B-cell receptor (BCR) is a B cell hallmark surface complex regulating multiple cellular processes in normal as well as malignant B cells. Igα (CD79a)/Igβ (CD79b) are essential components of BCR that are indispensable for its functionality, signal initiation, and signal transduction. CD79a/CD79b-mediated BCR signaling is required for the survival of normal as well as malignant B cells via a wide signaling network. Recent studies identified the great complexity of this signaling network and revealed the emerging role of CD79a/CD79b in signal integration. In this review, we have focused on functional features of CD79a/CD79b, summarized signaling consequences of CD79a/CD79b post-translational modifications, and highlighted specifics of CD79a/CD79b interactions within BCR and related signaling cascades. We have reviewed the complex role of CD79a/CD79b in multiple aspects of normal B cell biology and how is the normal BCR signaling affected by lymphoid neoplasms associated CD79A/CD79B mutations. We have also summarized important unresolved questions and highlighted issues that remain to be explored for better understanding of CD79a/CD79b-mediated signal transduction and the eventual identification of additional therapeutically targetable BCR signaling vulnerabilities.

• MeSH
• Cell Membrane MeSH
• Cognition MeSH
• Mutation MeSH
• Receptors, Antigen, B-Cell * genetics   MeSH
• Signal Transduction * MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Současná léčba non-Hodgkinských lymfomů je založena na nespecifických chemoterapeutických kombinacích. Nové léčebné strategie jsou tak nezbytné ke snížení toxicity a zlepšení účinnosti léčby. Signalizace z B-buněčného receptoru je jednou z nich. Lymfomy vzniklé z B-lymfocytů využívají minimálně dva typy signálu z B-buněčného receptoru: “chronicky aktivní“, připomínající antigenem spuštěnou signalizaci, a “tonický”, nutný k základnímu přežití B-lymfocytů. Předpokládáme, že typy signalizace z B-Buněčného receptoru se u lymfomů zásadně liší v úvodní fázi, kdy dochází k fosforylaci koreceptorových molekul B-buněčného receptoru CD79A/B a iniciaci signálu. S využitím nových molekulárně biologických metod a pokročilých modelů plánujeme popsat potenciál využití těchto charakteristik signalizace k cílené léčbě lymfomů. Výsledky získané analýzou na modelových buněčných liniích budou ověřeny na myších modelech a primárních nádorových buňkách. Navrhovaná studie má velký potenciál popsat nové vysoce specifické terapeutické cíle u lymfomů s predikcí odpovědi na inhibici B-buněčného receptoru.; New and more specific therapies for non-Hodgkin lymphomas (NHL) are greatly needed, since standard treatment is based on a non-specific and highly toxic chemotherapy combination over 40 years old. The B-cell receptor (BCR) inhibition is such emerging therapy applicable to various B-cell derived NHL, which were shown to use at least two types of BCR signaling, the “chronic active” (similar to antigen induced) and “tonic” (analogous to baseline BCR signaling in resting B-cells). Our hypothesis is that individual types of BCR signaling differ substantially in the initial events of BCR activation during phosphorylation of BCR co-receptor molecules CD79A/B and that those differences and detail characteristics can be used as therapeutic targets. We plan to address our hypothesis using modern methods of molecular biology with evaluation of the therapeutic potential using mouse models and primary lymphoma cells. The proposed study has a great potential to identify novel and highly specific targets for BCR inhibition and response prediction.

• Keywords
• léčba, therapy, non-hodgkinský lymfom, NHL, DLBCL, B-buněčný receptor, signalizace, ITAM, CD79A, CD79B, Src kinázy, non-Hodgkin lymphoma, diffuse large B-cell lymphoma, DLBCL, B-cell receptor, BCR, signal initiation, Immunoreceptor tyrosine-based activation motif, ITAM, CD79A, CD79B, Src family of kinases, NHL, difuzní velkobuněčný B-lymfom,

• NML Publication type
• závěrečné zprávy o řešení grantu AZV MZ ČR

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is typically treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). However, only 60% of patients are cured with R-CHOP. Polatuzumab vedotin is an antibody-drug conjugate targeting CD79b, which is ubiquitously expressed on the surface of malignant B cells. METHODS: We conducted a double-blind, placebo-controlled, international phase 3 trial to evaluate a modified regimen of R-CHOP (pola-R-CHP), in which vincristine was replaced with polatuzumab vedotin, as compared with standard R-CHOP, in patients with previously untreated intermediate-risk or high-risk DLBCL. Patients 18 to 80 years of age were randomly assigned in a 1:1 ratio to receive six cycles of either pola-R-CHP or R-CHOP, plus two cycles of rituximab alone. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival and safety. RESULTS: Overall, 879 patients underwent randomization: 440 were assigned to the pola-R-CHP group and 439 to the R-CHOP group. After a median follow-up of 28.2 months, the percentage of patients surviving without progression was significantly higher in the pola-R-CHP group than in the R-CHOP group (76.7% [95% confidence interval (CI), 72.7 to 80.8] vs. 70.2% [95% CI, 65.8 to 74.6] at 2 years; stratified hazard ratio for progression, relapse, or death, 0.73 by Cox regression; 95% CI, 0.57 to 0.95; P = 0.02). Overall survival at 2 years did not differ significantly between the groups (88.7% [95% CI, 85.7 to 91.6] in the pola-R-CHP group and 88.6% [95% CI, 85.6 to 91.6] in the R-CHOP group; hazard ratio for death, 0.94; 95% CI, 0.65 to 1.37; P = 0.75). The safety profile was similar in the two groups. CONCLUSIONS: Among patients with previously untreated intermediate-risk or high-risk DLBCL, the risk of disease progression, relapse, or death was lower among those who received pola-R-CHP than among those who received R-CHOP. (Funded by F. Hoffmann-La Roche/Genentech; POLARIX ClinicalTrials.gov number, NCT03274492.).

• MeSH
• Cyclophosphamide adverse effects   therapeutic use   MeSH
• Lymphoma, Large B-Cell, Diffuse drug therapy   mortality   MeSH
• Progression-Free Survival MeSH
• Adult MeSH
• Doxorubicin adverse effects   therapeutic use   MeSH
• Double-Blind Method MeSH
• Immunoconjugates administration & dosage   adverse effects   MeSH
• Middle Aged MeSH
• Humans MeSH
• Antibodies, Monoclonal administration & dosage   adverse effects   MeSH
• Prednisone adverse effects   therapeutic use   MeSH
• Antineoplastic Combined Chemotherapy Protocols adverse effects   therapeutic use   MeSH
• Rituximab adverse effects   therapeutic use   MeSH
• Aged MeSH
• Vincristine adverse effects   therapeutic use   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH

• MeSH
• Antigens, CD19 pharmacology   classification   therapeutic use   MeSH
• CD79 Antigens pharmacology   therapeutic use   MeSH
• Lymphoma, Large B-Cell, Diffuse * drug therapy   therapy   MeSH
• Humans MeSH
• Agammaglobulinaemia Tyrosine Kinase antagonists & inhibitors   MeSH
• Antineoplastic Agents pharmacology   classification   therapeutic use   MeSH
• Check Tag
• Humans MeSH

CONTEXT: R-CHOP is the standard of care for newly diagnosed DLBCL patients; however, 40% remain uncured. Polatuzumab vedotin (Pola), a CD79b-targeting antibody-drug conjugate, has shown promising activity/safety in a Phase Ib/II study (Tilly, et al. Lancet Oncol 2019). We report the Phase III double-blind, placebo-controlled, international POLARIX study (NCT03274492), which compared Pola-R-CHP with R-CHOP in treatment-naïve DLBCL patients with an International Prognostic Index score of 2-5. DESIGN: Patients were randomized (1:1) to six cycles of Pola-R-CHP or R-CHOP and on Day 1 of each cycle received Pola 1.8mg/kg or vincristine 1.4mg/m2, plus intravenous rituximab 375mg/m2, cyclophosphamide 750mg/m2, and doxorubicin 50mg/m2. Patients also received oral prednisone 100mg once daily (Days 1-5) and two further cycles of rituximab. The primary endpoint was investigator-assessed progression-free survival (PFS). RESULTS: Overall, 879 patients (median age 65 [range 19-80] years) were randomized (Pola-R-CHP: n=440; R-CHOP: n=439). At primary data cut-off (28 June 2021), median follow-up was 28.2 months. PFS was superior with Pola-R-CHP vs R-CHOP (hazard ratio [HR] 0.73; 95% confidence interval [CI]: 0.57-0.95; P=0.02) and 2-year PFS rate was improved (76.7% [95% CI: 72.7-80.8] vs 70.2% [95% CI: 65.8-74.6], respectively). Investigator-assessed event-free survival favored Pola-R-CHP vs R-CHOP (HR 0.75; 95% CI: 0.58-0.96; P=0.02) and overall survival was comparable (HR 0.94; 95% CI: 0.65-1.37; P=0.75). While independent review committee-assessed end-of-treatment complete response rate by positron emission tomography-computed tomography was not significantly different with Pola-R-CHP (78.0%) vs R-CHOP (74.0%; P=0.16), disease-free survival suggested more durable responses with Pola-R-CHP vs R-CHOP (HR 0.70; 95% CI: 0.50-0.98). Safety profiles were similar for Pola-R-CHP vs R-CHOP: grade 3-4 adverse event (AE) rates, 57.7% vs 57.5%, respectively; serious AEs, 34.0% vs 30.6%; grade 5 AEs, 3.0% vs 2.3%; AEs leading to dose reduction, 9.2% vs 13.0%; and peripheral neuropathy, any grade, 52.9% vs 53.9%. At data cut-off, fewer patients treated with Pola-R-CHP (23%) vs R-CHOP (30%) had received ≥1 subsequent anti-lymphoma therapy. CONCLUSIONS: As the first-line treatment of DLBCL, Pola-R-CHP demonstrated a 27% reduction in the relative risk of disease progression, relapse, or death, and a similar safety profile, compared with R-CHOP.

• MeSH
• Cyclophosphamide adverse effects   MeSH
• Lymphoma, Large B-Cell, Diffuse * therapy   MeSH
• Adult MeSH
• Doxorubicin adverse effects   MeSH
• Immunoconjugates * adverse effects   MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Recurrence, Local drug therapy   MeSH
• Young Adult MeSH
• Antibodies, Monoclonal MeSH
• Prednisone adverse effects   MeSH
• Antineoplastic Combined Chemotherapy Protocols adverse effects   MeSH
• Rituximab therapeutic use   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Vincristine adverse effects   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH
• Randomized Controlled Trial MeSH

Over the last few years, treatment principles have been changed towards more targeted therapy for many B-cell lymphoma subtypes and in chronic lymphocytic leukemia (CLL). Immunotherapeutic modalities, namely monoclonal antibodies (mAbs), bispecific antibodies (bsAbs), antibody-drug conjugates (ADCs), and chimeric antigen receptor T (CAR-T) cell therapy, commonly use B-cell-associated antigens (CD19, CD20, CD22, and CD79b) as one of their targets. T-cell engagers (TCEs), a subclass of bsAbs, work on a similar mechanism as CAR-T cell therapy without the need of previous T-cell manipulation. Currently, several anti-CD20xCD3 TCEs have demonstrated promising efficacy across different lymphoma subtypes with slightly better outcomes in the indolent subset. Anti-CD19xCD3 TCEs are being developed as well but only blinatumomab has been evaluated in clinical trials yet. The results are not so impressive as those with anti-CD19 CAR-T cell therapy. Antibody-drug conjugates targeting different B-cell antigens (CD30, CD79b, CD19) seem to be effective in combination with mAbs, standard chemoimmunotherapy, or immune checkpoint inhibitors. Further investigation will show whether immunotherapy alone or in combinatory regimens has potential to replace chemotherapeutic agents from the first line treatment.

• MeSH
• Lymphoma, B-Cell drug therapy   immunology   pathology   MeSH
• Immunoconjugates therapeutic use   MeSH
• Immunotherapy methods   MeSH
• Humans MeSH
• Lymphoproliferative Disorders drug therapy   immunology   pathology   MeSH
• Antibodies, Monoclonal therapeutic use   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

• Keywords
• polatuzumab vedotin,
• MeSH
• CD79 Antigens antagonists & inhibitors   physiology   MeSH
• Bendamustine Hydrochloride therapeutic use   MeSH
• Lymphoma, Large B-Cell, Diffuse * drug therapy   immunology   MeSH
• Immunoconjugates * therapeutic use   MeSH
• Clinical Trials as Topic MeSH
• Drug Therapy, Combination MeSH
• Humans MeSH
• Antibodies, Monoclonal therapeutic use   MeSH
• Antineoplastic Agents therapeutic use   MeSH
• Rituximab therapeutic use   MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH

Difuzní velkobuněčný B lymfom (DLBCL) tvoří asi 40 % všech nově diagnostikovaných non‑Hodgkinových lymfomů. Ačkoliv jde o kurabilní onemocnění, přibližně 40‒50 % pacientů relabuje nebo má refrakterní chorobu. Osud relabujících pacientů ‒ zvláště těch, kteří nejsou schopni intenzivní chemoterapie nebo kteří relabují po vysokodávkované léčbě ‒ je velmi špatný, s mediánem přežití kolem šesti měsíců. V současné době není pro tuto skupinu pacientů k dispozici žádná doporučená a jednoznačně osvědčená léčebná metoda. Polatuzumab vedotin je konjugovaná protilátka proti receptoru CD79b B lymfocytů s navázaným monometyl auristatinem E, který účinkuje jako mikrotubulární inhibitor. Polatuzumab vedotin vykazuje jak v monoterapii, tak v kombinaci s rituximabem celkovou účinnost 13‒56 %. Kombinace polatuzumab vedotinu s bendamustinem a rituximabem ukázala signifikantně lepší účinnost než kombinace bendamustinu s rituximabem u pacientů s relabovaným DLBCL nevhodným k vysokodávkované léčbě. Polatuzumab vedotin představuje novou možnost účinné léčby u jinak velmi svízelné skupiny relabovaných nemocných s DLBCL.

Diffuse large B‑cell lymphoma (DLBCL) represents approximately 40% of all newly diagnosed non‑Hodgkin lymphomas. Although DLBCL is a curable disease, 40‒50% of patients are refractory or relapse. The fate of the relapsed patients, especially those who are not able to undergo an intensive chemotherapy or patients progressing after a high‑dose therapy, is very poor with median overall survival of approximately 6 months. Up till now, there is no standard recommendation or reliable therapy for this subgroup of patients. Polatuzumab vedotin is a CD79b‑targeted antibody‑drug conjugate delivering monomethyl auristatin E, a microtubular inhibitor. Polatuzumab vedotin demonstrated overall response of 13‒56% in R/R DLBCL as monotherapy and combined with anti‑CD29. Polatuzumab vedotin combined with bendamustine and rituximab showed significantly better efficacy than bendamustine and rituximab alone in R/R DLBCL ineligible for high‑dose chemotherapy. Polatuzumab vedotin represents a new, efficacious treatment possibility in a subgroup of relapsed DLBCL patients with otherwise very poor outcome.

• Keywords
• polatuzumab,
• MeSH
• Lymphoma, Large B-Cell, Diffuse * drug therapy   MeSH
• Immunoconjugates therapeutic use   MeSH
• Lactation MeSH
• Humans MeSH
• Antibodies, Monoclonal * administration & dosage   adverse effects   therapeutic use   MeSH
• Pregnant People MeSH
• Check Tag
• Humans MeSH

Surface IgD is coexpressed with IgM on naive mature B cells. Still, the role of surface IgD remains enigmatic even 50 y after its initial discovery. In this study, we examined the in vivo role of surface IgD in human B cell homeostasis and Ab responses in four individuals with heterozygous nonsense mutations in IGHD All IGHD heterozygous individuals had normal numbers of B cells and serum Igs and did not show signs of immunodeficiency or immune dysregulation. IgD+ and IgD- naive mature B cells were present in equal numbers and showed similar immunophenotypes, except for decreased expression of CD79b in the IgD- subset. Furthermore, both IgD+ and IgD- naive mature B cells had normal replication histories and similar capacities to differentiate into plasma cells upon in vitro stimulation, and Ig class-switched memory B cells showed similar levels of somatic hypermutations. Thus, human B cells lacking IgD expression develop normally and generate immunological memory in vivo, suggesting that surface IgD might function more restrictedly in regulating of B cell activation to specific antigenic structures.

• MeSH
• Lymphocyte Activation MeSH
• B-Lymphocytes immunology   MeSH
• Cell Differentiation MeSH
• Haploinsufficiency MeSH
• Homeostasis MeSH
• Immunoglobulin D genetics   metabolism   MeSH
• Immunoglobulin M metabolism   MeSH
• Immunologic Memory MeSH
• Cells, Cultured MeSH
• Humans MeSH
• Membrane Proteins metabolism   MeSH
• Plasma Cells immunology   MeSH
• B-Lymphocyte Subsets immunology   MeSH
• Immunoglobulin Class Switching MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

BACKGROUND: The data on the clinical utility of the quantitative assessment of immunophenotypes in distinguishing mature CD5-positive B-cell neoplasms is limited. The study aim was to assess the diagnostic value of the quantitative assessment of a panel of 18 markers and to identify the most informative ones. METHODS: The immunophenotype of the neoplastic population was determined in diagnostic specimens from 188 patients. BD FACSCanto II flow cytometer and FACSDiva software were used to analyze the positivity/negativity and mean fluorescence intensity (MFI) of the surface expression of 18 markers. Advanced data mining methods were used to define the key differential diagnostic features of CLL/SLL (chronic lymphocytic leukemia/small lymphocytic lymphoma), MCL (mantle cell lymphoma), and CD5+ MZL (marginal zone lymphoma). RESULTS: The most informative markers for the distinction of CLL/SLL, MCL, CD5+ MZL, including atypical cases, were the MFI values of CD79b, CD20, CD23, CD43, CD38, CD11c, FMC7, CD200, kappa light chain, and their combinations. CD23 and CD200 were the most discriminant between CLL/SLL and MCL and CD23 plus CD79b between CLL/SLL and CD5+ MZL. The quantitative analysis of the most informative markers failed to accurately distinguish MCL and CD5+ MZL. The study highlights the data mining methods for the analysis and selection of the most informative immunophenotypic markers and for the design of a predictive model (diagnostic classifier), minimizing the subjectivity of expert-based assessment. CONCLUSIONS: Our data confirmed that the quantification of the expression of informative markers increases the diagnostic value of immunophenotyping in mature CD5+ B-cell neoplasms. © 2017 International Clinical Cytometry Society.

• MeSH
• CD5 Antigens analysis   MeSH
• Lymphoma, B-Cell diagnosis   immunology   MeSH
• Adult MeSH
• Immunophenotyping methods   MeSH
• Leukemia, B-Cell diagnosis   immunology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Biomarkers, Tumor analysis   immunology   MeSH
• Flow Cytometry methods   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH