, a promising balance in the efficacy and safety profiles of CAR T cells was observed in the lowest affinity mutant in response to targets with different antigen densities. Overall, the full dissection of all these variables offers additional knowledge for the proper design of a suitable anti-CD123 CAR for the treatment of AML.
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Katsoulas, Athanasia. "Design and mechanism of action of novel agents termed "combi-molecules" engineered for tandem targeting for Bcr-abl expressing leukemia cells." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111884.
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Bcr-abl expression being associated with anti-apoptotic signaling and expression of DNA repair enzymes, we surmised that single molecules capable of blocking abl tyrosine kinase (TK) function and damaging DNA should lead to compounds with potency superior to that of GleevecRTM. To this end, we designed novel agents termed "combi-molecules" programmed to not only behave as bcr-abl inhibitors on their own, but also to further degrade to another inhibitor and a DNA damaging species. The released inhibitor was designed to sustain bcr-abl inhibition following degradation of the combi-molecule and the DNA damaging species to activate pathways leading to apoptosis. To model this strategy termed "combi-targeting", we synthesized ZRCM5 (a monoalkyltriazene) that showed antiproliferative activity superior to that of the classical DNA damaging agent TemodalRTM, but not to that of Gleevec RTM. This result was imputed to the rather weak bcr-abl inhibitory activity of ZRCM5 and its strong DNA damaging property. Another prototype designed to contain an aniline mustard moiety (AK04) was a strong bcr-abl inhibitor but a poor DNA alkylating agent. Its cytotoxic activity was again stronger than that of the clinical alkylating agent chlorambucil but inferior to that of GleevecRTM. Further chemical studies directed at structural modification of the benzamide moiety led to the synthesis of ZRF1 with strong potency against bcr-abl TK and strong DNA damaging property. This novel optimized combi-molecule showed a 1.6-3-fold greater potency than GleevecRTM against bcr-abl expressing cells. Further investigation with ZRF1, showed that its cytotoxic potency was dependent on the p53 wild-type status of the cells. In cells expressing wild-type p53, p21 transactivation was associated with cell cycle arrest and that of Bax with apoptosis. In addition to, the pro-apoptotic effect of bcr-abl inhibition, these multiple mechanisms of action may synergistically enhance the cytotoxic potency of ZRF1 in p53 wild-type cells. The study conclusively demonstrated that p53 is a major determinant for the cytotoxic advantage of the novel combi-molecular approach in chronic myelogenous leukemia (CML), a disease in which 70-85% of all cases express wild-type p53.
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Nóbrega, Virginia Tafas 1981. "Efeitos tardios do tratamento antineoplásico em sobreviventes de leucemia linfoblástica aguda da infância no Grupo em Defesa da Criança com Câncer (GRENDACC)." [s.n.], 2014. http://repositorio.unicamp.br/jspui/handle/REPOSIP/312105.
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Orientador: Simone dos Santos Aguiar<br>Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas<br>Made available in DSpace on 2018-08-26T11:47:25Z (GMT). No. of bitstreams: 1
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Previous issue date: 2014<br>Resumo: Introdução: As taxas de sobrevida para leucemia linfoblástica aguda (LLA) na infância vêm apresentando aumento significativo nos últimos anos. Em decorrência disso, o número de adultos jovens sobreviventes se eleva a cada ano, tendo muitos deles uma série de complicações decorrentes do tratamento. O objetivo deste estudo é investigar a incidência e prevalência dos efeitos adversos tardios do tratamento antineoplásico, em sobreviventes de leucemia linfocítica aguda. Pacientes e Métodos: Desenho do estudo de coorte retrospectivo. Foram selecionados sobreviventes de LLA, que foram diagnosticados com menos de 18 anos, e estejam fora de tratamento há, pelo menos, dois anos. Os dados deste estudo foram coletados dos prontuários dos pacientes que foram submetidos a avaliação médica e exames complementares. Os efeitos adversos apresentados foram avaliados através desta revisão. Resultados obtidos: Dos 38 sobreviventes analisados, 55% (n=21) apresentaram algum tipo de comorbidade e 13,5% foram afetados por mais de uma alteração. A dislipidemia acometeu 18,4% (n=7) da população estudada, sendo a comorbidade mais prevalente com 35%. A baixa densidade óssea também apareceu com bastante frequência, acometendo 15% dos casos estudados. O tempo fora de terapia teve uma média de 7,92 anos (variação 2-16 anos). Conclusão: A necessidade de realizar o acompanhamento desses pacientes, não só através do exame físico, mas também de exames de imagem e laboratoriais foi evidente no nosso estudo. É possível que o acompanhamento regular, desde o término da terapia, até 20 ou 30 anos depois, leve à redução da intensidade e prevalência de comorbidades nessa população<br>Abstract: Background: Survival rates for acute lymphocytic leukemia in childhood have shown significant increase in recent years. Consequently, the number of young adult survivors rises each year, and some of those has a set of complications resulting from therapy. The aim of this study is to investigate the incidence and prevalence of late adverse effects of antineoplastic treatment in survivors of acute lymphoblastic leukemia. Patients and Methods: Retrospective cohort study. Survivors of acute lymphoblastic leukemia, younger than 18 years old at diagnosis, and off treatment for at least two years, have been selected. These were following-up at outpatient¿s clinic, where the information was collected and examinations performed. Adverse effects presented were evaluated by reviewing medical records. Results: Of the 38 survivors studied, 55,2% (n = 21) had some type of comorbidity and 13.5% were affected by more than one change. Dyslipidemia struck 18.4% (n = 7) of the population studied, and the most prevalent comorbidity with 35%. Low bone mineral density also appeared quite frequently, affecting approximately 16% of the group. The time off therapy had an average of 7.92 years (range 2-16 years). Conclusion: The necessity of follow-up of these patients, but only by physical examination, but imaging and laboratory was evident in our study. It is possible that with regular monitoring, since the completion of therapy, up to 20 or 30 years, leading to the reduction of the intensity and prevalence of comorbidities in this population<br>Mestrado<br>Saude da Criança e do Adolescente<br>Mestra em Ciências
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Buteyn, Nathaniel J. "Role of Innate Immunity Activators in the Treatment of Acute Myeloid Leukemia." The Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1574343556916953.
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Mani, Rajeswaran. "Preclinical development of a non-immunosuppressive FTY720 derivative OSU-2S forchronic lymphocytic leukemia and other B-cell malignancies." The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1404067069.
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Jaramillo, Segura Sonia [Verfasser]. "Condensed versus standard schedule of high-dose cytarabine consolidation therapy with pegfilgrastim growth factor support in acute myeloid leukemia / Sonia Jaramillo Segura." Ulm : Universität Ulm, 2017. http://d-nb.info/1148551069/34.
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CANI, Alice. "Targeting the PI3K/Akt/mTOR signaling pathway as a new therapeutic strategy for personalized treatments in acute lymphoblastic leukemia." Doctoral thesis, Università degli studi di Ferrara, 2015. http://hdl.handle.net/11392/2388996.
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Acute lymphoblastic leukemia (ALL) is a hematologic malignancy characterized by the uncontrolled proliferation of lymphoblasts that accumulate in the blood, bone marrow and other organs. It represents 20% of adult acute leukemia and is the most common leukemia in children.
The signal transduction pathway mediated by phosphatidylinositol 3-kinase (PI3K)/ Akt/mammalian target of rapamycin (mTOR) plays a key role in the regulation of important events for cells such as proliferation, differentiation and apoptosis, but also for the development of cancer and resistance to chemotherapy. In fact, the genes involved in the PI3K/Akt/mTOR pathway are often mutated and the activation signal mediated by these proteins is frequently altered in many cancer types, including ALL.
Therefore, the components of this pathway are potential new targets for the development of innovative targeted therapies which use molecules that inhibit the key components of those signal transduction pathways with high specificity, and which have a central role in the oncogenesis process.
The aim of this study is to evaluate the effects of small-molecule inhibitors (SMIs) on the PI3K/Akt/mTOR pathway using a panel of human leukemic cell lines and primary patient samples.
Drugs directed against the Akt and mTOR proteins were used, administered either alone or in combination, to assess their synergistic effects on cells. In particular, MK-2206, GSK690693 and Perifosine are specific inhibitors of Akt, while RAD001 and CCI-779 are directed against mTORC1 and Torin-2 is directed against mTORC1/2.
MK-2206, RAD001 and Torin-2 showed a specific cytotoxicity, inducing apoptosis and also caused cell cycle arrest in G0/G1 phase and autophagy both in cell lines and patient samples. They also down-regulated Akt and mTOR, as well as their downstream substrates.
Moreover, potential synergies between drugs that hit at different levels of the PI3K/Akt/mTOR signal transduction pathway have been studied: a dual action on two targets, has been analyzed, using either MK-2206 or GSK690693 and RAD001 or CCI-779, that showed a synergistic effect, not observable with Torin-2. Also the efficacy of a triple hit on the same target, i.e. Akt, has been analyzed using MK-2206, GSK690693 and Perifosine: the three drugs displayed a synergistic effect that allowed to minimize drug concentrations.
These results emphasize the increasing interest in studying pharmacological and personalized strategies for the development of new potential therapeutic protocols for cancer patients’ treatment, in order to overcome resistances and to improve clinical outcome.
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ALBERTI, GAIA. "Evaluation of a Tandem CD33-CD146 Chimeric Antigen Receptor (CAR) for the simultaneous targeting of Acute Myeloid Leukemia (AML) blasts and stromal cells in the niche." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2022. http://hdl.handle.net/10281/382304.
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La leucemia mieloide acuta (LMA) è la neoplasia ematologica maggiormente diagnosticata nei pazienti adulti (25%) e mentre rappresenta il 15-20% dei casi nei pazienti pediatrici. La chemioterapia convenzionale, che impiega antraciclina e citarabina, rappresenta il trattamento standard per l’LMA, con tassi di remissione completa dal 60% all'80% nei bambini e dal 40% al 60% negli adulti (>60 anni). Sfortunatamente, la ricaduta dopo tale terapia è comune e la sopravvivenza dei pazienti stimata a 5 anni è ancora inferiore al 30%. Risulta quindi di primaria importanza trovare alternative terapeutiche per i pazienti recidivanti e refrattari. Il recente successo clinico, ottenuto nelle leucemie di tipo B, dell'immunoterapia con cellule CAR (chimeric antigen receptor) T ha portato allo sviluppo di nuove strategie terapeutiche nell’ambito dell’LMA. Tuttavia, lo sviluppo del trattamento con cellule CAR T nel contesto dell'LMA è ancora agli albori a causa dell'eterogeneità della malattia, della mancanza di un antigene bersaglio adatto e del ruolo protettivo del microambiente tumorale (TME). Infatti, non esiste ancora un protocollo clinico approvato per il trattamento della leucemia mieloide. Per creare le cellule CAR T abbiamo scelto di utilizzare la piattaforma non virale Sleeping-Beauty (SB) per ingegnerizzare le cellule CIK (cytokine-induced killer). In primo luogo, abbiamo scelto di utilizzare come potenziale strumento per il targeting del TME le cellule CIK ingegnerizzate con anti-CD146.CAR. Di conseguenza, abbiamo ottimizzato 6 diverse molecole CAR aventi un design differente, ottenendo un'espressione ottimale di CD146 nella variante VLVH Long. Abbiamo quindi testato le cellule CD146.CAR-CIK in vitro, ottenendo l’attivazione specifica delle funzioni effettrici (in termini di capacità di killing, produzione di citochine e proliferazione) contro cellule target CD146+. In seguito, abbiamo progettato un Tandem CAR bispecifico (CD33xCD146.CAR-CIKs) che ha mostrato una significativa attività antileucemica in vitro. È stato ampiamente dimostrato che la nicchia midollare contribuisce al supporto e alla protezione delle cellule staminali leucemiche (CSLs). Quindi, per mimare al meglio l’azione del CAR nella nicchia midollare umana, abbiamo testato le cellule CD33xCD146.CAR-CIK contro le linee cellulari stromali CD146+ e le cellule mesenchimali (MSC) primarie sane (HD-) e di derivazione mieloide (LMA-). I dati mostrano una inibizione delle funzioni effettrici delle cellule CAR-CIK e una drastica diminuzione della produzione di citochine e della proliferazione. Inoltre, l'equilibrio tra citochine pro e antinfiammatorie è risultato alterato, infatti la produzione di citochine Th1/Tc1 da parte delle cellule CD146.CAR-CIK è stata inibita dalla co-coltura con cellule stromali, mentre è stato rilevato un aumento delle citochine Th2/Tc2. Questi risultati suggeriscono un potenziale ruolo immunosoppressivo del compartimento stromale nei confronti delle cellule CAR-CIK. Sulla base dell’ effetto immunomodulatorio delle MSC sui linfociti T, abbiamo ipotizzato che la nicchia midollare possa influenzare le funzioni effettrici delle cellule CAR T. Di conseguenza, il targeting del CD146 rappresenta una "proof-of-principles" del fatto che aggredire il microambiente leucemico possa migliorare la terapia CAR T nell’ambito dell’LMA. Per ridurre al minimo la tossicità "off-target ", stiamo cercando di selezionare un antigene bersaglio specifico ed overespresso sulle cellule stromali dell'LMA, che abbia un'espressione minima nello stroma sano e che sia coinvolto nelle interazioni leucemia/nicchia. Il nuovo marker di interesse sarà accoppiato al CD33.CAR nella creazione di un CAR bispecifico, che verrà confrontato con il costrutto CD33xCD146.CAR, valutandone i profili di efficacia e sicurezza sia in vitro che in vivo.<br>Acute myeloid leukemia (AML) is the most frequently diagnosed leukemia in adults (25%) and accounts for 15-20% cases in pediatric patients. Conventional chemotherapy employing anthracycline and cytarabine represents the gold standard treatment for AML, with rates of complete remission from 60% to 80% in children and from 40% to 60% in adults (>60 years). Despite these high rates, relapse after conventional therapy is common and the estimated five-year survival of AML patients is still below 30%. Indeed, there is an urgency to find alternative therapeutic strategies for relapsed and refractory patients. The recent clinical success of chimeric antigen receptor (CAR) T cell immunotherapy in the context of B-cell malignancies has opened a new route of investigation also towards AML. However, the development of CAR T cell therapy in the context of AML is still in its infancy due to heterogeneity of the disease, the lack of a suitable target antigen and the leukemia protective role of the tumor microenvironment (TME) and no approved CAR T cells study exists for AML treatment yet. Non-viral Sleeping-Beauty (SB) transposon platform was employed to redirect cytokine-induce killer (CIK) cell. In this scenario, we firstly characterize non-viral SB engineered CIK cells with anti-CD146.CAR as a potential tool for the targeting of the bone marrow (BM) microenvironment. We optimized the CAR design structure by testing 6 different CAR molecules, achieving a specific and efficient CD146 expression in the VLVH Long variant. CD146.CAR-CIK cells were subsequently tested in vitro, showing an optimal activation of effector functions (in terms of killing activity, cytokines production and proliferation) when they were engaged against CD146+ target cells. Consequently, we developed a bispecific Tandem CAR (CD33xCD146.CAR-CIKs), which displayed anti-leukemic activity in vitro. It has been extensively proven that BM niche contribute to establish a sanctuary in which leukemic stem cells (LSCs) are able to acquire drug-resistant phenotype, therefore, to better mimicking the human BM niche we tested CD33xCD146.CAR-CIK cells against CD146+ stromal cell lines (HS-27A and HS-5) and primary derived healthy (HD-) and patient-derived (AML-) mesenchymal stromal cells (MSCs). Results showed inhibition of the redirected CAR-CIK cells effector functions, resulting in a drastic decrease of cytokines production and proliferation. The balance between pro- and anti- inflammatory cytokines showed that Th1/Tc1 cytokines production by CD146.CAR-CIK cells was inhibited by the co-culture with stromal cells, while increase Th2/Tc2 cytokines was detected when CD146.CAR-CIK cells were co-cultured with stromal target cells. These results suggest a potential immunosuppressive role of the stromal compartment against CAR-CIK cells. According to these results, we hypothesized that BM stromal cells can potentially exert an immunomodulatory effect on T cells, suggesting that the niche microenvironment may be involved in the regulation of CAR T cells therapy effectiveness. Indeed, the targeting of CD146 on stroma represents a “proof-of-principle” that stromal components of leukemic microenvironment may be attractive targets for CAR T based immunotherapy. To minimize “off-tumor” toxicity, we are looking for a specific surface target antigen selectively overexpressed on AML stromal cells, with minimal expression in healthy stroma and possibly involved in leukemia/niche interactions. The newly marker of interest will be coupled to the CD33.CAR and this bispecific CAR will be compared with CD33xCD146.CAR construct, evaluating their efficacy and safety profiles both in vitro and in vivo.
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Aichelin, Katharina [Verfasser], and Peter [Akademischer Betreuer] Angel. "Development of a CD22-specific chimeric antigen receptor (CAR) for the adoptive T cell therapy of leukemia and lymphoma / Katharina Aichelin ; Betreuer: Peter Angel." Heidelberg : Universitätsbibliothek Heidelberg, 2020. http://d-nb.info/1211090434/34.
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Júnior, Edilson Diógenes Pinheiro. "Experiência do Serviço de Hematologia do Hospital das Clínicas da FMUSP com leucemia linfóide aguda do adulto: avaliação clínica, laboratorial e dos protocolos de tratamento." Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/5/5136/tde-24062008-122745/.
Full textAbstract:
A leucemia linfóide aguda nos adultos apresenta prognóstico reservado. Os objetivos deste estudo são descrição e análise de parâmetros clínicos, laboratoriais e fatores prognósticos em 102 pacientes tratados com diferentes protocolos de quimioterapia no período de 1990 a 2005, no Serviço de Hematologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Em estudo de coorte retrospectivo, com exclusão de LLA subtipo L3 (FAB) ou B-IV (EGIL), foram analisadas a taxa de remissão completa (RC), sobrevida global (SG) e sobrevida livre de doença (SLD) para a população geral e para os dois principais protocolos de tratamento. A análise estatística foi feita pelo programa SPSS 10.0. Associação entre variáveis, fatores prognósticos e resposta foram observados através do teste ?2 de Person. Curvas de SG e SLD foram construídas pelo método de Kaplan-Meier e as diferenças analisadas pelo teste de log-rank. A idade média foi de 30,6 anos (12 a 82 anos) e predominou o sexo masculino (55,9%). Ao diagnóstico, os achados clínicos foram: fadiga (58,2%), esplenomegalia (59,7%), hepatomegalia (54,6%), linfadenopatia (52,6), febre (38,8%), dor óssea(28,6%), sangramento (27,5%) e cefaléia (15,3%). Envolvimento do sistema nervoso central (SNC) foi detectado em 11 (11,8%) pacientes, enquanto envolvimento testicular acometeu um paciente. O valor médio de hemoglobina, leucócitos e plaquetas foram 8,5g/dl, 84.341/mm3 e 76.275/mm3, respectivamente. 98,7% dos pacientes apresentaram linfoblastos no sangue periférico. A classificação FAB foi igualmente observada entre os tipos L1 e L2. As LLA B e T foram observadas em 69,7% e 30,2%, respectivamente. O cariótipo foi realizado em 40 pacientes, e t (9;22) foi identificada em 20% (8/40) dos casos. Os pacientes foram tratados com quatro diferentes protocolos: BFM 86 modificado (BFM 86M) em 47,15% (48/102), Linker et al em 39,2% (40/102), Lister et al em 5,9% (6/102) e CHOP em 7,8% (8/102). Na análise para a população geral, na fase de indução, 70,6% (65/92) dos pacientes entraram em RC. Idade inferior a 18 anos e ausência de infiltração de SNC foram fatores preditores positivos de resposta em análise multivariada (p=0,03). Com mediana de seguimento de 49 meses, observamos taxa de 30,5% e 27% para SG e SLD em 4 anos. Ausência de sangramento e hepatomegalia, ao diagnóstico, e idade < 35 anos estiveram associados à maior SG através de análise multivariada (p=0,01). Os dois protocolos com maior número de pacientes, apresentaram distribuição semelhante de parâmetros clínicos e laboratoriais, a exceção da variável FAB. RC foi obtida em 76,7% e 63,9% dos pacientes tratados respectivamente com os protocolos BFM 86M e Linker (p=0,21). A SG foi de 49,5% com o BFM 86M em 4 anos Vs 16% com o protocolo Linker (p=0,004). Observou-se que o protocolo BFM86M teve melhor SG para pacientes com idade <35 anos (p=0,01), sem sangramento e hepatomegalia ao diagnóstico (p=0,03 e p=0,01) e sem leucocitose (B <30.000mm3 e T <100.000mm) (p=0,04); enquanto que pacientes com LLA T tratados com o protocolo Linker apresentaram SG inferior (p=0,05). A diferença de SLD entre os dois protocolos não foi significativa (p=0,58), entretanto na faixa etária entre 21-35 anos, o protocolo BFM se mostrou superior (p=0,03). Verificamos que o BFM 86M é superior ao Linker et al, sendo um bom protocolo para tratamento de LLA em pacientes adolescentes e adultos jovens sem fatores de risco.<br>Acute lymphoblastic leukemia in adults has a poor outcome. The aim of this study is to describe and evaluate clinical, laboratory and prognostic factors in 102 patients reated with different protocols of chemotherapy from 1990 to 2005. Adult ALLsubtype L3 (FAB) or B-IV (EGIL) was excluded. We evaluated complete remission (CR), overall survival (OS) and disease free survival (DFS) rates for the whole population and for the two principal treatment protocols. This retrospective cohort was done in hematology department of the FMUSP. Statistical analysis was done by SPSS 10.0. The association of features and prognosis was assessed by Person\'s chi-square. OS and DFS curves were constructed by Kaplan-Meier method and the differences were calculated by the log-rank test. Mean age was 30,6 (12 to 82) years and 55,9% was male. Clinical findings, at diagnosis, were fatigue (58,2%), splenomegaly (59,7%), hepatomegaly (54,6%), ymphadenopathy (52,6%), fever (38,8%), bone pain (28,6%), bleeding (27,5%) and headache (15,3%). Involvement of central nervous system (CNS) was detected in 11 (11,8%) patients and testicular involvement was observed in one patient. Mean blood values were 8,5g/dl, 84.341/mm3 and 76.275/mm3 for hemoglobin, leucocytes and platelets respectively. 98,7% of the patients presented with lymphoblasts in peripheral blood. FAB classification was equally observed between L1 and L2. B and T ALL was noted in 69,7% and 30,2% respectively. Karyotype analysis was performed in 40 cases, where Philadelphia chromosome (ph) was identified in 20% (8/40) of them. Patients were treated with four different protocols: BFM 86 modified (BFM 86M) in 47,1% (48/102), Linker et al in 39,2% (40/102), Lister et al in 5,9% (6/102) and CHOP in 7,8% (8/102) of the patients. In the judgment for the entire population, in induction treatment, 70,6% (65/92) of the patients had CR. Age below 18 years and no infiltration in CNS were positive factors for CR in multivariate analyses (p=0,03). In a median follow up of 49 months, we have observed a 4 years OS and DFS of 30,5% and 27% respectively. No bleeding and hepatomegaly, at diagnosis, and age less than 35 years were factors associated a better OS in multivariate analyses (p=0, 01). Protocols with highest number of patients (BFM and Linker) showed the same distribution of clinical and laboratory factors; exception FAB classification. CR were seen in 76,7% and 63,9% of the patients treated with BFM 86M and Linker respectively. (p=0,21). OS was 49,5% with BFM protocol in 4 years Vs 16% with Linker (p=0,004). We observed a better OS for patients with age below 35 years (p=0,01), no bleeding and no hepatomegaly at diagnosis (p=0,03 ; p=0,01) and no leucocytosis ( B < 30000/mm3 and T < 100000/mm3) treated with BFM 86M; however ALL - T treated with Linker protocols had inferior OS (p=0,05). DFS between protocols wasn\'t significant (p=0,58), but with age between 21 and 35 years BFM was better (p=0,03). We conclude that BFM 86M is superior than Linker et al and it is a good treatment for childhood / young adults without risk factors
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Maharry, Kati S. "Risk Factors for Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma Incidence in Postmenopausal Women: a Women’s Health Initiative (WHI) Study." The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1460981460.
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Heinrichs, Jessica Lauren. "Antigen Specific Induced T Regulatory Cellular Therapy for Graft-Versus-Host Disease Following Allogeneic Bone Marrow Transplantation." Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6093.
Full textAbstract:
Allogeneic hematopoietic stem cell transplantation (allo-HCT) has been a successful cellular therapy for patients suffering from hematological malignancies for many decades; however, the beneficial effects of graft-versus-leukemia (GVL) are classically offset by graft-versus-host disease (GVHD). GVHD occurs when major and/or minor human leukocyte antigen (HLA) mismatches between donor and recipient cause rapid expansion and activation of donor effector T cells (Teffs) resulting in end organ damage to the recipient’s epithelial tissues. Given the lymphoproliferative nature of this disease, the standard treatment option is broad immunosuppression, which can result in primary disease relapse, steroid refractory GVHD, and/or opportunistic infection. A more targeted therapy that can selectively suppress GVH responses with maintained GVL responses would achieve the optimal goal of allo-HCT. Regulatory T cells (Tregs) both natural (nTregs) or induced (iTregs) could be potential cellular therapies for the treatment of GVHD, given their innate suppressive function. Initial clinical trials using nTregs have yielded positive results; however, nTreg cellular therapy has been cumbersome due to the necessity for large scale ex vivo expansion given their low yield within an apheresis product and non-specific suppression. Conversely, iTregs can be generated from naïve T cells thus decreasing ex vivo culture times and can be educated with specific antigen thus providing targeted suppression, but a consensus on their efficacy for GVHD therapy has not been reached. Therefore, we investigated the efficacy of antigen specific iTreg therapy for the prevention of GVHD while maintaining GVL responses.
In Chapter 2, we evaluated the effectiveness of monoclonal HY-specific iTregs in GVHD attenuation. We chose HY as a target antigen because it is a naturally processed, ubiquitously expressed minor mismatch antigen carried by only male donors/recipients cited to increase GVHD prevalence when donor and recipient are sex-mismatched. Utilizing HY-transgenic mice in which all T cells recognize HY antigen exclusively, we generated HY specific iTregs which effectively attenuating GVHD in male, but not female recipients in three murine bone marrow transplantation (BMT) models (major mismatch, parent to F1, and miHAg mismatch). We found HY specific iTregs lost stability in female recipients but remained stable and suppressive in male recipients suggesting expression of HY antigen was required for their suppressive function and stability. GVL responses were not compromised with the addition of HY specific iTregs in recipient mice using a pre-established tumor model. Thus, HY-specific iTregs can be generated and suppress GVHD in an antigen-dependent manner while sparing the GVL effect.
In Chapter 3, we extend our findings in Chapter 2, which provided proof of principle that antigen specific iTregs effectively control GVHD; however, this therapy has a limited translational potential. Therefore, we generated alloreactive CD4 and CD8 iTregs and evaluated GVHD attenuation and GVL preservation in either full or haplo-MHC mismatched BMT models. We found alloreactive CD4 iTregs significantly suppress lethal GVHD, but completely abrogated the GVL effect against aggressive tumors. Conversely, alloreactive CD8 iTregs moderately attenuated GVHD and possessed direct cytotoxicity against tumor cells. Therefore, to rescue the impaired GVL effect mediated by CD4 iTregs, we established a combinational therapy with CD8 iTregs. Indeed we found combination CD4 and CD8 iTreg therapy significantly suppressed GVHD while sparing GVL responses compared to either CD4 or CD8 singular therapy. Mechanistically, this was achieved by potent suppression of both CD4 and CD8 Teffs coupled with preserved cytolytic molecule expression by both CD8 iTregs and Teffs.
Taken together, we propose antigen specific iTreg therapy can effectively attenuate GVHD while preserving GVL responses. We further uncovered unique characteristics of CD4 and CD8 iTregs that can be exploited to achieve the optimal cellular therapy following allo-HCT.
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Kübler, Ayline [Verfasser], and Rupert [Akademischer Betreuer] Handgretinger. "Optimization of NK cell-based immune therapy strategies against pediatric acute B cell precursor leukemia using a human-murine xenotransplantation model / Ayline Kübler ; Betreuer: Rupert Handgretinger." Tübingen : Universitätsbibliothek Tübingen, 2015. http://d-nb.info/1163664618/34.
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Popović, Jelena [Verfasser]. "Suitability of the TEL-AML1 chromosomal translocation for targeting by adoptive T cell therapy of leukemia : an investigation in a novel humanized mouse model / Jelena Popović." Berlin : Freie Universität Berlin, 2011. http://d-nb.info/1029847193/34.
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Trino, Stefania <1986>. "Targeting the p53–MDM2 interaction by the small-molecule MDM2 antagonist Nutlin-3a: a new challenged target therapy in adult Philadelphia positive acute lymphoblastic leukemia patients." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2014. http://amsdottorato.unibo.it/6198/1/Trino_Stefania_Tesi.pdf.
Full textAbstract:
The human p53 tumor suppressor, known as the “guardian of the genome”, is one of the most important molecules in human cancers. One mechanism for suppressing p53 uses its negative regulator, MDM2, which modulates p53 by binding directly to and decreasing p53 stability. In testing novel therapeutic approaches activating p53, we investigated the preclinical activity of the MDM2 antagonist, Nutlin-3a, in Philadelphia positive (Ph+) and negative (Ph-) leukemic cell line models, and primary B-Acute lymphoblastic leukemia (ALL) patient samples. In this study we demonstrated that treatment with Nutlin-3a induced grow arrest and apoptosis mediated by p53 pathway in ALL cells with wild-type p53, in time and dose-dependent manner. Consequently, MDM2 inhibitor caused an increase of pro-apoptotic proteins and key regulators of cell cycle arrest. The dose-dependent reduction in cell viability was confirmed in primary blast cells from Ph+ ALL patients with the T315I Bcr-Abl kinase domain mutation. In order to better elucidate the implications of p53 activation and to identify biomarkers of clinical activity, gene expression profiling analysis in sensitive cell lines was performed. A total of 621 genes were differentially expressed (p < 0.05). We found a strong down-regulation of GAS41 (growth-arrest specific 1 gene) and BMI1 (a polycomb ring-finger oncogene) (fold-change -1.35 and -1.11, respectively; p-value 0.02 and 0.03, respectively) after in vitro treatment as compared to control cells. Both genes are repressors of INK4/ARF and p21. Given the importance of BMI in the control of apoptosis, we investigated its pattern in treated and untreated cells, confirming a marked decrease after exposure to MDM2 inhibitor in ALL cells. Noteworthy, the BMI-1 levels remained constant in resistant cells. Therefore, BMI-1 may be used as a biomarker of response. Our findings provide a strong rational for further clinical investigation of Nutlin-3a in Ph+ and Ph-ALL.
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Trino, Stefania <1986>. "Targeting the p53–MDM2 interaction by the small-molecule MDM2 antagonist Nutlin-3a: a new challenged target therapy in adult Philadelphia positive acute lymphoblastic leukemia patients." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2014. http://amsdottorato.unibo.it/6198/.
Full textAbstract:
The human p53 tumor suppressor, known as the “guardian of the genome”, is one of the most important molecules in human cancers. One mechanism for suppressing p53 uses its negative regulator, MDM2, which modulates p53 by binding directly to and decreasing p53 stability. In testing novel therapeutic approaches activating p53, we investigated the preclinical activity of the MDM2 antagonist, Nutlin-3a, in Philadelphia positive (Ph+) and negative (Ph-) leukemic cell line models, and primary B-Acute lymphoblastic leukemia (ALL) patient samples. In this study we demonstrated that treatment with Nutlin-3a induced grow arrest and apoptosis mediated by p53 pathway in ALL cells with wild-type p53, in time and dose-dependent manner. Consequently, MDM2 inhibitor caused an increase of pro-apoptotic proteins and key regulators of cell cycle arrest. The dose-dependent reduction in cell viability was confirmed in primary blast cells from Ph+ ALL patients with the T315I Bcr-Abl kinase domain mutation. In order to better elucidate the implications of p53 activation and to identify biomarkers of clinical activity, gene expression profiling analysis in sensitive cell lines was performed. A total of 621 genes were differentially expressed (p < 0.05). We found a strong down-regulation of GAS41 (growth-arrest specific 1 gene) and BMI1 (a polycomb ring-finger oncogene) (fold-change -1.35 and -1.11, respectively; p-value 0.02 and 0.03, respectively) after in vitro treatment as compared to control cells. Both genes are repressors of INK4/ARF and p21. Given the importance of BMI in the control of apoptosis, we investigated its pattern in treated and untreated cells, confirming a marked decrease after exposure to MDM2 inhibitor in ALL cells. Noteworthy, the BMI-1 levels remained constant in resistant cells. Therefore, BMI-1 may be used as a biomarker of response. Our findings provide a strong rational for further clinical investigation of Nutlin-3a in Ph+ and Ph-ALL.