The therapeutic potential of targeting PI3K/AKT/PTEN signalling in B-cell malignancies remains attractive. Whilst PI3K-α/δ inhibitors demonstrate clinical benefit in certain B-cell lymphomas, PI3K signalling inhibitors have been inadequate in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) in part, due to treatment related toxicities. Clinically, AKT inhibitors exhibit a differentiated tolerability profile offering an alternative approach for treating patients with B-cell malignancies. To explore how AKT inhibition complements other potential therapeutics in the treatment of DLBCL patients, an in vitro combination screen was conducted across a panel of DLCBL cell lines. The AKT inhibitor, capivasertib, in combination with the BCL-2 inhibitor, venetoclax, produced notable therapeutic benefit in preclinical models of DLBCL. Capivasertib and venetoclax rapidly induced caspase and PARP cleavage in GCB-DLBCL PTEN wildtype cell lines and those harbouring PTEN mutations or reduced PTEN protein, driving prolonged tumour growth inhibition in DLBCL cell line and patient derived xenograft lymphoma models. The addition of the rituximab further deepened the durability of capivasertib and venetoclax responses in a RCHOP refractory DLBCL in vivo models. These findings provide preclinical evidence for the rational treatment combination of AKT and BCL-2 inhibitors using capivasertib and venetoclax respectively alongside anti-CD20 antibody supplementation for treatment of patients with DLBCL.
- MeSH
- apoptóza účinky léků MeSH
- bicyklické sloučeniny heterocyklické * farmakologie terapeutické užití MeSH
- difúzní velkobuněčný B-lymfom * farmakoterapie patologie MeSH
- fosfohydroláza PTEN metabolismus MeSH
- lidé MeSH
- myši SCID MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- protokoly antitumorózní kombinované chemoterapie * farmakologie terapeutické užití MeSH
- protoonkogenní proteiny c-akt * metabolismus MeSH
- protoonkogenní proteiny c-bcl-2 * antagonisté a inhibitory metabolismus MeSH
- pyrimidiny * farmakologie terapeutické užití MeSH
- pyrroly farmakologie terapeutické užití MeSH
- rituximab farmakologie terapeutické užití MeSH
- sulfonamidy * farmakologie terapeutické užití MeSH
- xenogenní modely - testy antitumorózní aktivity * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is driven by aberrant activation of the B-cell receptor (BCR) and the TLR/MyD88 signaling pathways. The heat-shock protein HSP110 is a candidate for their regulation as it stabilizes MyD88. However, its role in overall BCR signaling remains unknown. Here, we used first-in-class HSP110 inhibitors to address this question. HSP110 inhibitors decreased the survival of several ABC-DLBCL cell lines in vitro and in vivo, and reduced the phosphorylation of BCR signaling kinases, including BTK and SYK. We identified an interaction between HSP110 and SYK and demonstrated that HSP110 promotes SYK phosphorylation. Finally, the combination of the HSP110 inhibitor with the PI3K inhibitor copanlisib decreases SYK/BTK and AKT phosphorylation synergistically, leading to suppression of tumor growth in cell line xenografts and strong reduction in patient-derived xenografts. In conclusion, by regulating the BCR/TLR signaling pathway, HSP110 inhibitors are potential drug candidates for ABC-DLBCL patients.
- MeSH
- chinazoliny MeSH
- difúzní velkobuněčný B-lymfom * farmakoterapie metabolismus patologie MeSH
- fosforylace účinky léků MeSH
- kinasa Syk * antagonisté a inhibitory metabolismus MeSH
- lidé MeSH
- myši SCID MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádorové buňky kultivované MeSH
- proteiny tepelného šoku HSP110 * metabolismus MeSH
- pyrimidiny farmakologie MeSH
- receptory antigenů B-buněk * metabolismus MeSH
- signální transdukce * účinky léků MeSH
- xenogenní modely - testy antitumorózní aktivity * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
INTRODUCTION: Significant proportion of patients with diffuse large B-cell lymphoma (DLBCL) is refractory or relapse (R/R) after the treatment. The prognosis of this patient cohort remains poor. Novel strategies mainly based on immunotherapy and targeted agents are currently being studied. Glofitamab is novel T-cell-engaging bispecific antibody possessing a 2:1 structure with bivalent CD20 binding. Its safety and efficacy in R/R B-cell non-Hodgkin lymphoma including DLBCL were evaluated in phase I-II NP30179 trial. AREAS COVERED: The article summarizes the milestones and latest reports on glofitamab development in the field of B-cell lymphoma treatment. EXPERT OPINION: Recently, phase II part of the NP30179 study and several other reports were published proving glofitamab potential in R/R DLBCL patients. Based on the published data, glofitamab was approved by regulatory authorities worldwide for the monotherapy of R/R DLBCL in conventional time-limited manner. It is readily accessible in case of rapidly progressing disease, and it compares well with other novel treatment options. Its side effects are similar to those of other T-cell-engaging agents and can be mitigated by pretreatment with obinutuzumab or step-up dosing. Its safety profile with manageable toxicities heads the clinical development toward combination strategies and its use in earlier therapeutic phases.
Východiska: Folikulární lymfom (FL) je nejčastějším indolentním non-Hodgkinským lymfomem v západním světě. U většiny pacientů se jedná o indolentní onemocnění, ale u cca 20 % případů dochází po úvodní léčbě k časnému relapsu, což je spojeno s kratším celkovým přežitím. Další prognosticky závažnou událostí je histologická transformace FL do agresivního lymfomu, nejčastěji do difuzního velkobuněčného B-lymfomu. Díky genomickým studiím a myším modelům se nám lépe daří chápat molekulární podstatu vzniku FL a evoluci „agresivních“ subklonů buněk. Zároveň se také v posledních letech podařilo popsat deregulace molekulárních drah přispívajících k histologické transformaci FL. Cíl: V tomto přehledovém článku shrnujeme komplexní mechanizmy, které jsou na molekulární úrovni zodpovědné za vznik, progresi a agresivitu FL a jeho transformaci. Domníváme se, že tato pozorování u FL mají obecnější přesah pro pochopení mechanizmů, které vedou k evoluci „agresivity“ nádorového onemocnění jako je divergentní evoluce, intraklonální variabilita a nádorová plasticita.
Background: Follicular lymphoma (FL) is the most common indolent non-Hodgkin‘s lymphoma in the Western world. It is an indolent disease in most patients, but about 20% of patients experience an early relapse after initial treatment, which is associated with shorter overall survival. A histological transformation into an aggressive lymphoma, most frequently diffuse large-cell B-lymphoma, represents another prognostically unfavorable event in the course of the disease. Thanks to recent genomic studies and mouse models, we are able to better understand the molecular nature of the FL onset and evolution of “aggressive” subclones of cells. Recently, deregulation of several molecular pathways associated with the histological transformation has also been described. Purpose: This review summarizes the complex molecular mechanisms responsible for FL onset, progression, aggressiveness, and transformation. We believe that the observations in FL have some general implications for understanding the mechanisms leading to the evolution of cancer “aggressiveness,” such as divergent evolution, intraclonal variability and tumor plasticity.
- Klíčová slova
- histologická transformace, transformovaný folikulární lymfom,
- MeSH
- difúzní velkobuněčný B-lymfom genetika patologie MeSH
- folikulární lymfom * genetika patologie MeSH
- lidé MeSH
- nádorová transformace buněk * genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease that exhibits constitutive activation of phosphoinositide 3-kinase (PI3K) driven by chronic B-cell receptor signaling or PTEN deficiency. Since pan-PI3K inhibitors cause severe side effects, we investigated the anti-lymphoma efficacy of the specific PI3Kβ/δ inhibitor AZD8186. We identified a subset of DLBCL models within activated B-cell-like (ABC) and germinal center B-cell-like (GCB) DLBCL that were sensitive to AZD8186 treatment. On the molecular level, PI3Kβ/δ inhibition decreased the pro-survival NF-κB and AP-1 activity or led to downregulation of the oncogenic transcription factor MYC. In AZD8186-resistant models, we detected a feedback activation of the PI3K/AKT/mTOR pathway following PI3Kβ/δ inhibition, which limited AZD8186 efficacy. The combined treatment with AZD8186 and the mTOR inhibitor AZD2014 overcame resistance to PI3Kβ/δ inhibition and completely prevented outgrowth of lymphoma cells in vivo in cell line- and patient-derived xenograft mouse models. Collectively, our study reveals that subsets of DLBCLs are addicted to PI3Kβ/δ signaling and thus identifies a previously unappreciated role of the PI3Kβ isoform in DLBCL survival. Furthermore, our data demonstrate that combined targeting of PI3Kβ/δ and mTOR is effective in all major DLBCL subtypes supporting the evaluation of this strategy in a clinical trial setting.
- MeSH
- difúzní velkobuněčný B-lymfom * patologie MeSH
- fosfatidylinositol-3-kinasy * metabolismus MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- signální transdukce MeSH
- TOR serin-threoninkinasy metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Richterův syndrom (RS) je závažnou komplikací chronické lymfocytární leukemie, která se ročně vyskytuje ve 2-10 % případů. I přes nové modality léčby na poli hematoonkologie zůstává RS zásadní klinickou výzvou. Tato kazuistika prezentuje případ pacienta, u kterého i přes využití různých novodobých léčebných přístupů nedošlo ke kontrole onemocnění. Tento případ tak demonstruje krajně nepříznivou prognózu pacientů s RS a klinickou naléhavost vývoje nových terapeutických přístupů.
Richter ́s syndrome (RS) is a serious complication of chronic lymphocytic leukemia, occurring yearly in 2-10 % of cases. Despite new treatment modalities in the field of haematooncology, RS remains a major clinical challenge. This case report presents a patient in whom disease control was not achieved despite the use of various novel therapeutic approaches. This case thus demonstrates the extremely unfavorable prognosis of RS patients and the clinical urgency of developing new therapeutic approaches.
- Klíčová slova
- Richterova transformace,
- MeSH
- chronická lymfatická leukemie * diagnóza farmakoterapie komplikace patologie MeSH
- cílená molekulární terapie metody MeSH
- difúzní velkobuněčný B-lymfom diagnóza farmakoterapie patologie MeSH
- imunoterapie adoptivní metody MeSH
- lidé středního věku MeSH
- lidé MeSH
- lymfadenopatie MeSH
- PET/CT metody MeSH
- protokoly antitumorózní kombinované chemoterapie aplikace a dávkování terapeutické užití MeSH
- terapie neúspěšná MeSH
- transplantace kmenových buněk MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Tisagenlecleucel (tisa-cel) is a CD19-specific CAR-T cell product approved for the treatment of relapsed/refractory (r/r) DLBCL or B-ALL. We have followed a group of patients diagnosed with childhood B-ALL (n = 5), adult B-ALL (n = 2), and DLBCL (n = 25) who were treated with tisa-cel under non-clinical trial conditions. The goal was to determine how the intensive pretreatment of patients affects the produced CAR-T cells, their in vivo expansion, and the outcome of the therapy. Multiparametric flow cytometry was used to analyze the material used for manufacturing CAR-T cells (apheresis), the CAR-T cell product itself, and blood samples obtained at three timepoints after administration. We present the analysis of memory phenotype of CD4/CD8 CAR-T lymphocytes (CD45RA, CD62L, CD27, CD28) and the expression of inhibitory receptors (PD-1, TIGIT). In addition, we show its relation to the patients' clinical characteristics, such as tumor burden and sensitivity to prior therapies. Patients who responded to therapy had a higher percentage of CD8+CD45RA+CD27+ T cells in the apheresis, although not in the produced CAR-Ts. Patients with primary refractory aggressive B-cell lymphomas had the poorest outcomes which was characterized by undetectable CAR-T cell expansion in vivo. No clear correlation of the outcome with the immunophenotypes of CAR-Ts was observed. Our results suggest that an important parameter predicting therapy efficacy is CAR-Ts' level of expansion in vivo but not the immunophenotype. After CAR-T cells' administration, measurements at several timepoints accurately detect their proliferation intensity in vivo. The outcome of CAR-T cell therapy largely depends on biological characteristics of the tumors rather than on the immunophenotype of produced CAR-Ts.
During innate immune responses, myeloid differentiation primary response 88 (MyD88) functions as a critical signaling adaptor protein integrating stimuli from toll-like receptors (TLR) and the interleukin-1 receptor (IL-1R) family and translates them into specific cellular outcomes. In B cells, somatic mutations in MyD88 trigger oncogenic NF-κB signaling independent of receptor stimulation, which leads to the development of B-cell malignancies. However, the exact molecular mechanisms and downstream signaling targets remain unresolved. We established an inducible system to introduce MyD88 to lymphoma cell lines and performed transcriptomic analysis (RNA-seq) to identify genes differentially expressed by MyD88 bearing the L265P oncogenic mutation. We show that MyD88L265P activates NF-κB signaling and upregulates genes that might contribute to lymphomagenesis, including CD44, LGALS3 (coding Galectin-3), NFKBIZ (coding IkBƺ), and BATF. Moreover, we demonstrate that CD44 can serve as a marker of the activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) and that CD44 expression is correlated with overall survival in DLBCL patients. Our results shed new light on the downstream outcomes of MyD88L265P oncogenic signaling that might be involved in cellular transformation and provide novel therapeutical targets.
- MeSH
- adaptorové proteiny signální transdukční metabolismus MeSH
- antigeny CD44 genetika metabolismus MeSH
- difúzní velkobuněčný B-lymfom * patologie MeSH
- galektin 3 metabolismus MeSH
- lidé MeSH
- mutace MeSH
- NF-kappa B * genetika metabolismus MeSH
- protein MyD88 genetika metabolismus MeSH
- stanovení celkové genové exprese MeSH
- transkripční faktory bZIP genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Anti-CD19 immunotherapy tafasitamab is used in combination with lenalidomide in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who are ineligible for autologous stem cell transplant. Open-label, phase 1b, First-MIND study assessed safety and preliminary efficacy of tafasitamab + R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) ± lenalidomide as first-line therapy in patients with DLBCL. From December 2019 to August 2020, 83 adults with untreated DLBCL (International Prognostic Index 2-5) were screened and 66 were randomly assigned (33 per arm) to R-CHOP-tafasitamab (arm T) or R-CHOP-tafasitamab-lenalidomide (arm T/L) for 6 cycles. Primary end point was safety; secondary end points included end-of-treatment (EoT) overall response rate (ORR) and complete response (CR) rate. All patients had ≥1 treatment-emergent adverse event, mostly grade 1 or 2. Grade ≥3 neutropenia and thrombocytopenia occurred, respectively, in 57.6% and 12.1% (arm T) and 84.8% and 36.4% (arm T/L) of patients. Nonhematologic toxicities occurred at similar rates among arms. R-CHOP mean relative dose intensity was ≥89% in both arms. EoT ORR was 75.8% (CR 72.7%) in arm T and 81.8% (CR 66.7%) in arm T/L; best ORR across visits was 90.0% and 93.9%. Eighteen-month duration of response and of CR rates were 72.7% and 74.5% (arm T) and 78.7% and 86.5% (arm T/L); 24-month progression-free and overall survival rates were 72.7% and 90.3% (arm T) and 76.8% and 93.8% (arm T/L). Manageable safety and promising signals of efficacy were observed in both arms. Potential benefit of adding tafasitamab + lenalidomide to R-CHOP is being investigated in phase 3 frontMIND (NCT04824092). This study is registered at www.clinicaltrials.gov as #NCT04134936.
- MeSH
- cyklofosfamid škodlivé účinky MeSH
- difúzní velkobuněčný B-lymfom * patologie MeSH
- dospělí MeSH
- doxorubicin škodlivé účinky MeSH
- lenalidomid terapeutické užití MeSH
- lidé MeSH
- myší monoklonální protilátky škodlivé účinky MeSH
- prednison škodlivé účinky MeSH
- protokoly antitumorózní kombinované chemoterapie škodlivé účinky MeSH
- rituximab škodlivé účinky MeSH
- vinkristin škodlivé účinky MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze I MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
