Mantle cell lymphoma (MCL) is a rare aggressive type of B-cell non-Hodgkin's lymphoma. Response to chemotherapy tends to be short and virtually all patients sooner or later relapse. The prognosis of relapsed patients is extremely poor. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered one of the novel experimental molecules with strong antitumor effects. TRAIL triggers extrinsic apoptotis in tumor cells by binding to TRAIL 'death receptors' on the cell surface. Recombinant TRAIL has shown promising pro-apoptotic effects in a variety of malignancies including lymphoma. However, as with other drugs, lymphoma cells can develop resistance to TRAIL. Therefore, the aim of this study was to identify the molecular mechanisms responsible for, and associated with TRAIL resistance in MCL cells. If identified, these features may be used as molecular targets for the effective elimination of TRAIL-resistant lymphoma cells. From an established TRAIL-sensitive mantle cell lymphoma cell line (HBL-2) we derived a TRAIL-resistant HBL-2/R subclone. By TRAIL receptor analysis and differential proteomic analysis of HBL-2 and HBL-2/R cells we revealed a marked downregulation of all TRAIL receptors and, among others, the decreased expression of 3 key enzymes of purine nucleotide metabolism, namely purine nucleoside phosphorylase, adenine phosphoribosyltransferase and inosine-5'-monophosphate dehydrogenase 2, in the resistant HBL-2/R cells. The downregulation of the 3 key enzymes of purine metabolism can have profound effects on nucleotide homeostasis in TRAIL-resistant lymphoma cells and can render such cells vulnerable to any further disruption of purine nucleotide metabolism. This pathway represents a 'weakness' of the TRAIL-resistant MCL cells and has potential as a therapeutic target for the selective elimination of such cells.

• MeSH
• Electrophoresis, Gel, Two-Dimensional MeSH
• Cell Membrane metabolism   MeSH
• Cell Death drug effects   MeSH
• Drug Resistance, Neoplasm drug effects   MeSH
• Humans MeSH
• Lymphoma, Mantle-Cell enzymology   pathology   MeSH
• Cell Line, Tumor MeSH
• Neoplasm Proteins metabolism   MeSH
• TNF-Related Apoptosis-Inducing Ligand pharmacology   MeSH
• Proteomics MeSH
• Flow Cytometry MeSH
• Purines metabolism   MeSH
• Reproducibility of Results MeSH
• Receptors, TNF-Related Apoptosis-Inducing Ligand metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

BACKGROUND: Central nervous system (CNS) involvement in mantle cell lymphoma (MCL) is uncommon, and the manifestations and natural history are not well described. PATIENTS AND METHODS: We present the data on 57 patients with MCL who developed CNS involvement, from a database of 1396 consecutively treated patients at 14 institutions. RESULTS: The crude incidence of CNS involvement was 4.1%, with 0.9% having CNS involvement at diagnosis. Blastoid histology, B-symptoms, elevated lactate dehydrogenase, Eastern Cooperative Group performance status >=2 and a high Mantle Cell Lymphoma International Prognostic Index score were enriched in the cohort with CNS involvement, and the presence of >=1 of these features defined a high-risk subset (an actuarial risk of CNS involvement 15% at 5 years) in a single-institution subset. The median time to CNS relapse was 15.2 months, and the median survival from time of CNS diagnosis was 3.7 months. The white blood cell count at diagnosis <10.9 x 109/l, treatment of CNS involvement with high-dose anti-metabolites, consolidation with stem cell transplant and achievement of complete response were all associated with improved survival. CONCLUSIONS: In MCL, CNS involvement is uncommon, although some features may predict risk. Once manifest outlook is poor; however, some patients who receive intensive therapy survive longer than 12 months.

• MeSH
• Central Nervous System * pathology   MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Lymphoma, Mantle-Cell * drug therapy   MeSH
• Central Nervous System Neoplasms drug therapy   prevention & control   secondary   MeSH
• Leukocyte Count MeSH
• Survival MeSH
• Antimetabolites, Antineoplastic therapeutic use   MeSH
• Retrospective Studies MeSH
• Risk MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Geographicals
• Europe MeSH

TNF-related apoptosis-inducing ligand (TRAIL) is a pro-apoptotic ligand from the TNF-alpha family that is under consideration, along with agonistic anti-TRAIL receptor antibodies, as a potential anti-tumor agent. However, most primary human tumors are resistant to monotherapy with TRAIL apoptogens, and thus the potential applicability of TRAIL in anti-tumor therapy ultimately depends on its rational combination with drugs targeting these resistances. In our high-throughput screening for novel agents/drugs that could sensitize TRAIL-resistant colorectal cancer cells to TRAIL-induced apoptosis, we found homoharringtonine (HHT), a cephalotaxus alkaloid and tested anti-leukemia drug, to be a very effective, low nanomolar enhancer of TRAIL-mediated apoptosis/growth suppression of these resistant cells. Co-treatment of TRAIL-resistant RKO or HT-29 cells with HHT and TRAIL led to the effective induction of apoptosis and the complete elimination of the treated cells. HHT suppressed the expression of the anti-apoptotic proteins Mcl-1 and cFLIP and enhanced the TRAIL-triggered activation of JNK and p38 kinases. The shRNA-mediated down-regulation of cFLIP or Mcl-1 in HT-29 or RKO cells variably enhanced their TRAIL-induced apoptosis but it did not markedly sensitize them to TRAIL-mediated growth suppression. However, with the notable exception of RKO/sh cFLIP cells, the downregulation of cFLIP or Mcl-1 significantly lowered the effective concentration of HHT in HHT + TRAIL co-treatment. Combined HHT + TRAIL therapy also led to the strong suppression of HT-29 tumors implanted into immunodeficient mice. Thus, HHT represents a very efficient enhancer of TRAIL-induced apoptosis with potential application in TRAIL-based, anti-cancer combination therapy.

• MeSH
• Apoptosis drug effects   MeSH
• HT29 Cells MeSH
• Drug Resistance, Neoplasm drug effects   MeSH
• Harringtonines pharmacology   MeSH
• Humans MeSH
• Mice, Inbred NOD MeSH
• Mice, SCID MeSH
• Mice MeSH
• TNF-Related Apoptosis-Inducing Ligand pharmacology   MeSH
• Apoptosis Regulatory Proteins metabolism   MeSH
• Transplantation, Heterologous MeSH
• Neoplasm Transplantation MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Lymfom z plášťových buněk (MCL) je nevyléčitelná agresivní forma B-nehodgkinského lymfomu. Preklinické testování nových protilymfomových léčebných strategií představuje základní předpoklad pro vytvoření pozdějších klinických studií. Prvním cílem projektu je výzkum účinnosti kombinované angiangiogenní terapie, jejíž protinádorový mechanismus spočívá v potlačení nádorové neovaskularizace. Dalšími cíly projektu je analýza role receptorů pro VEGF a vybraných adhezivních molekul (CD31, CD44) v přežití, růstu, šíření a terapeutické odpovědi MCL a prognostický význam exprese těchto molekul na primárních buňkách pacientů. Experimenty budou prováděny na myším modelu lidského MCL. Studie přinese preklinické odůvodnění pro budoucí testování kombinované antiangiogenní terapie u pacientů s MCL a povede k objasnění role vybraných molekul účastnících se angiogeneze v biologii MCL. Předpokládáme, že výsledky studie budou mít dopad na vytváření nových terapeutických postupů v léčbě rezistentních forem MCL u člověka.; Mantle cell lymphoma (MCL) is incurable B-cell non-Hodgkin lymphoma. Preclinical testing of experimental treatment strategies is requisite for design of future clinical trials. Antiangiogenic molecules appear to be uniquely active in MCL, including temsirolimus and lenalidomide. Treatment approaches targeting angiogenesis, the anti-tumor activity of which lie in blockage of tumor neovascularization and prosurvival angiogenic signaling, cannot be tested in vitro, but require sophisticated animal models. In the first part of the project we will test anti-MCL efficacy of combined antiangiogenic therapy. In the second part of the project we wil analyze role of VEGF receptors and selected adhesion molecules (CD31, CD44) on MCL biology (engraftment, growth, spread) and response to antiangiogenic therapy. Prognostic relevance of these molecules will be determined on primary MCL samples by immunohisochemistry. The results of this project will have direct implications for the therapy of MCL.

• MeSH
• Antibodies, Monoclonal, Humanized MeSH
• Lymphoma, Mantle-Cell therapy   MeSH
• Neovascularization, Pathologic MeSH
• Survival MeSH
• Therapeutic Equivalency MeSH

• Conspectus
• Patologie. Klinická medicína
• NML Fields
• hematologie a transfuzní lékařství
• onkologie
• NML Publication type
• závěrečné zprávy o řešení grantu IGA MZ ČR

Mantle cell lymphoma (MCL) is characterized by an aggressive clinical course and inevitable development of refractory disease, stressing the need to develop alternative therapeutic strategies. To this end, we evaluated pevonedistat (MLN4924), a novel potent and selective NEDD8-activating enzyme inhibitor in a panel of MCL cell lines, primary MCL tumor cells, and 2 distinct murine models of human MCL. Pevonedistat exposure resulted in a dose-, time-, and caspase-dependent cell death in the majority of the MCL cell lines and primary tumor cells tested. Of interest, in the MCL cell lines with lower half-maximal inhibitory concentration (0.1-0.5 μM), pevonedistat induced G1-phase cell cycle arrest, downregulation of Bcl-xL levels, decreased nuclear factor (NF)-κB activity, and apoptosis. In addition, pevonedistat exhibited additive/synergistic effects when combined with cytarabine, bendamustine, or rituximab. In vivo, as a single agent, pevonedistat prolonged the survival of 2 MCL-bearing mouse models when compared with controls. Pevonedistat in combination with rituximab led to improved survival compared with rituximab or pevonedistat monotherapy. Our data suggest that pevonedistat has significant activity in MCL preclinical models, possibly related to effects on NF-κB activity, Bcl-xL downregulation, and G1 cell cycle arrest. Our findings support further investigation of pevonedistat with or without rituximab in the treatment of MCL.

• MeSH
• Apoptosis drug effects   MeSH
• Cyclopentanes pharmacology   therapeutic use   MeSH
• Enzyme Inhibitors pharmacology   therapeutic use   MeSH
• Caspases metabolism   MeSH
• Small Molecule Libraries pharmacology   therapeutic use   MeSH
• Cell Cycle Checkpoints drug effects   MeSH
• Humans MeSH
• Lymphoma, Mantle-Cell drug therapy   genetics   pathology   MeSH
• Mice, SCID MeSH
• Cell Line, Tumor MeSH
• NF-kappa B metabolism   MeSH
• Antineoplastic Agents pharmacology   therapeutic use   MeSH
• Proto-Oncogene Proteins c-bcl-2 metabolism   MeSH
• Pyrimidines pharmacology   therapeutic use   MeSH
• Gene Expression Regulation, Neoplastic drug effects   MeSH
• Rituximab pharmacology   therapeutic use   MeSH
• Cell Separation MeSH
• Gene Expression Profiling MeSH
• Ubiquitins antagonists & inhibitors   metabolism   MeSH
• Cell Survival drug effects   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

Východiska: Lymfom z plášťových buněk představuje specifický podtyp B‑non‑Hodgkinova lymfomu charakterizovaný na molekulární úrovni přítomností translokace t(11;14)(q13;q32), která vede k aberantní expresi cyklinu D1 a následné deregulaci buněčného cyklu. Navzdory sporadickému výskytu indolentních forem lymfomu z plášťových buněk nevyžadujících řadu měsíců či dokonce let terapii převažují v běžné klinické praxi jednoznačně agresivní formy lymfomu z plášťových buněk. Přestože má lymfom z plášťových buněk chemosenzitivní povahu, cca 10 % pacientů na léčbu neodpoví (refrakterní nemoc) a většina zbylých pacientů prodělá dříve či později návrat (relaps) choroby. Průběh léčby lymfomu z plášťových buněk tak z dlouhodobé perspektivy obvykle probíhá pod obrazem chronicky relabujícího onemocnění vyžadujícího aplikace dalších a dalších linií léčby. Prognóza relabujícího lymfomu z plášťových buněk je však extrémně nepříznivá. Cíl: Cílem tohoto přehledu je shrnout současné postupy v diagnostice a terapii lymfomu z plášťových buněk. Výsledky: Terapeutický algoritmus primoterapie lymfomu z plášťových buněk doznal v poslední dekádě řady modifikací, které významně zlepšily prognózu pacientů. Mezi klíčové milníky léčby lymfomu z plášťových buněk patří např. včlenění monoklonální protilátky rituximab do indukční části terapie, intenzifikace polychemoterapeutických režimů u mladších pacientů včetně implementace vysokodávkovaného cytarabinu, pevné ukotvení konsolidace léčebné odpovědi pomocí vysokodávkované terapie a autologní transplantace kostní dřeně u mladších pacientů nebo začlenění udržovací léčby rituximabem. Kromě této „optimalizace“ primoterapie bylo dalším klíčovým faktorem zlepšení prognózy pacientů s lymfomem z plášťových buněk schválení nových účinných léků v posledních několika letech. Nové léky totiž zásadním způsobem rozšířily paletu léčebných možností relapsů či refrakterních forem lymfomu z plášťových buněk, které byly dříve indikovány k paliativní či symptomatické léčbě. Mezi tyto léky patří staronové cytostatikum bendamustin, inhibitor Brutonovy tyrozinkinázy ibrutinib, imunomodulační látka lenalidomid, inhibitor mTOR temsirolimus a inhibitor proteazomu bortezomib. Závěr: Díky dvěma klíčovým faktorům, tj. 1. optimalizaci primoterapie pomocí „konvenčních“ protilymfomových léků a postupů a 2. významnému rozšíření možností léčby relapsů pomocí nových léků, se celkové přežití pacientů s lymfomem z plášťových buněk za posledních 10 let v zásadě zdvojnásobilo (z 3–4 let v první dekádě nového tisíciletí na současných 6–8 let). Optimální využití nových léků včetně jejich vzájemných kombinací povede zcela jistě v blízké budoucnosti k dalšímu zlepšení prognózy pacientů s lymfomem z plášťových buněk.

Background: Mantle cell lymphoma represents a specific subtype of B‑cell non‑Hodgkin lymphoma characterized on the molecular level by translocation t(11;14)(q13;q32) leading to aberrant overexpression of cyclin D1 and deregulation of the cell cycle. Despite sporadic indolent forms of mantle cell lymphoma, majority of patients present with advanced aggressive disease that requires immediate treatment. Despite chemosensitive nature of mantle cell lymphoma, approximately 10% patients present with a refractory disease, and the vast majority of patients who initially respond to therapy, relapse sooner or later. The course of mantle cell lymphoma thus represents a chronically relapsing malignancy requiring further and further lines of therapies. Prognosis of relapsed or refractory (R/R) mantle cell lymphoma is dismal. Aim: The goal of this article is to provide a cutting‑edge review of currently used diagnostic and treatment approaches for mantle cell lymphoma. Results: Several key modifications of the therapeutic algorithm of mantle cell lymphoma treatment implemented in the past 10 years resulted in significantly improved prognosis of patients. The milestones in the therapy of mantle cell lymphoma include incorporation of anti‑CD20 monoclonal antibody rituximab into induction therapy, intensification of polychemotherapeutic regimen including implementation of high‑dose cytarabine, consolidation of response with high‑dose therapy and autologous stem cell transplantation (HDT‑ASCT) in younger fit patients, and maintenance therapy with rituximab in the elderly patients. Besides such “optimization” of front‑line therapy, introduction of novel anti‑lymphoma agents into therapy of R/R mantle cell lymphoma also contributed (and will contribute in the future) to improved prognosis of mantle cell lymphoma. Among these agents, there is a new cytostatic drug bendamustine, Bruton tyrosine‑kinase inhibitor ibrutinib, immunomodulatory agent lenalidomide, mTOR inhibitor temsirolimus and proteasome inhibitor bortezomib. Conclusion: The overall survival of mantle cell lymphoma virtually doubled in the recent 10 years as a result of two key factors: 1. optimization of front‑line therapy with “conventional” anti‑lymphoma agents, and 2. brand new possibilities of therapy for R/R mantle cell lymphoma thanks to the introduction of novel anti‑lymphoma agents. Combinatorial approaches using most efficacious combinations of novel and conventional anti‑mantle cell lymphoma agents will definitely lead to further improvements of survival parameters in mantle cell lymphoma patients in near future. Key words: mantle cell lymphoma – minimal residual disease – autologous transplantation This study was supported by project PRVOUK-27//LF1/1, IGA-MZ NT/13072-4, IGA-MZ NT 13201-4/2012. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 24. 9. 2015 Accepted: 27. 9. 2015

• Keywords
• imunochemoterapie, preemptivní terapie,
• MeSH
• Transplantation, Autologous MeSH
• Induction Chemotherapy methods   MeSH
• Combined Modality Therapy MeSH
• Consolidation Chemotherapy methods   MeSH
• Humans MeSH
• Lymphoma, Mantle-Cell * diagnosis   drug therapy   genetics   MeSH
• Antibodies, Monoclonal, Murine-Derived therapeutic use   MeSH
• Prognosis MeSH
• Disease Progression MeSH
• Antineoplastic Agents MeSH
• Antineoplastic Combined Chemotherapy Protocols MeSH
• Recurrence * MeSH
• Neoplasm, Residual diagnosis   MeSH
• Rituximab MeSH
• Bone Marrow Transplantation MeSH
• Maintenance Chemotherapy methods   MeSH
• Age Factors MeSH
• Check Tag
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

Mantle cell lymphoma (MCL) is an aggressive type of B-cell non-Hodgkin lymphoma (NHL) associated with poor prognosis. Animal models of MCL are scarce. We established and characterized various in vivo models of metastatic human MCL by tail vein injection of either primary cells isolated from patients with MCL or established MCL cell lines (Jeko-1, Mino, Rec-1, Hbl-2, and Granta-519) into immunodeficient NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl)/SzJ mice. MCL infiltration was assessed with immunohistochemistry (tissues) and flow cytometry (peripheral blood). Engraftment of primary MCL cells was observed in 7 out of 12 patient samples. The pattern of engraftment of primary MCL cells varied from isolated involvement of the spleen to multiorgan infiltration. On the other hand, tumor engraftment was achieved in all five MCL cell lines used and lymphoma involvement of murine bone marrow, spleen, liver, and brain was observed. Overall survival of xenografted mice ranged from 22 ± 1 to 54 ± 3 days depending on the cell line used. Subsequently, we compared the gene expression profile (GEP) and phenotype of the engrafted MCL cells compared with the original in vitro growing cell lines (controls). We demonstrated that engrafted MCL cells displayed complex changes of GEP, protein expression, and sensitivity to cytotoxic agents when compared with controls. We further demonstrated that our MCL mouse models could be used to test the therapeutic activity of systemic chemotherapy, monoclonal antibodies, or angiogenesis inhibitors. The characterization of MCL murine models is likely to aid in improving our knowledge in the disease biology and to assist scientists in the preclinical and clinical development of novel agents in relapsed/refractory MCL patients.

• MeSH
• Immunophenotyping MeSH
• Immunohistochemistry MeSH
• Liver metabolism   MeSH
• Kaplan-Meier Estimate MeSH
• Bone Marrow metabolism   MeSH
• Middle Aged MeSH
• Humans MeSH
• Lymphoma, Mantle-Cell drug therapy   genetics   metabolism   MeSH
• Disease Models, Animal * MeSH
• Brain metabolism   MeSH
• Mice, Inbred NOD MeSH
• Mice, Knockout MeSH
• Mice, SCID MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Tumor Cells, Cultured MeSH
• Interleukin Receptor Common gamma Subunit deficiency   genetics   MeSH
• Gene Expression Regulation, Neoplastic * MeSH
• Aged MeSH
• Spleen metabolism   MeSH
• Transcriptome genetics   MeSH
• Transplantation, Heterologous MeSH
• Animals MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Mice MeSH
• Aged MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Tumor immunotherapy based on the use of chimeric antigen receptor modified T cells (CAR T cells) is a promising approach for the treatment of refractory hematological malignancies. However, a robust response mediated by CAR T cells is observed only in a minority of patients and the expansion and persistence of CAR T cells in vivo is mostly unpredictable.Lenalidomide (LEN) is an immunomodulatory drug currently approved for the treatment of multiple myeloma (MM) and mantle cell lymphoma, while it is clinically tested in the therapy of diffuse large B-cell lymphoma of activated B cell immunophenotype. LEN was shown to increase antitumor immune responses at least partially by modulating the activity of E3 ubiquitin ligase Cereblon, which leads to increased ubiquitinylation of Ikaros and Aiolos transcription factors, which in turn results in changed expression of various receptors on the surface of tumor cells. In order to enhance the effectiveness of CAR-based immunotherapy, we assessed the anti-lymphoma efficacy of LEN in combination with CAR19 T cells or CAR20 T cells in vitro and in vivo using various murine models of aggressive B-cell non-Hodgkin lymphomas (B-NHL).Immunodeficient NSG mice were transplanted with various human B-NHL cells followed by treatment with CAR19 or CAR20 T cells with or without LEN. Next, CAR19 T cells were subjected to series of tests in vitro to evaluate their response and signaling capacity following recognition of B cell in the presence or absence of LEN.Our data shows that LEN significantly enhances antitumor functions of CAR19 and CAR20 T cells in vivo. Additionally, it enhances production of interferon gamma by CAR19 T cells and augments cell signaling via CAR19 protein in T cells in vitro. Our data further suggests that LEN works through direct effects on T cells but not on B-NHL cells. The biochemical events underlying this costimulatory effect of LEN are currently being investigated. In summary, our data supports the use of LEN for augmentation of CAR-based immunotherapy in the clinical grounds.

• MeSH
• Receptors, Chimeric Antigen therapeutic use   MeSH
• Immunomodulation MeSH
• Immunomodulating Agents therapeutic use   MeSH
• Lenalidomide * therapeutic use   MeSH
• Humans MeSH
• Lymphoma therapy   MeSH
• Disease Models, Animal MeSH
• Mice MeSH
• Antineoplastic Agents, Immunological * therapeutic use   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH

Mantle cell lymphoma (MCL) is a chronically relapsing aggressive type of B-cell non-Hodgkin lymphoma considered incurable by currently used treatment approaches. Fludarabine is a purine analog clinically still widely used in the therapy of relapsed MCL. Molecular mechanisms of fludarabine resistance have not, however, been studied in the setting of MCL so far. We therefore derived fludarabine-resistant MCL cells (Mino/FR) and performed their detailed functional and proteomic characterization compared to the original fludarabine sensitive cells (Mino). We demonstrated that Mino/FR were highly cross-resistant to other antinucleosides (cytarabine, cladribine, gemcitabine) and to an inhibitor of Bruton tyrosine kinase (BTK) ibrutinib. Sensitivity to other types of anti-lymphoma agents was altered only mildly (methotrexate, doxorubicin, bortezomib) or remained unaffacted (cisplatin, bendamustine). The detailed proteomic analysis of Mino/FR compared to Mino cells unveiled over 300 differentially expressed proteins. Mino/FR were characterized by the marked downregulation of deoxycytidine kinase (dCK) and BTK (thus explaining the observed crossresistance to antinucleosides and ibrutinib), but also by the upregulation of several enzymes of de novo nucleotide synthesis, as well as the up-regulation of the numerous proteins of DNA repair and replication. The significant upregulation of the key antiapoptotic protein Bcl-2 in Mino/FR cells was associated with the markedly increased sensitivity of the fludarabine-resistant MCL cells to Bcl-2-specific inhibitor ABT199 compared to fludarabine-sensitive cells. Our data thus demonstrate that a detailed molecular analysis of drug-resistant tumor cells can indeed open a way to personalized therapy of resistant malignancies.

• MeSH
• Drug Resistance, Neoplasm * MeSH
• Chromatography, Liquid methods   MeSH
• Isotope Labeling methods   MeSH
• Humans MeSH
• Lymphoma, Mantle-Cell drug therapy   metabolism   MeSH
• Biomarkers, Tumor metabolism   MeSH
• Tumor Cells, Cultured MeSH
• Proteomics methods   MeSH
• Antineoplastic Agents pharmacology   MeSH
• Tandem Mass Spectrometry methods   MeSH
• Vidarabine analogs & derivatives   pharmacology   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Tumor immune surveillance paradigm presumes that most pre-malignant cells or early malignant lesions can be eliminated (or at least controlled) by cells of the immune system. A critical feature that distinguishes advanced tumors from early neoplastic lesions is their capability to evade immune control. As a consequence, vast majority of clinically evident (advanced) tumors are poorly immunogenic. The principle goal of immunotherapy is thus a resurrection of the patient's inefficient or suppressed immune system so that it would once again become capable of launching sustained cytolytic attacks against tumor cells, which would ideally result in total and permanent eradication of cancer. Such activation of patient's anticancer immunity, however, can be achieved by strikingly different ways. This current review discusses diverse innovative immunotherapy approaches, which in the last 20 years achieved miraculous successes in the ever-lasting battle against cancer, including cytokine-based immunotherapy approaches, therapeutic monoclonal antibodies and their derivatives, cancer vaccines, and cell-based immunotherapy approaches.

• MeSH
• Antigens, Neoplasm immunology   MeSH
• Cytokines immunology   MeSH
• Immunotherapy * MeSH
• Humans MeSH
• Antibodies, Monoclonal therapeutic use   MeSH
• Neoplasms immunology   therapy   MeSH
• Cancer Vaccines therapeutic use   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH