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Introduction: Focal myositis (FM) is an uncommon, localized inflammatory process that affects a single muscle, with unknown aetiology. In the head and neck region, involvement of perioral musculature, floor of the mouth, and sternocleidomastoid muscle have been reported. FM affecting the tongue is very rare, with only four cases previously published to date. Aim: This report describes five additional cases of tongue FM. Case Report: Three patients were male and two were female (mean age, 56 years), and three had symptomatic short‐term nodular swelling. Results: By immunohistochemistry, M2 macrophages and CD4+ T cells were predominant. Focally, CD15+ granulocytes and CD20+ B cells were visualized. Polyclonal CD138+ plasma cells, with a predominance of IgG+ cells (rarely IgG4+), were detected. All patients evolved with complete resolution after biopsy and no signs of clinical or systemic progression were observed during the follow‐up. Conclusions: FM should be considered in the differential diagnosis of rapidly growing nodular lingual lesions. By immunohistochemistry, a predominance of M2 macrophages and CD4+ T cells is typical, and it can help in the differential diagnosis with myositis of other origins. [ABSTRACT FROM AUTHOR]

ABSTRACT Canine mucosal melanoma (CMM) is the most common oral malignancy in dogs and is significantly more aggressive than its cutaneous counterpart (CCM), yet the reasons for this disparity remain unclear. Cancer‐associated stroma (CAS) plays a crucial role in tumour progression, but a detailed understanding of CAS in canine melanoma is missing. To assess stromal reprogramming, we analysed CAS from 21 CMM, 14 CCM and normal stroma from 10 skin and 9 oral mucosa samples by laser‐capture microdissection followed by RNA sequencing. Results were assessed in relation to subtypes, prognostic factors including mitotic count (MC), ulceration, necrosis, pigmentation and immune cell infiltration (CD3, CD20 and CD68), scored using immunohistochemistry and RNA in situ hybridisation. Stromal reprogramming was evident in both subtypes but significantly more pronounced in CMM. Immune‐excluded tumours exhibited higher MC than desert/cold ones. MC strongly correlated with genes associated with B‐cells, T‐helper cells and CTLA4 in CCM, suggesting CAS reprogramming to depend on tumour malignancy. Finally, we identify an immune‐suppressive stromal signature in a subset of CMM characterised by the downregulation of key immune checkpoints and pathways. Together, these findings provide a solid foundation for understanding the role of CAS in canine melanoma, specific to cutaneous and mucosal subtypes. [ABSTRACT FROM AUTHOR]

Objectives: Good's syndrome (GS) is a rare secondary immunodeficiency which is characterized by hypogammaglobulinemia and thymoma. This study aims to investigate the expression and distribution of B cells in thymoma tissue, given that B cells had been found to be reduced or absent in peripheral blood or bone marrow. Methods: This study retrospectively analyzed thymoma tissues from 5 GS patients at the First Affiliated Hospital of Wenzhou Medical University and Zhejiang Provincial People's Hospital. Tissues from 20 patients with simple thymoma were used as controls. Immunohistochemistry analyses were performed to detect the markers CD19, CD20, PAX5 and CD138 to evaluate the expression of B cells or plasma cells. Results: Compared to the control group, 4 GS patients exhibited a complete absence of B cells in their thymoma tissue, while 1 GS patient exhibited a notable reduction in B cells. The expression levels of CD19, CD20 and PAX5 in the thymoma tissues of GS patients were dramatically lower than those in the control group (0 vs. 85%, 20 vs. 85%, 20 vs. 85%, respectively; P < 0.05). However, no significant difference was observed in the expression frequency of CD138 between the thymoma tissues of the two groups (0 vs. 30%, P > 0.05). Conclusion: This is the first report of B cell deficiency in 5 thymoma tissues of GS patients. [ABSTRACT FROM AUTHOR]

Introduction: Point-of-care (POC) manufacturing of chimeric antigen receptor (CAR) modified T cell has expanded rapidly over the last decade. In addition to the use of CD19 CAR T cells for hematological diseases, there is a growing interest in targeting a variety of tumor-associated epitopes. Methods: Here, we report the manufacturing and characterization of autologous anti-CD20 CAR T cells from melanoma patients within phase I clinical trial (NCT03893019). Using a second-generation lentiviral vector for the production of the CD20 CAR T cells on the CliniMACS Prodigy®. Results: We demonstrated consistency in cell composition and functionality of the products manufactured at two different production sites. The T cell purity was >98.5%, a CD4/CD8 ratio between 2.5 and 5.5 and transduction rate between 34% and 61% on day 12 (harvest). Median expansion rate was 53-fold (range, 42-65-fold) with 1.7-3.8×109 CAR T cells at harvest, a sufficient number for the planned dose escalation steps (1×105/kg, 1×106/kg, 1×107/kg BW). Complementary research of some of the products pointed out that the CAR+ cells expressed mainly central memory T-cell phenotype. All tested CAR T cell products were capable to translate into T cell activation upon engagement of CAR target cells, indicated by the increase in pro-inflammatory cytokine release and by the increase in CAR T cell amplification. Notably, there were some interindividual, cell-intrinsic differences at the level of cytokine release and amplification. CAR-mediated T cell activation depended on the level of CAR cognate antigen. Discussion: In conclusion, the CliniMACS Prodigy® platform is well suited for decentralized POC manufacturing of anti-CD20 CAR T cells and may be likewise applicable for the rapid and automated manufacturing of CAR T cells directed against other targets. [ABSTRACT FROM AUTHOR]

B-cell lymphoma, clinically, comprises a heterogeneous group of malignancies that encompass various subtypes. CD20 is an optimal target for therapeutic antibodies in B-cell lymphoma immunotherapy since approximately 90% of B-cell malignancies typically exhibit CD20 expression on their surface, while its presence is limited in normal tissues. In this study, we have developed a series of novel non-IgG-like T cell-dependent bispecific antibodies by constructing Fab-FabCH3, referred to as Tandem Antigen-binding Fragment 002 (TFAB002), which specifically target CD20 for the treatment of malignant B-cell lymphoma. TFAB002s display strong binding affinity with CD20 and moderate binding affinity with CD3, thereby triggering target-specific T-cell activation, cytokine release, and tumor cell lysis in vitro. Furthermore, TFAB002s exhibit potent cytotoxicity against B-cell malignancies that express varying levels of CD20. Besides, the TFAB002s show potent pharmacodynamic activity in vivo in the WIL2-S cells CDX mouse model. Collectively, these results underscore the potential of TFAB002s as a highly promising therapeutic approach for selectively depleting CD20-positive B cells, thereby warranting further clinical evaluation as a viable treatment option for CD20-expressing B-cell malignancies. [ABSTRACT FROM AUTHOR]

Summary Since the approval of the CD20‐targeting monoclonal antibody (mAb) rituximab for the treatment of lymphoma in 1997, mAb therapy has significantly transformed cancer treatment. With over 90 FDA‐approved mAbs for the treatment of various hematological and solid cancers, modern cancer treatment relies heavily on these therapies. The overwhelming success of mAbs as cancer therapeutics is attributed to their broad applicability, high safety profile, and precise targeting of cancer‐associated surface antigens. Furthermore, mAbs can induce various anti‐tumor cytotoxic effector mechanisms including antibody‐dependent cellular cytotoxicity (ADCC), antibody‐dependent cellular phagocytosis (ADCP), and complement‐dependent cytotoxicity (CDC), all of which are mediated via their fragment crystallizable (Fc) domain. Over the past decades, these effector mechanisms have been substantially improved through Fc domain engineering. In this review, we will outline the different approaches to enhance Fc effector functions via Fc engineering of mAbs, with a specific emphasis on the so‐called “HexaBody” technology, which is designed to enhance the hexamerization of mAbs on the target cell surface, thereby inducing greater complement activation, CDC, and receptor clustering. The review will summarize the development, preclinical, and clinical testing of several HexaBodies designed for the treatment of B‐cell malignancies, as well as the potential use of the HexaBody technology beyond Fc‐mediated effector functions. [ABSTRACT FROM AUTHOR]

Objectives: This study systematically evaluated the relationship between tertiary lymphoid structures (TLS) and clinical pathological features as well as immune infiltrating cells in gastrointestinal cancers. Methods: We searched Web of science, Pubmed, Embase, and Cochrane Library for studies that met the requirements as of July 1, 2023, and the odds ratio, the corresponding 95% confidence interval or mean and standard deviation, were included in the analysis. Findings: We eventually included 20 studies, involving a total of 4856 patients. TLS were found to be significantly associated with T stage, N stage, TNM stage, and tumor size. Moreover, patients with positive TLS showed significantly elevated expression of T‐cell related markers, including CD3, CD4, CD8, CD45RO; B‐cell related markers, such as CD11c and CD20; and dendritic cell‐related marker CD103. On the other hand, positive TLS correlated significantly with low expression of FOXP3 and CD68. Additionally, there was a significant positive association between TLS and overall infiltration of tumor‐infiltrating lymphocytes. Conclusion: The presence of TLS is significantly correlated with the infiltration of various immune cells in gastrointestinal cancers. To determine the ideal balance between the presence of mature TLS and appropriate immune cell infiltration, further high‐quality and multicenter clinical studies need to be conducted. [ABSTRACT FROM AUTHOR]

Background: Atopic dermatitis (AD) is a chronic inflammatory skin condition whose origins remain unclear. Existing epidemiological evidence suggests that inflammation and immune factors play pivotal roles in the onset and progression of AD. However, previous research on the connection between immune inflammation and AD has yielded inconclusive results. Methods: To evaluate the causal relationship between immunological characteristics and AD, this study employed a bidirectional, two‐sample Mendelian randomization (MR) approach. We utilized large‐scale, publicly available genome‐wide association studies to investigate the causal associations between 731 immunological feature cells and the risk of AD. Results: Significant associations were identified between six immune phenotypes and AD risk: increased Basophil %CD33dim HLA DR−CD66b−, CD25 on IgD+ CD24+, CD40 on monocytes, HLA DR on CD14+ CD16−monocytes, HLA DR on CD14+monocytes correlated with higher AD risk, while elevated CD3 on CD4 Treg was linked to lower risk. Reverse MR analysis revealed AD as a risk factor for IgD+ CD38br AC and IgD+ CD38br %B cell, but a protective factor against CD20 on IgD+ CD38− naive and CD8 on NKT. Conclusion: Our findings elucidate the intricate interplay between immune cells and AD, informing future research into AD pathophysiology and therapeutics. [ABSTRACT FROM AUTHOR]

Rituximab (RTX) is a chimeric monoclonal antibody that targets the CD20 antigen on B cells and is used in various autoimmune disorders. In this study, we aimed to measure the awareness of pediatric rheumatologists about the use of RTX through a survey. Between February and March 2023, a 42-question survey was sent via email to pediatric rheumatology specialists in Turkey. The participants were questioned for which diagnoses and system involvement they preferred to use RTX, which routine tests they performed, vaccination policy, and adverse events that occurred during or after infusion. Forty-one pediatric rheumatologists answered the survey. They prescribed RTX most frequently for systemic lupus erythematosus (87.8%) and ANCA-associated vasculitis (9.8%). Prior to the administration of RTX, 95% of clinicians checked renal and liver function tests, as well as immunoglobulin levels. The most frequently tested hepatitis markers before treatment were HBsAg and anti-HBs antibody (97.6%), while 85.4% of rheumatologists checked for anti-HCV. Clinicians (31.4%) reported that they postpone RTX infusion 2 weeks following an inactivated vaccine. Sixty-one percent of rheumatologists reported starting RTX treatment 1 month after live vaccines, while 26.8% waited 6 months. The most frequent adverse events were an allergic reaction during RTX infusion (65.9%), hypogammaglobulinemia (46.3%), and rash (36.6%). In the event of hypogammaglobulinemia after RTX treatment, physicians reported that they frequently (58.5%) continued RTX after intravenous immunoglobulin administration. Conclusions: RTX has become a common treatment option in pediatric rheumatology in recent years. Treatment management may vary between clinician such as vaccination and routine tests. What is Known: • During the course of rituximab therapy, clinicians should be attentive to specific considerations in pre-treatment, during administration, and in post-treatment patient monitoring. What is New: • There are differences in practice among clinicians in the management of RTX therapy. These practice disparities have the potential to impact the optimal course of treatment. • This study highlights that standardized guidelines are needed for RTX treatment in pediatric rheumatology, particularly for vaccination policies and routine tests. [ABSTRACT FROM AUTHOR]

ABSTRACT Hodgkin‐like lymphoma (HLL) is a rare neoplasm in cats that shares characteristics with the human disease. The hallmark of HLL is the presence of Reed‐Sternberg (RS) cells expressing CD30 and CD20. This study aimed to elucidate the clinicopathologic features, immunophenotype and clonality patterns of feline HLL. A comprehensive retrospective review of clinicopathologic and molecular data of nodal lymphomas over a 6‐year period was conducted in MyLav laboratory. Twenty‐four cases were identified. All cats presented with submandibular or retropharyngeal lymphadenopathy. Histopathologic examination revealed a multifocal to diffuse proliferation of medium‐to‐large lymphoid cells with low mitotic activity, interspersed RS cells, and a heterogeneous inflammatory infiltrate comprising T‐cells, plasma cells and neutrophils. In addition, extensive necrosis was a consistent finding. Immunohistochemistry showed a variable membranous CD20 and nuclear PAX5 expression in neoplastic cells, while RS cells displayed only mild to moderate CD20 positivity and were negative to PAX5. In 21/24 cases (87.5%), RS cells were diffusely CD30‐positive. PARR analysis demonstrated clonal B‐cell expansion in 60% of cases, with the remaining 40% exhibiting polyclonality. For the 10 cats with available follow‐up, the prognosis was generally favourable, with only two cats succumbing to progressive disease. In conclusion, diagnosing feline HLL is challenging. The expression of CD30 and CD20 by RS cells should be considered a hallmark of the disease, but only after excluding differential diagnoses such as anaplastic B‐cell lymphoma and granulomatous lymphadenopathy. [ABSTRACT FROM AUTHOR]

Mycosis fungoides (MF) represents the most common type of primary cutaneous T‐cell lymphoma. Recognition of MF variants with divergent immunophenotypes is important for accurate diagnosis and appropriate management, as they can be confused with other lymphoma subtypes. We present a case of a 49‐year‐old male previously diagnosed with a cutaneous lymphoproliferative disorder with an unusual NK/T‐cell phenotype. He presented with a 10‐year history of pelvic girdle rash involving the right hip and upper thigh. The lesions were characterized as atrophic patches concentrated in sun‐protected areas and involving 10% of the body surface area. Shave biopsies revealed an atypical epidermotropic infiltrate composed of hyperchromatic small to medium‐sized lymphocytes with perinuclear halos and "tagging" along the dermal–epidermal junction. The immunophenotype was unusual in that the neoplastic lymphocytes showed complete loss of pan T‐cell antigens along with expression of CD56, cytotoxic markers, and weak CD20. All other B‐cell markers were negative. The combination of clinical findings, in addition to the histopathologic and immunophenotypic profile, were diagnostic of null T‐cell phenotype MF with aberrant expression of CD56 and CD20. Null T‐cell phenotype MF is very uncommon, can be diagnostically challenging, and can mislead the diagnosis of aggressive lymphoma subtypes. [ABSTRACT FROM AUTHOR]

AbstractThis real-world retrospective cohort study using Australian Pharmaceutical Benefits Scheme (PBS) 10% investigated changes in chronic lymphocytic leukemia (CLL) treatment by line of therapy, time-to-next-treatment, treatment duration, and overall survival (OS). Overall, 803 patients received their first PBS-reimbursed CLL medication between 1 January 2011 to 31 July 2021 (median age: 70 years; 64.6% male), 289 post-1 August 2020. In 2011, most first-line (1 L) prescribing was fludarabine, cyclophosphamide, and rituximab (FCR). By 2021, common 1L were chlorambucil ± CD20 (26.1%), Bruton Tyrosine Kinase inhibitor (BTKi) (26.1%), and CD20 monotherapy (23.9%). In 2011, relapsed/refractory (R/R) CLL treatment was CD20 monotherapy or FCR. By 2021, BTKi (57.7%) and venetoclax ± CD20 (26.1%) were most common. Compared to FCR, 1 L treatment duration (Hazard Ratio) was shorter for CD20 monotherapy (1.7) or chlorambucil ± CD20 (2.5). In R/R CLL, median duration was 24 (ibrutinib) and 19 months (venetoclax). Median OS was 127 months. CLLtreatment pattern shave greatly changed in Australia since the introduction of novel therapies. [ABSTRACT FROM AUTHOR]

Summary: We reviewed cases with aggressive B‐cell non‐Hodgkin lymphoma who relapsed or progressed following glofitamab. The prognosis was poor, with low rates of response to subsequent salvage therapies, and a median overall survival of 4.1 months from the time of progression. There were high rates of CD20 loss (59%) at the time of relapse. In a field where CD20 × CD3 bispecific antibodies are entering routine clinical use, our experience highlights a potential means of resistance. It illustrates both the need to further characterise mechanisms of CD20 loss, and to pursue clinical trials of novel non‐CD20‐directed treatments in this cohort. [ABSTRACT FROM AUTHOR]

A novel compound chimeric antigen receptor T-cell therapy (cCAR) has been developed to target CD20-CD19 positive B-cell acute leukemias and B-cell lymphoma. The therapy consists of two distinct CARs that independently target CD20 and CD19 surface antigens. In vitro and in vivo experiments demonstrated the efficacy of the therapy in killing target cells and improving survival outcomes. The CD20-CD19 cCAR T cells may provide an enhanced therapeutic approach for patients with relapsed or refractory disease due to antigen escape. [Extracted from the article]

Mosunetuzumab (Mosun) is a CD20xCD3 T‐cell engaging bispecific antibody that redirects T cells to eliminate malignant B cells. The approved step‐up dose regimen of 1/2/60/30 mg IV is designed to mitigate cytokine release syndrome (CRS) and maximize efficacy in early cycles. A population pharmacokinetic (popPK) model was developed from 439 patients with relapsed/refractory B‐Cell Non‐Hodgkin lymphoma receiving Mosun IV monotherapy, including fixed dosing (0.05–2.8 mg IV every 3 weeks (q3w)) and Cycle 1 step‐up dosing groups (0.4/1/2.8–1/2/60/30 mg IV q3w). Prior to Mosun treatment, ~50% of patients had residual levels of anti‐CD20 drugs (e.g., rituximab or obinutuzumab) from prior treatment. CD20 receptor binding dynamics and rituximab/obinutuzumab PK were incorporated into the model to calculate the Mosun CD20 receptor occupancy percentage (RO%) over time. A two‐compartment model with time‐dependent clearance (CL) best described the data. The typical patient had an initial CL of 1.08 L/day, transitioning to a steady‐state CL of 0.584 L/day. Statistically relevant covariates on PK parameters included body weight, albumin, sex, tumor burden, and baseline anti‐CD20 drug concentration; no covariate was found to have a clinically relevant impact on exposure at the approved dose. Mosun CD20 RO% was highly variable, attributed to the large variability in residual baseline anti‐CD20 drug concentration (median = 10 μg/mL). The 60 mg loading doses increased Mosun CD20 RO% in Cycle 1, providing efficacious exposures in the presence of the competing anti‐CD20 drugs. PopPK model simulations, investigating Mosun dose delays, informed treatment resumption protocols to ensure CRS mitigation. [ABSTRACT FROM AUTHOR]

A captive 17‐year‐old male cynomolgus monkey (Macaca fascicularis) developed diffuse large B‐cell lymphoma (DLBCL). This was the first report of DLBCL presenting with a mandible mass and violation of the paranasal sinus in a cynomolgus monkey. The neoplasm showed marked microscopical malignant aspects. Immunohistochemical staining showed strong positive expression of CD20. These features may contribute to the diagnosis and therapeutics of DLBCL in NHPs. [ABSTRACT FROM AUTHOR]

This article discusses a case report of a patient with severe epidermolysis bullosa acquisita (EBA), a rare autoimmune disease characterized by auto-antibodies against type-VII collagen. The patient had previously tried various treatments without success, but achieved sustained clinical remission (CR) for 5 years after receiving rituximab infusions. Rituximab, a monoclonal antibody targeting B lymphocytes, has shown promise in inducing long-term remission for patients unresponsive to conventional therapies. The article highlights the patient's improvement in symptoms, decrease in disease activity scores, and improved quality of life following rituximab treatment. This case adds to the existing evidence for rituximab as an effective treatment for severe EBA. [Extracted from the article]

Objective: The choice of neoadjuvant therapy for esophageal squamous cell carcinoma (ESCC) is controversial. This study aims to provide a basis for clinical treatment selection by establishing a predictive model for the efficacy of neoadjuvant immunochemotherapy (NICT). Methods: A retrospective analysis of 30 patients was conducted, divided into Response and Non-response groups based on whether they achieved major pathological remission (MPR). Differences in genes and immune microenvironment between the two groups were analyzed through nextgeneration sequencing (NGS) and multiplex immunofluorescence (mIF). Variables most closely related to therapeutic efficacy were selected through LASSO regression and ROC curves to establish a predictive model. An additional 48 patients were prospectively collected as a validation set to verify the model’s effectiveness. Results: NGS suggested seven differential genes (ATM, ATR, BIVM-ERCC5, MAP3K1, PRG, RBM10, and TSHR) between the two groups (P < 0.05). mIF indicated significant differences in the quantity and location of CD3+, PD-L1+, CD3+PD-L1+, CD4+PD-1+, CD4+LAG-3+, CD8+LAG-3+, LAG-3+ between the two groups before treatment (P < 0.05). Dynamic mIF analysis also indicated that CD3+, CD8+, and CD20+ all increased after treatment in both groups, with a more significant increase in CD8+ and CD20+ in the Response group (P < 0.05), and a more significant decrease in PD-L1+ (P < 0.05). The three variables most closely related to therapeutic efficacy were selected through LASSO regression and ROC curves: Tumor area PD-L1+ (AUC= 0.881), CD3+PD-L1+ (AUC= 0.833), and CD3+ (AUC= 0.826), and a predictive model was established. The model showed high performance in both the training set (AUC= 0.938) and the validation set (AUC= 0.832). Compared to the traditional CPS scoring criteria, the model showed significant improvements in accuracy (83.3% vs 70.8%), sensitivity (0.625 vs 0.312), and specificity (0.937 vs 0.906). Conclusion: NICT treatment may exert anti-tumor effects by enriching immune cells and activating exhausted T cells. Tumor area CD3+, PD-L1+, and CD3+PDL1+ are closely related to therapeutic efficacy. The model containing these three variables can accurately predict treatment outcomes, providing a reliable basis for the selection of neoadjuvant treatment plans. [ABSTRACT FROM AUTHOR]

Tumor-infiltrating lymphocytes (TILs) represent a subset of immunological constituents within the tumor microenvironment that can influence cancer growth. We retrospectively evaluate the density and pattern of CD3 and CD20 expression in salivary gland tumors and their relation to clinical pathologic parameters. A total of 44 formalin-fixed paraffin-embedded blocks of salivary gland tumors were included. These tumors were stained immunohistochemically with CD3 and CD20. The chi-square test was used to relate immune scoring, intensity, and clinical pathological parameters to different salivary tumors. p-value < 0.05 was considered statistically significant. The intra-tumoral CD3 infiltrating count was high and diffused in (71.4%) of pleomorphic adenomas (PAs) followed by mucoepidermoid carcinomas (MECs) (66.7%). At the same time, adenoid cystic carcinomas (AdCCs) exhibited significantly low infiltration (71.4%) (p = 0.046). The three types of tumors exhibited high tumor-infiltrating counts diffused in peripheral areas with significant differences between malignant tumors (p = 0.047). The intra-tumoral CD20 infiltrating count significantly differed among the tumors (p = 0.002); it was low in all PAs and AdCCs, while MECs showed an equal percentage of expression. However, in the peripheral area, PAs and MECs exhibited significantly (p = 0.007) high infiltrating counts (69.2% and 84.6), and the lowest infiltrating count was predominantly found for AdCCs. The two markers had a significant positive correlation between the mean of CD3 in the intra-tumoral and peripheral regions and CD20 in the peripheral zone across the total samples. In conclusion, the density of CD3 expression is notably higher than CD20 across tumor types. PAs and MECs showed high-density scores, while AdCCs were characterized by low scores. TIL expression was found to be significantly associated with patients' outcomes in the intra-tumoral area. [ABSTRACT FROM AUTHOR]

CD20 located predominantly on the B cells plays a crucial role in their development, differentiation, and activation, and serves as a key therapeutic target for the treatment of B-cell malignancies. The breakthrough of monoclonal antibodies directed against CD20, notably exemplified by rituximab, revolutionized the prognosis of B-cell malignancies. Rituximab, approved across various hematological malignancies, marked a paradigm shift in cancer treatment. In the current landscape, immunotherapies targeting CD20 continue to evolve rapidly. Beyond traditional mAbs, advancements include antibody-drug conjugates (ADCs), bispecific antibodies (BsAbs), and chimeric antigen receptor-modified (CAR) T cells. ADCs combine the precision of antibodies with the cytotoxic potential of drugs, presenting a promising avenue for enhanced therapeutic efficacy. BsAbs, particularly CD20xCD3 constructs, redirect cytotoxic T cells to eliminate cancer cells, thereby enhancing both precision and potency in their therapeutic action. CAR-T cells stand as a promising strategy for combatting hematological malignancies, representing one of the truly personalized therapeutic interventions. Many new therapies are currently being evaluated in clinical trials. This review serves as a comprehensive summary of CD20-targeted therapies, highlighting the progress and challenges that persist. Despite significant advancements, adverse events associated with these therapies and the development of resistance remain critical issues. Understanding and mitigating these challenges is paramount for the continued success of CD20-targeted immunotherapies. [ABSTRACT FROM AUTHOR]

The mammalian olfactory system detects and discriminates between millions of odorants to elicit appropriate behavioral responses. While much has been learned about how olfactory sensory neurons detect odorants and signal their presence, how specific innate, unlearned behaviors are initiated in response to ethologically relevant odors remains poorly understood. Here, we show that the 4-transmembrane protein CD20, also known as MS4A1, is expressed in a previously uncharacterized subpopulation of olfactory sensory neurons in the main olfactory epithelium of the murine nasal cavity and functions as a mammalian olfactory receptor that recognizes compounds produced by mouse predators. While wildtype mice avoid these predator odorants, mice genetically deleted of CD20 do not appropriately respond. Together, this work reveals a CD20-mediated odor-sensing mechanism in the mammalian olfactory system that triggers innate behaviors critical for organismal survival. How animals sense and properly avoid predators remains incompletely understood. Here, Jiang et al. show that the B cell co-receptor, CD20 also functions as an olfactory receptor and mediates the innate avoidance of predator derived odors. [ABSTRACT FROM AUTHOR]

Introduction: In monoclonal B cell lymphocytosis (MBL) and chronic lymphocytic leukemia (CLL), the expansion of malignant B cells disrupts the normal homeostasis and interactions between B cells and T cells, leading to immune dysregulation. CD20+ T cells are a subpopulation of T cells that appear to be involved in autoimmune diseases and cancer. Methods: Here, we quantified and phenotypically characterized CD20+ T cells from MBL subjects and CLL patients using flow cytometry and correlated our findings with the B-cell receptor mutational status and other features of the disease. Results and discussion: CD20+ T cells were more represented within the CD8+ T cell compartment and they showed a predominant memory Tc1 phenotype. CD20+ T cells were less represented in MBL and CLL patients vs healthy controls, particularly among those with unmutated IGVH gene. The expansion of malignant B cells was accompanied by phenotypic and functional changes in CD20+ T cells, including an increase in follicular helper CD4+ CD20+ T cells and CD20+ Tc1 cells, in addition to the expansion of the TCR Vb 5.1 in CD4+ CD20+ T cells in CLL. [ABSTRACT FROM AUTHOR]

Summary: Literature regarding prognostic relevance of CD20 antigen expression among paediatric B‐lineage acute lymphoblastic leukaemia (B‐ALL) patients is sparse and contradictory. We analysed clinical laboratory parameters and survival characteristics pertinent to CD20 expression among 224 treatment‐naïve paediatric B‐ALL patients. 50% patients had CD20 expression (CD20+ B‐ALL). There was no difference in the clinical & laboratory presentation and end of induction measurable residual disease (EOI‐MRD) status according to CD20 expression. As compared to CD20− B‐ALL patients, CD20+ B‐ALL patients had two times more relapse (16% vs. 29%, p = 0.034), inferior relapse‐free survival (79% vs. 66%, p = 0.025) but no difference in overall survival (75% vs. 69%, p = 0.126). Similar to high‐risk NCI status and EOI‐MRD positivity, CD20 expression was an independent predictor for inferior relapse‐free survival (HR: 1.860, 95% CI: 1.008–3.432, p = 0.047). Compared to baseline, there was a significant increase in CD20‐expressing EOI‐residual blasts among CD20− B‐ALL patients (5% vs. 13%, p = 0.001). EOI residual blasts of both CD20+ and CD20− patients had three times increased normalized CD20 expression intensity (nCD20), with the intensity among CD20− B‐ALL patients reaching the pretreatment nCD20 of CD20+ B‐ALL patients (4.9 vs. 3.6, p = 0.666). Rituximab can be considered in managing EOI‐MRD‐positive CD20− B‐ALL patients as the residual blasts of these patients have quantitative and qualitative increases in CD20 expression. [ABSTRACT FROM AUTHOR]

Chagas disease is a Neglected Tropical Disease with limited and ineffective therapy. In a search for new anti-trypanosomal compounds, we investigated the potential of the metabolites from the bacteria living in the corals and sediments of the southeastern Brazilian coast. Three corals, Tubastraea coccinea, Mussismilia hispida, Madracis decactis, and sediments yielded 11 bacterial strains that were fully identified by MALDI-ToF/MS or gene sequencing, resulting in six genera—Vibrio, Shewanella, Mesoflavibacter, Halomonas, Bacillus, and Alteromonas. To conduct this study, EtOAc extracts were prepared and tested against Trypanosoma cruzi. The crude extracts showed IC50 values ranging from 15 to 51 μg/mL against the trypomastigotes. The bacterium Mesoflavibacter zeaxanthinifaciens was selected for fractionation, resulting in an active fraction (FII) with IC50 values of 17.7 μg/mL and 23.8 μg/mL against the trypomastigotes and amastigotes, respectively, with neither mammalian cytotoxicity nor hemolytic activity. Using an NMR and ESI-HRMS analysis, the FII revealed the presence of unsaturated iso-type fatty acids. Its lethal action was investigated, leading to a protein spectral profile of the parasite altered after treatment. The FII also induced a rapid permeabilization of the plasma membrane of the parasite, leading to cell death. These findings demonstrate that these unsaturated iso-type fatty acids are possible new hits against T. cruzi. [ABSTRACT FROM AUTHOR]

Background: Hepatitis C virus (HCV) infection is a global health problem and continues to be a major disease burden in the world, associated with serious health challenges including liver cirrhosis, cancer, lymphomas and death. This study was carried out to determine the prevalence of HCV infection among students of the University of Calabar. Methodology: In a cross-sectional study, 200 students were tested for the presence of anti-HCV antibodies using a rapid immunochromatographic (ICT) assay (CTK Biotech, Inc. USA). Seropositive samples were confirmed using reverse transcriptase-polymerase chain reaction (RT-PCR) assay for detection of HCV RNA. Structured questionnaires were used to collect subjects' socio-demographic data and risk factors of infection. Data were analyzed using SPSS version 16.0, with the level of significance set at p<0.05. Results: Of the 200 students screened, the seroprevalence of HCV was 15.0% (n=30) and 9.5% (n=19) was positive for HCV RNA by RT-PCR assay. The prevalence of anti-HCV antibody was significantly higher in females (18.8%, 12/64) than males (13.2%, 18/136) (x²=3.84, p=0.036). Alcohol consumption (OR=4.67, 95% CI=2.04-10.67, p=0.002), skin piercing (OR=32.99, 95% CI=5.95-72.37, p<0.0001), multiple sexual partners (OR=4.03, 95% CI=1.7-9.6, p=0.0018), and history of blood transfusion (OR=8.00, 95% CI=2.97-21.58, p<0.001) were risk factors significantly associated with HCV infection in the study participants. Conclusion: The findings of 15.0% and 9.5% prevalence of HCV infection by anti-HCV antibody and HCV RNA, respectively in this study, showed that there is relatively high prevalence of HCV infection among the students' population in University of Calabar, Nigeria. Hence, routine medical screening of students for HCV infection using rapid ICT and RT-PCR techniques is hereby recommended. [ABSTRACT FROM AUTHOR]

Backround: Inflammation characterized by the presence of T and B cells is often observed in prostate cancer, but it is unclear how T‐ and B‐cell levels change during carcinogenesis and whether such changes influence disease progression. Methods: The study used a retrospective sample of 73 prostate cancer cases (45 whites and 28 African Americans) that underwent surgery as their primary treatment and had a benign prostate biopsy at least 1 year before diagnosis. CD3+, CD4+, and CD20+ lymphocytes were quantified by immunohistochemistry in paired pre‐ and post‐diagnostic benign prostate biopsy and tumor surgical specimens, respectively. Clusters of similar trends of expression across two different timepoints and three distinct prostate regions—benign biopsy glands (BBG), tumor‐adjacent benign glands (TAG), and malignant tumor glandular (MTG) regions—were identified using Time‐series Anytime Density Peaks Clustering (TADPole). A Cox proportional hazards model was used to estimate the hazard ratio (HR) of time to biochemical recurrence associated with region‐specific lymphocyte counts and regional trends. Results: The risk of biochemical recurrence was significantly reduced in men with an elevated CD20+ count in TAG (HR = 0.81, p = 0.01) after adjusting for covariates. Four distinct patterns of expression change across the BBG‐TAG‐MTG regions were identified for each marker. For CD20+, men with low expression in BBG and higher expression in TAG compared to MTG had an adjusted HR of 3.06 (p = 0.03) compared to the reference group that had nominal differences in CD20+ expression across all three regions. The two CD3+ expression patterns that featured lower CD3+ expression in the BBG compared to the TAG and MTG regions had elevated HRs ranging from 3.03 to 4.82 but did not reach statistical significance. Conclusions: Longitudinal and spatial expression patterns of both CD3+ and CD20+ suggest that increased expression in benign glands during prostate carcinogenesis is associated with an aggressive disease course. [ABSTRACT FROM AUTHOR]

Background/Aim: Patients with malignant lymphoma, in a latent state of weakened immune function, are at risk of chemotherapy-induced immunosuppression and cytomegalovirus (CMV) infection. Concomitant therapy with bendamustine and rituximab or obinutuzumab intensifies immunosuppression, potentially affecting CMV onset. This study aimed to assess CMV onset differences between bendamustine monotherapy and combination therapy with rituximab or obinutuzumab using the Japanese Adverse Drug Event Report database (JADER). Patients and Methods: A JADER analysis dataset (April 2004 to September 2022) defined CMV infection using 31 preferred term (PT) words from MedDRA 25.1J HLT "Cytomegalovirus infection (10011827)". Reporting odds ratios (ROR) calculated CMV infection signals for bendamustine monotherapy, rituximab, obinutuzumab, bendamustine+rituximab (BR), and bendamustine+obinutuzumab (GB). ROR confidence intervals exceeding 1 indicated a CMV signal. Days of CMV infection were calculated based on adverse event onset and administration start. Results: CMV signals were confirmed for monotherapy and combination therapies. CMV infection durations (median, interquartile range) were 41.0 days (23.5-69.5) for bendamustine monotherapy, 63.5 days (35.2-95.0) for BR, and 61.0 days (33.0-102.5) for GB, with cases exceeding 200 days. Conclusion: JADER analysis detected significant CMV signals for rituximab, obinutuzumab, and bendamustine. Caution may be warranted 7-9 months post-bendamustine administration, necessitating further investigation, including cell-mediated immunity suppression assessment. [ABSTRACT FROM AUTHOR]

Background/Aim: Given that gastric small cell neuroendocrine carcinoma (SCNEC) is notably more aggressive than conventional adenocarcinoma, and a platinum-based regimen aligned with the treatment for pulmonary SCNEC is advocated when chemotherapy is needed, ensuring an accurate pathological diagnosis is paramount. Case Report: A 63-year-old man, examined for melena, underwent gastroscopy which revealed a total circumferential Borrmann type 3 lesion extending from the pylorus to the antrum of the stomach. He underwent a distal gastrectomy with D2 lymphadenectomy. The microscopic examination revealed SCNEC with a minor adenocarcinoma component. Immunohistochemically, the SCNEC was diffusely positive for synaptophysin, CD56, and INSM1, very focally positive for chromogranin A, and negative for leukocyte common antigen, CD3, and CD20. A significant observation in this case was the complete negativity for epithelial markers including keratin (CK7, CK8, CK20, CAM5.2, and AE1/AE3) and epithelial membrane antigen. Conclusion: Diffuse positivity for neuroendocrine markers, negativity for other lineage markers, and a transition from the adenocarcinoma component, if present, serve as significant diagnostic clues for gastric SCNEC with loss of epithelial markers expression. SCNEC should not be excluded solely based on the negative result for epithelial markers. [ABSTRACT FROM AUTHOR]

The management of persistent symptomatic coronavirus disease 2019 (COVID-19) infections in immunocompromised patients remains unclear. Here, we present the first case of successful antiviral therapy (nirmatrelvir/ritonavir and remdesivir) in combination with intravenous immunoglobulin (IVIg) in a patient who had received CD20 depleting therapy for follicular lymphoma and experienced recurrent COVID-19 relapses. After the patient received IVIg treatment, the viral load decreased without recurrence. Subsequently, it was found that the anti-spike antibody titer in the administered immunoglobulin was high at 9528.0 binding antibody units/mL. Our case highlights the potential of combination therapy with selective IVIg and antiviral drugs for relapsed immunocompromised COVID-19 patients who have received CD20 depleting therapy. [ABSTRACT FROM AUTHOR]

The prognosis of r/r DLBCL has changed substantially over the past decade due to the introduction of T‐cell‐activating therapies. Besides generating a new curative perspective for a proportion of r/r DLBCL, chimeric antigen receptor T‐cell therapy and bispecific antibodies are generating new unmet needs. The report by Grigg and colleagues now shows that glofitamab‐refractory, CD20‐negative patients represent a new unmet medical need requiring therapeutic targets other than CD20 and novel therapies to reduce the risk of CD20 loss. Commentary on: Grigg et al. Relapse after glofitamab has a poor prognosis, and rates of CD20 loss are high. Br J Haematol 2024;205:122–126. [ABSTRACT FROM AUTHOR]

Amyloidosis involves the deposition of misfolded proteins. Even though it is caused by different pathogenic mechanisms, in aggregate, it shares similar features. Here, we tested and confirmed a hypothesis that an amyloid antibody can be engineered by a few mutations to target a different species. Amyloid light chain (AL) and β-amyloid peptide (Aβ) are two therapeutic targets that are implicated in amyloid light chain amyloidosis and Alzheimer's disease, respectively. Though crenezumab, an anti-Aβ antibody, is currently unsuccessful, we chose it as a model to computationally design and prepare crenezumab variants, aiming to discover a novel antibody with high affinity to AL fibrils and to establish a technology platform for repurposing amyloid monoclonal antibodies. We successfully re-engineered crenezumab to bind both Aβ42 oligomers and AL fibrils with high binding affinities. It is capable of reversing Aβ42-oligomers-induced cytotoxicity, decreasing the formation of AL fibrils, and alleviating AL-fibrils-induced cytotoxicity in vitro. Our research demonstrated that an amyloid antibody could be engineered by a few mutations to bind new amyloid sequences, providing an efficient way to reposition a therapeutic antibody to target different amyloid diseases. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus–related malignancies have been linked to variations in the sequences of EBV genes, notably EBNA1. Therefore, the purpose of this study was to examine the DBD/DD domain and USP7 binding domain sequences at the C-terminus of the EBNA1 gene in patients with chronic lymphocytic leukemia (CLL). This study included 40 CLL patients and 21 healthy volunteers. Using commercial kits, total DNA was extracted from buffy coat samples, and each sample was tested for the presence of the EBV genome. The C-terminus of EBNA1 was then amplified from positive samples, using nested PCR. Sanger sequencing was used to identify mutations in the PCR products, and the results were analyzed using MEGA11 software. The mean ages of CLL patients and healthy individuals were 61.07 ± 10.2 and 59.08 ± 10.3, respectively. In the EBNA-1 amplicons from CLL patients and healthy individuals, 38.5% and 16.7%, respectively, harbored mutations in the DBD/DD domain of the C-terminal region of the EBNA1 gene (P = 0.378). The mutation frequency at locus 97,320 was significantly higher in CLL patients than in healthy individuals (P = 0.039). Three EBV subtypes based on residue 487 were detected. The frequency of alanine, threonine, and valine in both groups was 88, 8, and 4 percent, respectively (P = 0.207). Moreover, all of the isolates from healthy donors had alanine at this position. The findings indicated that the presence of threonine or valine at residue 487 as well as a synonymous substitution at residue 553 in the C-terminal region of EBNA1 might be involved in the pathogenesis of EBV in CLL patients. [ABSTRACT FROM AUTHOR]

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare primary cutaneous lymphoma which often be very complexed to be diagnosed. Here we reported a case of a 38-year-old lady with wax and wane course of left facial swelling associated with prolonged pyrexia of unknown origin, lethargy and prominent weight loss. Multiple investigations were conducted to reach to the conclusive diagnosis. Histopathological showed infiltration of neoplastic lymphoid cells within the adipocyte clusters with hyperchromatic nuclei, small nucleoli and scant cytoplasm. Immunohistochemical analysis were immunoreactive to CD3, CD8 & TIA and negative to CD20, CD4 & CD56. Based on clinical findings, histopathology report and immunohistochemical analysis, the patient diagnosed with SPTCL. Hence, any suspicious maxillofacial swelling without obvious sign of infection and trauma shall be investigated until a final diagnosis is reached. [ABSTRACT FROM AUTHOR]

Objective: To present the technical verification and clinical validation of the companion diagnostic assay, cobas® EZH2 Mutation Test (cobas EZH2 Test), targeting gain-of-function EZH2 mutations in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). The focus is on patient clinical samples proving that the test met the performance criteria required for FDA approval of a companion diagnostic test. Design: Epizyme, Inc., Eisai Co., Ltd., and Roche Molecular Systems, Inc., collaborated to develop the cobas EZH2 Test on an RT-PCR platform. The assay design needed to detect the gain-of-function EZH2 mutations found in FL and DLBCL indications. Thus, the test was optimized for investigational purposes in a clinical trial setting. Part of its technical verification included testing of patient tumor samples with a documented diagnosis of FL and DLBCL procured from commercial vendors, and the clinical validation used patient samples from the Epizyme clinical study. Both the technical performance verification method correlation study (104 clinical commercially acquired samples) and the clinical validation accuracy study (341 patient samples from the therapeutic study) used next-generation sequencing as a reference method to establish true vs. false results by cobas EZH2 Test. The reproducibility study used a 15-member panel of DNA samples with varying EZH2 mutation status from procured clinical FL and DLBCL patient samples under multiple variables. Results: Single and rare, infrequent double EZH2 mutations were detected in FL and DLBCL samples. Agreements between results from cobas EZH2 and sequencing were >98% from commercial clinical samples and from the therapeutic study clinical samples. The reproducibility study obtained 178 to 180 valid results for each panel member, with an overall invalid rate of 0.37%. The agreement for each per panel member was 100%. Conclusion: cobas EZH2 Test data demonstrated that the test is reliable and will perform well in a commercial customer environment. [ABSTRACT FROM AUTHOR]

Lavender essential oil (LVEO) (Lavandula angustifolia L) was investigated for its impacts on broiler chicken growth, intestinal histomorphology, blood biomarkers, and immunological status. Four hundred 3-days-old male chicks (ROSS 308 broilers) (91.47 ± 0.15 g) were randomised to receive four test groups and nourished on basal diets having four levels of LVEO: 0, 200, 400, and 600 mg Kg−1 over 35 days. Dietary addition of LVEO linearly increased the body weight and weight gain during the grower period, while its addition did not affect the overall growth performance. Dietary LVEO increased the villous height, and the higher villous height was detected in the LVEO600 group. Dietary LVEO increased cluster of differentiation (CD3 and CD20) immunoexpression within the spleens of birds given LVEO400 and LVEO600 diets. Serum triiodothyronine and thyroxine hormone levels were the highest in the LVEO400 and LVEO600 groups. LVEO supplementation raised serum growth hormone levels in a dosage-dependent manner. The serum concentrations of glucose and leptin hormone did not vary significantly between the LVEO-supplemented and LVEO0 groups. All levels of supplemental LVEO diminished serum cholesterol, triglyceride, and low-density lipoprotein cholesterol levels, while raising the high-density lipoprotein cholesterol concentration. Total protein values were augmented in all LVEO groups, with the highest concentrations of albumin and globulin in the LVEO600 group, followed by the LVEO400 group. Supplemental LVEO increased serum concentration of complement 3, interleukin-10, and lysozyme activity in a level-dependent manner. Modifications in the birds' physiological activities, blood biochemical, intestinal morphological characteristics, and immunological status support the conclusion that dietary LVEO supplementation had numerous positive effects. However, it didn't influence the birds' growth. LVEO supplementation linearly increased the body weight during the grower stage, while its addition did not affect the overall growth performance. LVEO supplementation had a hypolipidemic effect, and the LVEO400 and LVEO600 groups showed the highest serum triiodothyronine and thyroxine hormone levels. LVEO supplementation (200-600 mg Kg−1 diet) improved the immune status of birds, indicated by increased serum concentration of complement 3, interleukin-10, and lysozymes activity with increased CD3 and CD20 immunoexpression in the spleens of LVEO400 and LVEO600 groups. [ABSTRACT FROM AUTHOR]

Herbal medicine treatment for Hepatitis C Virus (HCV) infection is a promising alternative to common medical HCV treatments because it has low unwanted side effects and production costs. This study aimed to evaluate the methanol extract of Garcinia lattissima stem barks as an antiviral compound against strain JFH1 (HCV) genotype 2a. Garcinia lattissima stem bark methanolic extract (GL-SB) was added to Huh7it-1 cells infected with JFHI. Anti HCV activity was determined by Focus-forming unit (FFU) assay and the cytotoxicity activity was analyzed using the 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay. The GL-SB showed its efficacy as the anti-HCV agent with a 50% cytotoxicity concentration (CC50) of 34.2 µg/mL and a 50% effective concentration (EC50) of 4.7 µg/mL. The co-addition and post-infection phases of GL-SB showed an anti-HCV activity, according to a time-of-addition investigation. These findings imply that GL-SB might be a promising candidate for add-on therapy in the treatment of HCV infections. [ABSTRACT FROM AUTHOR]

Extranodal NK/T‐cell lymphoma (ENKTL) is a subtype of non‐Hodgkin lymphoma mainly derived from NK cells and, uncommonly, T‐cells. A diagnostic challenge is presented when an atypical phenotype and gene rearrangement are encountered. Herein, we report a case of ENKTL with CD20 expression and IGH gene rearrangement, which is extremely rare. A 57‐year‐old female patient was seen in 2021 due to a nodule on her left leg and simultaneously impaired eyesight for 6 months. Skin biopsy and immunohistochemistry were performed. The lymphoid cells were positive for CD3, CD56, granzyme B, and TIA‐1, partially positive for CD2, and mildly positive for CD20. In situ hybridization for Epstein–Barr virus was positive. Molecular studies revealed immunoglobulin heavy chain (IGH) gene rearrangement, while no T‐cell receptor gene rearrangement was detected. The positron emission tomography scan showed that the lymphoma affected bilateral adrenal glands, pelvic cavity, peritoneal cavity, small intestine, skin, and subcutis of the bilateral lower extremities of the patient. Her disease progressed despite eight cycles of chemotherapy and radiation therapy. The importance of this case lies in the atypical phenotype and IGH gene rearrangements, necessitating comprehensive interpretation of clinicopathological data. [ABSTRACT FROM AUTHOR]

Inebilizumab, a humanized, glycoengineered, IgG1 monoclonal antibody that depletes CD19+ B‐cells, is approved to treat aquaporin 4 (AQP4) IgG‐seropositive neuromyelitis optica spectrum disorder (NMOSD). Inebilizumab is afucosylated and engineered for enhanced affinity to Fc receptor III‐A (FCGR3A) receptors on natural killer cells to maximize antibody‐dependent cellular cytotoxicity. Previously, the F allele polymorphism at amino acid 158 of the FCGR3A gene (F158) was shown to decrease IgG‐binding affinity and reduce rituximab (anti‐CD20) efficacy for NMOSD attack prevention. In contrast, our current findings from inebilizumab‐treated NMOSD patients indicate similar clinical outcomes between those with F158 and V158 allele genotypes. [ABSTRACT FROM AUTHOR]

Objective: This paper observes the efficacy of chemotherapy combined with CD19 and CD20 monoclonal antibodies in clearing minimal residual disease (MRD) and bridging transplantation for refractory acute B-lymphoblastic leukemia (B-ALL) in children and reviews the literature. Methods: A 4-year-old boy diagnosed with B-ALL in our hospital was treated with the SCCLG-ALL-2016 protocol. MRD and gene quantification decreased after induction but remained persistently positive, with poor efficacy. After this patient received three cycles of consolidation chemotherapy combined with blinatumomab and rituximab, MRD and fusion gene quantification became negative, and he received allogeneic hematopoietic stem cell transplantation (allo-HSCT). Results: During the use of monoclonal antibodies, neurotoxicity, CRS, or other side effects did not occur. Before transplantation, MRD became negative, and the bone marrow had been in complete remission since transplantation (13 months). Conclusion: Chemotherapy combined with blinatumomab for refractory B-ALL in children can bring a better remission rate for patients and is a means of bridging transplantation. Nevertheless, sequential CD20 monoclonal antibody therapy is the first report, and no adverse effects were observed in our case. It is well tolerated and can be used as one of the treatments for refractory B-ALL. [ABSTRACT FROM AUTHOR]

Epcoritamab is a subcutaneously administered CD3xCD20 bispecific Ab that showed deep, durable responses with a manageable safety profile in patients with relapsed or refractory (R/R) diffuse large B‐cell lymphoma (DLBCL) in the global multicenter pivotal phase II trial EPCORE NHL‐1. Here, we present results from the similar EPCORE NHL‐3 phase I/II trial evaluating epcoritamab monotherapy in Japanese patients with R/R CD20+ B‐cell non‐Hodgkin's lymphoma previously treated with two or more lines of therapy. Epcoritamab was dosed subcutaneously in 28‐day cycles; once weekly during cycles 1–3, every 2 weeks during cycles 4–9, and every 4 weeks from cycle 10 until disease progression or unacceptable toxicity. Step‐up dosing and cytokine release syndrome (CRS) prophylaxis were used during treatment cycle 1. As of January 31, 2022, 36 patients received treatment with 48 mg epcoritamab monotherapy. At a median follow‐up of 8.4 months, overall response and complete response rates by independent review committee were 55.6% and 44.4%, respectively. The median duration of response, duration of complete response, and overall survival were not reached at the time of data cut‐off. The most common treatment‐emergent adverse events of any grade were CRS (83.3%), injection‐site reactions (69.4%), infections (44.4%), neutropenia (38.9%), hypokalemia (27.8%), and decreased lymphocyte count (25.0%). Cytokine release syndrome occurrence was predictable; events were primarily low grade (grade 1–2), all resolved, and none led to treatment discontinuation. These encouraging results are consistent with previous findings and support the ongoing clinical evaluation of epcoritamab for the treatment of R/R DLBCL, including in earlier treatment lines. [ABSTRACT FROM AUTHOR]

Resistance to rituximab B-cell depletion therapy is a clinically pertinent adverse sequela that can have significant implications for the treatment of immune-mediated glomerular diseases. The true incidence of rituximab resistance remains unknown; however, it is an increasingly recognized treatment complication. Resistance typically presents with suboptimal treatment response, rapid B-cell reconstitution, and a relapsing disease course. Although the diverse mechanisms resulting in rituximab resistance are ongoing topics of research, both primary and secondary mechanisms have been identified as key catalysts.The emergence of human antichimeric antibodies (HACAs) is a major cause of secondary resistance to rituximab therapy and typically appears following repeated drug exposure. Frequently, HACAs develop in the setting of underlying autoimmune disease and contribute to poor B-cell depletion, reduced rituximab therapeutic efficacy, and enhanced drug clearance.The clinical challenge of rituximab resistance necessitates heightened awareness among clinicians. Screening for HACAs should be considered in individuals with poor clinical response to rituximab, more rapid B-cell reconstitution, and relapsing disease. Detection of HACAs may guide treatment alterations, including addition of further immunosuppressive therapy and transitioning to a humanized B-cell depleting monoclonal antibody.

Anti-DNA antibodies are hallmark autoantibodies produced in systemic lupus erythematosus (SLE), but their pathogenetic role is not fully understood. Accumulating evidence suggests that some anti-DNA antibodies enter different types of live cells and affect the pathophysiology of SLE by stimulating or impairing these cells. Circulating neutrophils in SLE are activated by a type I interferon or other stimuli and are primed to release neutrophil extracellular traps (NETs) on additional stimulation. Anti-DNA antibodies are also involved in this process and may induce NET release. Thereafter, they bind and protect extracellular DNA in the NETs from digestion by nucleases, resulting in increased NET immunogenicity. This review discusses the pathogenetic role of anti-DNA antibodies in SLE, mainly focusing on recent progress in the two research fields concerning antibody penetration into live cells and NETosis. [ABSTRACT FROM AUTHOR]

Complement-dependent cytotoxicity (CDC), which eliminates aberrant target cells through the assembly and complex formation of serum complement molecules, is one of the major effector functions of anticancer therapeutic antibodies. In this study, we discovered that breaking the symmetry of natural immunoglobulin G (IgG) antibodies significantly increased the CDC activity of anti-CD20 antibodies. In addition, the expression of CD55 (a checkpoint inhibitor in the CDC cascade) was significantly increased in a rituximab-resistant cell line generated in-house, suggesting that CD55 overexpression might be a mechanism by which cancer cells acquire rituximab resistance. Based on these findings, we developed an asymmetric bispecific antibody (SBU-CD55 × CD20) that simultaneously targets both CD55 and CD20 to effectively eliminate rituximab-resistant cancer cells. In various cancer cell lines, including rituximab-resistant lymphoma cells, the SBU-CD55 × CD20 antibody showed significantly higher CDC activity than either anti-CD20 IgG antibody alone or a combination of anti-CD20 IgG antibody and anti-CD55 IgG antibody. Furthermore, the asymmetric bispecific antibody (SBU-CD55 × CD20) exhibited significantly higher CDC activity against rituximab-resistant cancer cells compared to other bispecific antibodies with symmetric features. These results demonstrate that enhancing CDC with an asymmetric CD55-binding bispecific antibody could be a new strategy for developing therapeutics to treat patients with relapsed or refractory cancers. [ABSTRACT FROM AUTHOR]

Background: PEGylated nanoparticles (PEG-NPs) are not effective for hematologic malignancies as they lack the enhanced permeability and retention effect (EPR effect). Tumor-targeted PEG-NPs can systemically track lymphoma and actively internalize into cancer cells to enhance therapeutic efficacy. We generated an anti-PEG bispecific antibody (BsAb; mPEG × CD20) which was able to simultaneously bind to methoxy PEG on liposomes and CD20 to form multivalent αCD20-armed liposomes. This αCD20-armed liposome was able to crosslink CD20 on lymphoma cells to enhance cellular internalization and the anti-cancer efficacy of the liposomes to lymphoma. We generated mPEG × CD20 and used this bispecific antibody to modify PEGylated liposomal doxorubicin (PLD) through a one-step formulation. Results: αCD20-armed PLD (αCD20/PLD) specifically targeted CD20+ Raji cells and enhanced PLD internalization 56-fold after 24 h. αCD20/PLD also increased cytotoxicity to Raji cells by 15.2-fold in comparison with PLD and control mPEG × DNS-modified PLD (αDNS/PLD). mPEG × CD20 significantly enhanced the tumor accumulation 2.8-fold in comparison with mPEG × DNS-conjugated PEGylated liposomal DiD in Raji tumors. Moreover, αCD20/PLD had significantly greater therapeutic efficacy as compared to αDNS/PLD (P < 0.0001) and PLD(P < 0.0001), and αCD20/PLD-treated mice had a 90% survival rate at 100-day post-treatment. Conclusions: Modification of mPEG × CD20 can confer PLD with CD20 specificity to enhance the internalization and the anti-cancer efficacy of PEG-NPs. This therapeutic strategy can conveniently be used to modify various PEG-NPs with anti-PEG BsAb to overcome the lack of EPR effect of hematologic malignancies and improve therapeutic efficacy. [ABSTRACT FROM AUTHOR]

The variability in disease outcome for indolent non-Hodgkin lymphomas (iNHL) and mantle-cell lymphoma (MCL) could be related to single nucleotide polymorphisms (SNPs) in genes that affect immune and inflammatory response. We investigated SNPs that could have a prognostic role for patients receiving bendamustine and rituximab (BR). All samples were genotyped for the IL-2 (rs2069762), IL-10 (rs1800890, rs10494879), VEGFA (rs3025039), IL-8 (rs4073), CFH (rs1065489) and MTHFR (rs1801131) SNPs by allelic discrimination assays using TaqMan SNP Genotyping Assays. We report a long-term follow-up analysis of 79 iNHL and MCL patients that received BR. Overall response rate was 97.5% (CR rate 70.9%). After a median follow-up of 63 months, median PFS and OS were not reached. We report a significant association between SNP in IL-2 (rs2069762) and reduced PFS and OS (p<.0001). We suggest a role for cytokine SNPs in disease outcome, while SNPs seem not related to long-term toxicity or secondary malignancies. [ABSTRACT FROM AUTHOR]

Background and Objective: Although tumor lysis syndrome was reported with obinutuzumab and rituximab, the association with CD20 monoclonal antibodies for chronic lymphocytic leukemia is unclear. Methods: A disproportionality analysis was conducted to investigate the link between CD20 monoclonal antibodies and tumor lysis syndrome by accounting for known confounders and comparing with other anticancer drugs, using data from the US Food and Drug Administration Adverse Event Reporting System. Reporting odds ratios and the information component were calculated as disproportionality measures. A stepwise sensitivity analysis was conducted to test the robustness of disproportionality signals. Bradford Hill criteria were adopted to globally assess the potential causal relationship. Results: From 2004 to 2022, 197, 368, 41, and 14 tumor lysis syndrome reports were detected for obinutuzumab, rituximab, ofatumumab, and alemtuzumab (CD52 monoclonal antibody), respectively. Disproportionality signals were found for the above four monoclonal antibodies when compared with other anticancer drugs. Sensitivity analyses confirmed robust disproportionality signals for obinutuzumab, rituximab, and ofatumumab. The median onset time was 4.5, 1.5, and 2.5 days for rituximab, obinutuzumab, and ofatumumab, respectively. A potential causal relationship was fulfilled by assessing Bradford Hill criteria. Conclusions: This pharmacovigilance study on the FDA Adverse Event Reporting System detected a plausible association between CD20 monoclonal antibodies (but not CD52) and tumor lysis syndrome by assessing the adapted Bradford Hill criteria. Urgent clarification of drug- and patient-related risk factors is needed through large comparative population-based studies. [ABSTRACT FROM AUTHOR]

Glofitamab is a CD3xCD20 bi‐specific antibody with two fragments directed to the CD20 antigen and a single CD3‐binding fragment. Encouraging response and survival rates were recently reported in a pivotal phase II expansion trial conducted in patients with relapsed/refractory (R/R) B‐cell lymphoma. However, the real‐world data of patients of all ages with no strict selection criteria are still lacking. Herein, this retrospective study aimed to evaluate the outcomes of diffuse large B‐cell lymphoma (DLBCL) patients who received glofitamab via compassionate use in Turkey. Forty‐three patients from 20 centers who received at least one dose of the treatment were included in this study. The median age was 54 years. The median number of previous therapies was 4, and 23 patients were refractory to first‐line treatment. Twenty patients had previously undergone autologous stem cell transplantation. The median follow‐up time was 5.7 months. In efficacy‐evaluable patients, 21% and 16% of them achieved complete response and partial response, respectively. The median response duration was 6.3 months. The median progression‐free survival (PFS) and overall survival (OS) was 3.3 and 8.8 months, respectively. None of the treatment‐responsive patients progressed during the study period, and their estimated 1‐year PFS and OS rate was 83%. The most frequently reported toxicity was hematological toxicity. Sixteen patients survived, while 27 died at the time of the analysis. The most common cause of death was disease progression. One patient died of cytokine release syndrome during the first cycle after receiving the first dose of glofitamab. Meanwhile, two patients died due to glofitamab‐related febrile neutropenia. This is the largest real‐world study on the effectiveness and toxicity of glofitamab treatment in R/R DLBCL patients. The median OS of 9 months seems promising in this heavily pretreated group. The toxicity related mortality rates were the primary concerns in this study. [ABSTRACT FROM AUTHOR]

To evaluate the anti-tumor activities of CD20/HLA-DR CrossmabCH1-CL through cell and animal models. Based on "knobs-into-holes" and "crossover" technology, CrossMab, targeting CD20 and HLA-DR, was constructed. A binding assay and a competitive inhibition assay were performed to confirm its specificity. The effects of CrossMab on antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity were measured. Cell apoptosis, lysosome-mediated cell death, and lysosomal permeability were quantified. In addition, the effects of CrossMab on peripheral blood leukocytes were tested. The pharmacokinetics were determined with a noncompartmental analysis model. Human malignant lymphoma xenograft models in CB17-SCID mice were established for an in-vivo efficacy study. The antitumor activities of CrossMab were shown both in vitro and in vivo. CrossMab exhibited strong binding to CD20 and HLA-DR at the same time in Raji cells. CrossMab also demonstrated antilymphoma effects by inducing antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Furthermore, CrossMab altered the lysosomal membrane permeability. The toxicity of CrossMab on normal peripheral blood lymphocytes (PBLs) was specific to B cells. A mouse xenograft model demonstrated the antitumor activities of CrossMab in vivo. CrossMab exhibited an enhanced antigen recognition ability and antitumor activities in lymphoma without evident toxicity. CrossMab could be an effective immunotherapeutic strategy for non-Hodgkin lymphoma. [ABSTRACT FROM AUTHOR]

Introduction: The prognostic significance of CD20 in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) remains unclear. Therefore, in this study, we evaluated the prognostic value of CD20 expression in leukemia blasts in pediatric BCP-ALL at our institute. Methods: Between 2005 and 2017, 796 children with newly diagnosed Philadelphia-negative BCP-ALL were enrolled consecutively; clinical characteristics and treatment outcomes were analyzed and compared between CD20-positive and CD20-negative groups. Results: CD20 positivity was observed in 22.7% of enrolled patients. The analysis of overall and event-free survival showed that white blood cell count ≥50 × 109/L, no ETV6-RUNX1, day 33 minimal residual disease (MRD) ≥0.1%, and week 12 MRD ≥0.01% were independent risk factors. Meanwhile, in the CD20-positive group, week 12 MRD ≥0.01% was the only factor associated with long-term survival. Moreover, subgroup analysis revealed that in patients with extramedullary involvement (p = 0.047), MRD ≥0.1% on day 33 (p = 0.032), or MRD ≥0.01% at week 12 (p = 0.004), CD20 expression led to a poorer outcome compared to those without CD20 expression. Conclusions: Pediatric BCP-ALL with CD20 expression had unique clinicopathological characteristics, and MRD remained the major prognostic factor. CD20 expression had no prognostic value in pediatric BCP-ALL. [ABSTRACT FROM AUTHOR]

Introduction: Rituximab (R), an anti-CD20 monoclonal antibody (mAb) and the world's first approved antibody for oncology patients, was combined with the CHOP chemotherapy regimen and markedly improved the prognosis of all B- cell--derived lymphomas, the most common hematological malignancy worldwide. However, there is a 35% disease recurrence with no advancement in the first-line treatment since R was combined with the archetypal CHOP chemotherapy regimen nearly 30 years ago. There is evidence that R synergizes with chemotherapy, but the pharmacological interactions between R and CHOP or between newer anti-CD20 mAbs and CHOP remain largely unexplored. Methods: We used in vitro models to score pharmacological interactions between R and CHOP across various lymphoma cell lines. We compared these pharmacological interactions to ofatumumab, a second-generation anti-CD20 mAb, and CHOP. Lastly, we used RNA-sequencing to characterize the transcriptional profiles induced by these two antibodies and potential molecular pathways that mediate their different effects. Results: We discovered vast heterogeneity in the pharmacological interactions between R and CHOP in a way not predicted by the current clinical classification. We then discovered that R and ofatumumab differentially synergize with the cytotoxic and cytostatic capabilities of CHOP in separate distinct subsets of B-cell lymphoma cell lines, thereby expanding favorable immunochemotherapy interactions across a greater range of cell lines beyond those induced by R-CHOP. Lastly, we discovered these two mAbs differentially modulate genes enriched in the JNK and p38 MAPK family, which regulates apoptosis and proliferation. Discussion: Our findings were completely unexpected because these mAbs were long considered to be biological and clinical equivalents but, in practice, may perform better than the other in a patient-specific manner. This finding may have immediate clinical significance because both immunochemotherapy combinations are already FDA-approved with no difference in toxicity across phase I, II, and III clinical trials. Therefore, this finding could inform a new precision medicine strategy to provide additional therapeutic benefit to patients with B-cell lymphoma using immunochemotherapy combinations that alreadymeet the clinical standard of care. [ABSTRACT FROM AUTHOR]