anti-CD20 Antibody Research Articles

Optimizing rWTC-MBTA Vaccine Formulations, Dosing Regimens, and Cryopreservation Techniques to Enhance Anti-Metastatic Immunotherapy

Metastatic cancer poses significant clinical challenges, necessitating effective immunotherapies with minimal systemic toxicity. Building on prior research demonstrating the rWTC-MBTA vaccine’s ability to inhibit tumor metastasis and growth, this study focuses on its clinical translation by optimizing vaccine composition, dosing regimens, and freezing techniques. The vaccine formula components included three TLR ligands (LTA, Poly I:C, and Resiquimod) and an anti-CD40 antibody, which were tested in melanoma and triple-negative breast cancer (TNBC) models. The formulations were categorized as rWTC-MBT (Mannan-BAM with LTA, Poly I:C, Resiquimod), rWTC-MBL (LTA), rWTC-MBP (Mannan-BAM with Poly I:C), and rWTC-MBR (Resiquimod). In the melanoma models, all the formulations exhibited efficacy that was comparable to that of the full vaccine, while in the “colder” TNBC models, the formulations with multiple TLR ligands or Resiquimod alone performed the best. Vaccine-induced activation of dendritic cell (DC) subsets, including conventional DCs (cDCs), myeloid DCs (mDCs), and plasmacytoid DCs (pDCs), was accompanied by significant CD80+CD86+ population induction, suggesting robust innate immune stimulation. An initial three-dose schedule followed by booster doses (3-1-1-1 or 3-3-3-3) reduced the metastatic burden effectively. Gradual freezing (DMSO-based preservation) maintained vaccine efficacy, underscoring the importance of intact cell structure. These findings highlight the potential of simplified formulations, optimized dosing, and freezing techniques in developing practical, scalable immunotherapies for metastatic cancers.

Echovirus serotype 11 induced sepsis in a young female patient with multiple sclerosis treated with anti-CD20 monoclonal antibody ocrelizumab.

Enterovirus infection has been described as a cause of severe viral sepsis in humorally immunosuppressed patients. A 20-year-old female with a history of multiple sclerosis on ocrelizumab therapy with persistent agammaglobulinemia and autoimmune hepatitis treated with azathioprine/budesonide presented with subacute sensorineural hearing loss, hepatitis, pneumonia, enterocolitis and pancreatitis. Molecular pathological techniques detected enterovirus RNA in samples from the liver, blood, ascites fluid, and pleural effusions, confirming Echovirus serotype 11. The case was managed successfully with supportive care and high-dose intravenous immunoglobulins in addition to fluoxetine. This patient's unique presentation and clinical course presents important implications for the care of immunosuppressed patients with cryptic complaints.

Two Are Better than One: The Bi-Specific Antibody Mosunetuzumab Reveals an Improved Immune Response of Vγ9Vδ2 T Cells Targeting CD20 in Malignant B Cells in Comparison to the Mono-Specific Antibody Obinutuzumab

In treating cancer, immunotherapy has been established as a later-line treatment option in clinical practice. That includes stem cell transplantation, modified or activated immune cells, and antibodies directed against aberrant cells. As an unconventional immune cell subgroup, γδ T cells have been shown to provide effects against malignant cells. They exhibit an MHC-independent activation process, which could diminish graft-versus-host disease after an adoptive transfer of allogeneic cells. Over the last years, the efficacy of therapeutic antibodies has been improved. As a bi-specific antibody, mosunetuzumab binds to both CD3 and CD20, thereby providing close proximity between effector and target cells. Here, we set out to analyze the efficiency of γδ T cells’ anti-tumor effects in combination with mosunetuzumab vs. the monoclonal anti-CD20 antibody obinutuzumab. Mosunetuzumab revealed improved responses of γδ T cells regarding their expression of IFN-γ and CD107a and their cytotoxicity towards malignant B cells from lymphoma B cell lines. In comparison to obinutuzumab, mosunetuzumab led to an equivalent or enhanced cytotoxicity against B cell lymphoma cell lines and primary patient samples, where this effect was even more prominent. In summary, we consider the combination of stimulated γδ T cells and mosunetuzumab to be a promising therapeutic approach for future clinical trials.

Case report: Single infusion of combined anti-CD20 and anti-CD38 monoclonal antibodies in pediatric refractory lupus nephritis

Lupus nephritis (LN), present in 30%–50% of systemic lupus erythematosus (SLE) patients, often necessitates standard immunosuppressive therapy (glucocorticoids, MMF, CYC) as suggested by the European League Against Rheumatism/European Renal Association–European Dialysis and Transplant Association (EULAR/ERA-EDTA) and Kidney Disease Improving Global Outcomes (KDIGO) guidelines. However, a subset of subjects remains refractory. Recent findings suggested the efficacy of targeting CD38-long-lived plasma cells in LN and SLE refractory to standard treatment. However, previous experiences were limited to adult patients and described different therapeutical schemes based on daratumumab, with the addition or absence of belimumab. Moreover, the minimal effective dose of daratumumab has yet to be fully defined. In this report, we describe two cases of juvenile-onset refractory LN/SLE successfully managed with a combination of a single infusion of rituximab (targeting CD20 on B cells) and daratumumab (targeting CD38 on long-lived plasma cells), unlike prior regimens requiring prolonged daratumumab infusions. Our approach was safe and effective and may potentially reduce adverse effects and costs, providing a novel therapeutic option for juvenile refractory LN.

Frontline treatment of follicular lymphoma: What will it take to change current practice?

Follicular lymphoma is the most common subtype of indolent lymphoma. Despite multiple trials over the past decade showing improved progression-free survival with new first-line therapeutic strategies -such as anti-CD20 maintenance therapy and new glycoengineered anti-CD20 antibodies- no standardized approach has been widely adopted in routine clinical practice. Several factors may explain this, including the increased incidence of infectious adverse events associated with these therapies, particularly during the COVID-19 pandemic, and the lack of overall survival benefit despite long-term follow-up. A general consensus has emerged acknowledging the high prognostic variability of follicular lymphoma, which complicates the adoption of a one-size-fits-all first-line treatment strategy. A plethora of prognostic scores (FLIPI, FLIPI2, PRIMA-PI, m7-FLIPI, FLEX, 23-gene score, etc) has been proposed but none can reliably identify the ~20% of patients that will die within 10 years of first-line immunochemotherpay and for whom a critical medical need remains despite recent therapeutic improvements. Consequently, current prognostic models mainly serve as tools to cross-compare and stratify clinical trials. In this review, we highlight current and future strategies aimed at reshaping frontline treatment paradigms to improve outcomes, including tailored approaches based on risk- or response-adapted designs, development of new predictive -rather than prognostic- tools, approaches to reduce adverse events to enhance health-related quality of life, and the potential use of T-cell-engaging therapies to improve survival in the highest risk patients.

Ultrasensitive Detection of Circulating Plasma Cells Using Surface-Enhanced Raman Spectroscopy and Machine Learning for Multiple Myeloma Monitoring.

Multiple myeloma is a hematologic malignancy characterized by the proliferation of abnormal plasma cells in the bone marrow. Despite therapeutic advancements, there remains a critical need for reliable, noninvasive methods to monitor multiple myeloma. Circulating plasma cells (CPCs) in peripheral blood are robust and independent prognostic markers, but their detection is challenging due to their low abundance. Next-generation flow cytometry is commonly used for CPC detection but is not performed in routine clinical practice because it requires expensive instruments, is costly, and time-consuming. This study introduces a cost-effective, rapid surface-enhanced Raman spectroscopy (SERS) assay leveraging gold-deposited magnetic nanoparticles and plasmonic nanoparticles functionalized with anti-CD138 and anti-CD38 antibodies for detecting CPCs in peripheral blood samples. A portable optical device was used for signal recording, enhancing the potential for point-of-care applications. The developed assay is highly sensitive and specific, capable of detecting as few as one or two cells. The application of machine learning algorithms to SERS signal analysis yielded area under the curve values ranging from 0.90 to 0.95, demonstrating excellent performance in differentiating multiple myeloma patients from healthy donors. This SERS method provides a sensitive and accessible way for CPC detection, showing significant potential for multiple myeloma diagnosis, treatment monitoring, and prognosis prediction.

Impact of Thrombopoietin Receptor Agonists on Pathophysiology of Pediatric Immune Thrombocytopenia.

Immune thrombocytopenia (ITP) in pediatric patients is a common cause of isolated thrombocytopenia. Various pathophysiological mechanisms are implicated in ITP pathogenesis, including the production of autoantibodies against components of platelets (PLTs) by B-cells, the activation of the complement system, phagocytosis by macrophages mediated by Fcγ receptors, the dysregulation of T cells, and reduced bone marrow megakaryopoiesis. ITP is commonly manifested with skin and mucosal bleeding, and it is a diagnosis of exclusion. In some ITP cases, the disease is self-limiting, and treatment is not required, but chronic-persistent disease can also be developed. In these cases, anti-CD20 monoclonal antibodies, such as rituximab and thrombopoietin (TPO) receptor agonists, can be used. TPO agonists have become standard of care today. It has been reported in the published literature that the efficacy of TPO-RAs can be up to 80% in the achievement of several end goals, such as PLT counts. In the current literature review, the data regarding the impact of TPO agonists in the pathogenesis of ITP and treatment outcomes of the patients are examined. In the era of precision medicine, targeted and individualized therapies are crucial to achieving better outcomes for pediatric patients with ITP, especially when chronic refractory disease is developed.

B cells recruitment promotes M2 macrophage polarization to inhibit inflammation during wound healing.

Wound healing causes heavy economic burdens for families and society, becoming a critical issue in the global healthcare system. While the role of immune cells in the wound healing process is well-established, the involvement of B cells remains poorly understood. This study aims to elucidate the essentiality of B cells in wound repair. Our findings demonstrate a rise in B cell population during the early stage of wound healing, which further intensifies during the later stage. We employed anti-CD20 antibodies to deplete B cells in mice and created a whole skin excisional wound mice model, analyzing wound closure over 12 days. B cells were isolated from the animals' spleen and co-cultured with macrophages from bone marrow. The polarization of M1 and M2 macrophages was analyzed by real-time qPCR and flow cytometry. The wound healing process in mice was observed to be considerably delayed following the elimination of B cells. The wounds exhibited a state of inflammation primarily characterized by the presence of pro-inflammatory M1 macrophages. The decrease in M2 macrophages within the local wound area resulted in impairment of the wound repair mechanism. B cell-macrophage co-culture system revealed that B cells effectively induce the polarization of macrophages towards M2-like phenotype. Furthermore, we found that follicular B cells play predominant role in modulating the polarization of M2 macrophages. Consequently, our findings indicate that B cells can be recruited to the wound site and facilitate the polarization of M2-like macrophages, thereby accelerating the healing process during wound healing.

Comparison of the effectiveness of RB and R-CHOP regimens in first-line therapy in 277 patients with grade 1–2 follicular lymphoma: a retrospective single-center analysis

Background. Chemoimmunotherapy, including cytotoxic drugs and anti-CD20 monoclonal antibodies have significantly improved outcomes in patients with newly diagnosed follicular lymphoma (FL) compared with chemotherapy. A number of clinical studies have compared the effectiveness of the two most popular treatment regimens, rituximab plus bendamustine (RB) and rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP), with conflicting results.Aim. To conduct a retrospective analysis of the treatment results of a large cohort of patients with grade 1–2 FL who received RB or R-CHOP regimens in the first line therapy in real-life clinical practice, to analyze the impact of individual prognostic factors, as well as rituximab maintenance therapy on survival, the incidence of secondary malignancies and causes of mortality.Materials and methods. Data were collected on patients with grade 1–2 FL who were treated at the Botkin Hospital from November 2006 to November 2022. The inclusion criteria for the study were newly diagnosed histologically confirmed FL of grade 1–2, age ≥18 years, RB or R-CHOP therapy as first line. No radiation therapy was allowed. Response assessment was performed according to the 2007 International Working Group criteria.Results. The inclusion criteria for the study were met by 277 patients; 164 patients received R-CHOP and 113 patients received RB. Overall response rate was comparable between groups (96 % vs 94 % in the RB and R-CHOP groups, respectively, p = 0.3396). The median followup period was 35 (3–117) months in the RB group and 50 (3–200) months in R-CHOP group. The median progression-free survival (PFS) in the R-CHOP group was 86 months, while the median of PFS in the RB group was not reached, the differences did not reach statistical significance (hazard ratio (HR) 0.65; 95 % confidential interval (CI) 0.42–1.004; p = 0.0665). Three-year PFS was 81 and 72 %, and five-year PFS was 66 and 57 % in the RB and R-CHOP groups, respectively. Progression within 24 months of initiation of therapy was more common in R-CHOP group (20 % vs 11 %, p = 0.0466). The median time to next therapy in R-CHOP group was 90 months and was not reached in RB group (HR 0.75; 95 % CI 0.48–1.18; p = 0.2277). Unifactor analysis of individual prognostic factors showed superior PFS in most subgroups receiving RB regimen. R-CHOP regimen showed a trend towards improved PFS only in patients with maximum standardized uptake value (SUVmax) >14 (HR 2.46; 95 % CI 0.52–11.62; p = 0.2211). The use of rituximab maintenance therapy improved PFS in both treatment groups: in R-CHOP group, the differences reached the level of significance (HR 0.22; 95 % CI 0.05–1.01; p<0.0001) , in RB group they did not reach the level of significance (HR 0.41; 95 % CI 0.02–8.67; p = 0.3605). There were no significant differences in overall survival. The 5-year cumulative incidence of secondary malignancies as well as the incidence of grade 5 infections were comparable between groups.Conclusion. In summary, our study shows that RB regimen generally has comparable long-term efficacy to R-CHOP regimen in first-line therapy in patients with grade 1–2 FL. Unifactor analysis of individual prognostic factors showed better PFS in most subgroups using the RB regimen. The use of rituximab maintenance therapy significantly improved PFS in R-CHOP group compared with RB regimen. Our study with a significant median follow-up did not find differences in the incidence of secondary malignancies or non-lymphoma related mortality.

Effectiveness of Ocrelizumab on Disease Progression and Disability Status in Multiple Sclerosis Patients: A Two-Year Prospective Cohort Study.

Background and Objectives: Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by inflammation and neurodegeneration. Ocrelizumab, a humanized anti-CD20 monoclonal antibody, has shown promise in reducing disease activity in MS patients. This prospective study aims to assess the effectiveness of ocrelizumab in reducing confirmed disability progression in patients with relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS) over a two-year period. By evaluating clinical data, and MRI findings, this study seeks to provide comprehensive insights into ocrelizumab's impact on disease dynamics and disability. Materials and Methods: Ninety-eight patients aged 18 to 65 with confirmed MS were enrolled under ocrelizumab therapy at the Neurology Department of "Pius Brinzeu" Clinical Emergency Hospital in Romania between July 2020 and July 2024. Participants were assessed at baseline and every six months over two years. The key outcomes measured were changes in the Expanded Disability Status Scale (EDSS) as a measure of confirmed disability progression (CDP), annualized relapse rate (ARR), and MRI findings. Results: Over the two-year period, the mean EDSS score significantly decreased from 5.2 ± 1.8 to 4.6 ± 1.7 (mean change = -0.6 ± 0.9; p = 0.032), indicating improved neurological function. The proportion of patients experiencing relapses dropped markedly from 61.2% to 14.3% (p < 0.001). The MRI results showed significant reductions in patients with new or enlarging T2 lesions from 68.4% to 27.6% (p < 0.001) and gadolinium-enhancing lesions from 44.9% to 15.3% (p < 0.001). Patients previously treated with natalizumab exhibited a greater reduction in EDSS scores (-1.0 ± 0.8; p = 0.001) compared to other treatments. Multivariate regression identified the baseline EDSS score (β = 0.65; p < 0.001), previous natalizumab use (β = -0.30; p = 0.013), and age at diagnosis (β = 0.02; p = 0.048) as significant predictors of two-year EDSS scores. While markers of active inflammation decreased, the proportion of patients with brain atrophy increased from 31.6% to 43.9% (not statistically significant; p = 0.105). SPMS patients had higher rates of brain atrophy at baseline (61.1% vs. 25.0%; p = 0.007) and at two years (100.0% vs. 31.3%; p < 0.001) compared to RRMS patients. Conclusions: Ocrelizumab effectively reduced disease activity and improved neurological disability over two years in both RRMS and SPMS patients. Significant reductions in relapse rates and MRI markers of inflammation were observed. Previous natalizumab treatment was associated with greater improvements. Despite these benefits, the progression of neurodegeneration, particularly brain atrophy in SPMS patients, underscores the need for additional strategies targeting neurodegenerative aspects of MS.

Is There a Role for Daratumumab Retreatment in Patients with Relapsed/Refractory Multiple Myeloma?

Multiple myeloma (MM) is a hematologic disease characterized by the clonal expansion of malignant plasma cells that accumulate in the bone marrow, leading to osteolytic bone disease, hypercalcemia, anemia, and renal dysfunction. Daratumumab was the first monoclonal anti-CD38 antibody approved for the treatment of MM, initially in relapse/refractory settings and, more recently, for newly diagnosed patients. Increased first-line usage of daratumumab will also substantially change treatment approaches for patients with relapsed/refractory disease. Due to the cost and availability of bispecific T cell redirecting antibodies (BsAbs) and chimeric antigen receptor T cell therapy (CAR-T) in real-life settings in many countries, retreatment with daratumumab in subsequent lines of therapy might be a reasonable choice. Data regarding efficacy and optimal combinations of daratumumab retreatment are lacking, and here we provide a short literature review of available data. We identified only a small number of articles based on retrospective analysis of medical records in real-life settings. A strong consistency in results regarding response rates and treatment duration was noticed among mainly heavily pre-treated MM patients, with approximately half of patients achieving at least partial remission (PR) after retreatment with daratumumab-based protocol. The duration of treatment and time to the next treatment for retreatment episodes were considerable and consistent with clinical expectations for later lines of therapy. The analysis of data in this literature review indicates that daratumumab retreatment may provide meaningful clinical benefit to some patients with relapsed/refractory MM despite having prior exposure. However, further research is needed to identify clinical and biological parameters that may predict favorable responses to daratumumab retreatment.

Inferior Outcomes of Fludarabine-Cyclophosphamide-Rituximab Chemotherapy in Korean Chronic Lymphocytic Leukemia Patients with Concurrent Thrombocytopenia and Anemia.

Background/Objectives: Anti-CD20 monoclonal antibodies combined with alkylator-based chemotherapy enhance survival in chronic lymphocytic leukemia (CLL). However, the risks of infection and bone marrow suppression may mean that new, targeted therapies are more appropriate for some patients than fludarabine-cyclophosphamide-rituximab (FCR). In the Republic of Korea, where insurance limits coverage to novel agents, FCR therapy should be carefully considered for patients with CLL. Methods: Using clinical data from 144 FCR-treated patients with CLL, we retrospectively analyzed clinical characteristics impacting survival outcomes, the impact of cytopenia after FCR, and the durable remission status in terms of measurable residual disease (MRD). We compared the impact of bicytopenia with those of other hematologic conditions. Results: The 5-year overall survival (OS) and 5-year progression-free survival (PFS) for all patients were 84.4% and 68.3%, respectively. FCR-treated patients in the bicytopenia and TP53-positive groups exhibited poor OS and PFS; in particular, the bicytopenia group often experienced prolonged anemia and thrombocytopenia (6-12 months). The responder group achieved sustained remission for a median of 5 years for MRD negativity. Conclusions: In bicytopenia, FCR can induce prolonged cytopenia, making it difficult to switch to second-line therapy or complete cycles of chemoimmunotherapy, directly affecting poor survival outcomes. The cautious application of FCR therapy in CLL without bicytopenia or TP53 positivity can achieve long-term remission.

Generation of antagonistic biparatopic anti-CD30 antibody from an agonistic antibody by precise epitope determination and utilization of structural characteristics of CD30 molecule

Abstract Background CD30 is a member of the tumor necrosis factor receptor superfamily. Recently, blocking CD30-dependent intracellular signaling has emerged as potential strategy for immunological regulation. Development of antibody-based CD30 antagonists is therefore of significant interest. However, a key challenge is that the bivalent form of natural antibody can crosslink CD30 molecules, leading to signal transduction even in the absence of specific ligand, CD153. Biparatopic antibodies (BpAbs) offer a solution, using two different variable fragments (Fvs) to bind distinct epitopes on a single antigen molecule. BpAbs format is an attractive alternative of natural antibody by potentially avoiding unwanted crosslinking and signaling induction. Methods We systematically characterized 36 BpAbs, each designed with pairs of Fvs binding to nine distinct epitopes across the CD30 extracellular domain. We first identified the precise epitope sites of the nine antibodies by assessing the binding to multiple orthologous CD30 proteins and mutants. We then produced the 36 BpAbs and analyzed their biological activities and binding modes. Results Among 36 BpAbs, we identified both potent ligand-independent agonists and ligand-blocking antagonists, with many displayed reduced signal activation, including 1:1-binding antagonists derived from AC10, a strong agonist developed for lymphoma therapy. Epitope dependency in reduced signaling activity was observed and associated with the flexible nature of CD30 protein. Conclusions We successfully developed antagonistic BpAbs against CD30 by controlling the stoichiometry of antibody–antigen binding mode. This study elucidated the mechanism of signaling induction, informing the design strategies of the development of biparatopic antibodies. Statement of Significance Thirty-six bivalent biparatopic antibodies targeting pairs of nine distinct topographical epitopes distributed over CD30 were developed. These BpAbs exhibited a range of signaling activities from agonism to antagonism, with many displaying reduced signal activation. Notably, 1:1-binding antagonists were developed with no signal induction. The mechanism was elucidated by epitope information.

Genetically engineered pig heart transplantation in non-human primates

BackgroundImprovement in gene modifications of donor pigs has led to the prevention of early cardiac xenograft rejection and significantly prolonged cardiac xenograft survival in both heterotopic and orthotopic preclinical non-human primate (NHP) models. This progress formed the basis for FDA approval for compassionate use transplants in two patients.MethodsBased on our earlier report of 9-month survival of seven gene-edited (7-GE) hearts transplanted (life-supporting orthotopic) in baboons, we transplanted 10 gene-edited pig hearts into baboons (n = 4) using non-ischemic continuous perfusion preservation (NICP) and immunosuppression regimen based on co-stimulation blockade by anti-CD40 monoclonal antibody. This pivotal study expands on the 7-GE backbone, with 3 additional gene edits, using 10-GE pigs as donors to baboon recipients.Results10 GE cardiac xenografts provide life-supporting function up to 225 days (mean 128 ± 36 days) in a non-human primate model. Undetectable or latent porcine cytomegalovirus (PCMV) does not influence cardiac xenograft survival in this study but still needs more exploration with a larger cohort. Xenograft histology demonstrates adipose (Fat) deposition (n = 1), chronic vasculopathy (n = 1), micro and macro thrombosis, and acute cellular rejection (n = 1).ConclusionsThese data demonstrate that 10 GE cardiac xenografts have variable cardiac xenograft survival in NHP due to perhaps presence of 4th antigen and require further study. However, these 10GE organs may be suitable for clinical cardiac xenotransplantation and have already been utilized in two human cases.

Clinical and analytical monitoring of patients with multiple sclerosis on anti-CD20 therapeutics: a real-world safety profile study.

Anti-CD20 monoclonal antibodies are a class of immunosuppressive drugs widely used in the treatment of central nervous system (CNS) inflammatory diseases, with well-established efficacy and safety. Although rare, these therapies can be associated with serious adverse events including hematological and infectious complications. This study aims to evaluate their safety and tolerability profile in real-world clinical practice. We conducted a retrospective cohort study comprising patients diagnosed with multiple sclerosis (MS) treated with anti-CD20 drugs since 2016 followed in the Demyelinating Diseases clinic of a tertiary center. Clinical and paraclinical parameters were evaluated, including complete blood count and immunoglobulins measurements. A total of 160 with multiple sclerosis (pwMS) were included in our study, of whom 110 (68.8%) were female and 147 are currently receiving anti-CD20 therapies. Half of the patients were diagnosed with relapsing-remitting MS, while the remaining had progressive forms, including 23 with primary-progressive MS and 57 with secondary-progressive MS. Eighty-three patients were on ocrelizumab, 48 on rituximab, and 29 on ofatumumab. The mean follow-up duration from the start of anti-CD20 therapy was 30.5 ± 21.3 months. During this period, serious adverse events were observed in 9 patients, including SARS-CoV-2 infection (resulting in one death), urinary tract infection, febrile neutropenia, severe diarrhea, and acute hepatitis. The rate of serious infections in the ocrelizumab subgroup was consistent with the literature, although a higher rate was observed in the rituximab subgroup. A positive correlation was found between serious infectious complications and lower IgG levels. Additionally, longer exposure to anti-CD20 therapy in our cohort was associated with an increased risk of IgG deficiency and a higher incidence of serious infections. Lymphopenia was detected in 25 patients, though it was not directly linked to the occurrence of serious infections. Our work confirms the tolerability and safety of anti-CD20 drugs in a real-world clinical practice MS cohort, despite their frequent association with analytical changes such as lymphopenia and hypogammaglobulinemia. To better understand the clinical significance of hypogammaglobulinemia secondary to anti-CD20 treatment and to develop strategies for mitigating the associated potential infection risk, future studies with larger populations are essential.

Switching from natalizumab to antiCD20 monoclonal antibodies: Short transition interval is associated with improved outcome.

To investigate the impact of transition interval length when switching from natalizumab (NTZ) to anti-CD20 monoclonal antibodies (antiCD20) on recurrent disease activity and safety in relapsing multiple sclerosis (RMS). Aggregating data from 8 MS centres in Austria, Switzerland, and Germany, we included RMS patients who (i) continuously received NTZ for ≥3 months, (ii) were switched to antiCD20, and (iii) had ≥12 months follow-up after switch. The primary endpoint was occurrence of relapse after switch, secondary endpoints included severe infections (CTCAE grade ≥3). Overall, 139 RMS patients were included (70.5% females, mean age at switch 38.8 years [SD 9.7], mean disease duration at switch 11.3 years [SD 6.2], median duration on NTZ 4.4 years [range: 0.3-16.4], median transition interval 58 days [0-180]). Relapse occurred in 18 patients (12.9%) after NTZ discontinuation. Of those, 11 (61.1%) patients relapsed during the transition interval. No patient with a transition interval below 30 days experienced a relapse, compared to 11.1% and 16.1% with transition intervals of 30-44 days and ≥ 45 days, respectively. In multivariable Cox regression, a transition interval ≥ 45 days predicted a 4.73-fold increased risk of relapse. Over approximately 4 years of follow-up, six severe infections were reported without any noticeable effect of transition interval length. No PML occurred. Switching from NTZ to antiCD20 is generally both effective and safe. Keeping the transition interval below 30 days provides the optimal balance between preventing recurrent disease activity and ensuring safety.

Neoadjuvant intratumoral MBT(A) immunotherapy prevents distant metastases and recurrence in murine models.

Neoadjuvant immunotherapy represents a pioneering approach in the preoperative treatment of cancer, providing new strategies for tumor reduction and improved patient outcomes by modulating the immune response. This study investigated neoadjuvant immunotherapy using intratumoral administration of mannan-BAM, Toll-like receptor ligands, and anti-CD40 antibody (MBTA therapy) followed by surgery in murine models of MTT pheochromocytoma, B16-F10 melanoma, and 4T1 and E0771.lmb mammary carcinomas. In the MTT pheochromocytoma model, it was found that neoadjuvant MBTA therapy followed by surgery could prevent the development of distant metastases in 100% of treated animals, compared to a 60% mortality rate in the control group due to metastatic disease after surgery. These outcomes were achieved even in tumors three times larger than those in the control group. In the aggressive 4T1 model, neoadjuvant MBTA therapy resulted in slower tumor progression and a significant prolongation of survival. In the B16-F10 and E0771.lmb models, neoadjuvant MBTA therapy also protected animals from metastases development and tumor recurrence upon rechallenge with tumor cells after surgery. Transcriptomic analysis revealed enhanced effector immune cell infiltration, cytotoxicity, and antigen presentation in retransplanted tumors from MBTA-treated mice, indicating robust immune memory. Notably, the exclusion of the anti-CD40 antibody from the neoadjuvant MBTA therapy (MBT therapy) yielded comparable outcomes in protection against metastases development. These findings advocate for further investigation of intratumoral neoadjuvant MBTA therapy for immunologically "cold" tumors, including those at high risk of metastases or recurrence.

Daratumumab-associated varicella-zoster virus meningoencephalitis in relapsed refractory multiple myeloma

Daratumumab is a widely-used monoclonal anti-CD38 antibody both in newly-diagnosed and relapsed refractory multiple myeloma. CD38 is expressed on the surface of NK, regulatory B, and T cells. Therefore, patients receiving the drug are prone to decreased immunity, especially against herpes virus infections. Varicella-zoster virus is one of the herpesviruses, and reinfection typically occurs in immunocompromised individuals, including multiple myeloma patients, by reactivation of endogenous latent infection within the sensory ganglia. This type of infection (herpes zoster) usually presents in a dermatomal skin area. Here, we report a patient who developed varicella-zoster virus meningoencephalitis under daratumumab treatment.

Investigation of CD47 Expression in Renal Cell Tumors and Evaluation of Its Relationship with Prognostic Parameters.

Background/Objectives: Renal cell carcinoma is an aggressive form of kidney cancer, contributing to an estimated 138,000 deaths globally in 2017. Traditional treatments like chemotherapy and radiation are generally considered ineffective. Additionally, CD47 has been identified as a crucial tumor antigen involved in the development and progression of various cancers, including renal cell carcinoma. The interaction of CD47 with SIRPα triggers a "don't eat me" signal to the macrophages, inhibiting phagocytosis. Much progress has been made in targeting CD47 for cancer immunotherapy in solid tumors (STs) and hematological malignancies. This study aimed to evaluate CD47 expression in malignant and benign renal cell tumors and compare it with prognostic histopathological parameters. Methods: We included 160 malignant and 26 benign tumors. The malignant tumors consisted of renal cell carcinoma (RCC) subtypes including 37 clear cell, 30 chromophobe, 30 papillary type 1, 29 papillary type 2, and 34 unclassified RCC cases. As for the benign tumors, we included 26 oncocytoma cases. All samples were stained with anti-CD47 antibodies by immunohistochemistry methods. Results: The statistical analysis yielded a significant correlation between CD47 expression and survival, metastasis, and capsule invasion for the unclassified RCC cases. We did not find any further significant correlation between CD47 expression and the studied parameters. Conclusions: To the best of our knowledge, our study is the first to research CD47 expression in benign and malignant renal carcinoma subtypes. Further large-scale studies are needed to determine the expression profile of CD47 in renal cell tumors.

Microglia membrane-mediated trans-blood-brain barrier prodrug micelles enhance phagocytosis for glioblastoma chemo-immunotherapy.

Glioblastoma-associated macrophages & microglia (GAMs) are critical immune cells within the glioblastoma (GBM) microenvironment. Their phagocytosis of GBM cells is crucial for initiating both innate and adaptive immune responses. GBM cells evade this immune attack by upregulating the anti-phagocytic molecule CD47 on their surface. Although CD47 knockdown has shown promise in reducing tumor volume and increasing survival in GBM models, the efficacy of anti-CD47 antibodies remains limited clinically, partly due to the blood-brain tumor barrier (BBTB) and the insufficient pro-phagocytosis efficacy of CD47 blockade alone. Here, we introduce CSSOssMIT@MM-PEP20, a PEP20-linked microglia membrane (MM) camouflaged CSSOssMIT prodrug micelle. The MM targets vascular cell adhesion molecule-1 on the BBTB and enhances the penetration of CSSOssMIT@MM-PEP20 into the GBM tissue. CSSOssMIT@MM-PEP20 disassembles into MM-PEP20 and CSSOssMIT through the proton sponge effect in the acidic microenvironment. MM-PEP20 blocks the CD47-SIRPα axis, disabling the 'don't eat me' signal, while CSSOssMIT releases MIT within tumor cells to promote immunogenic cell death and amplify the 'eat me' signal. In an orthotopic GBM mouse model, CSSOssMIT@MM-PEP20 increased GAMs-mediated phagocytosis of GBM cells by 5.01-fold and enhanced CD8+ T cell infiltration by 8.63-fold, demonstrating significant GBM inhibition. Overall, this study presents a noninvasive strategy to traverse the BBTB and modulate GAMs phagocytosis, thereby facilitating effective anti-GBM chemo-immunotherapy.