anti-CD20 Antibody Research Articles

Severe Neutropenia Following Rituximab Treatment in Patients with Multiple Sclerosis

Increasing evidence suggests that B cells play a critical role in the pathogenesis of multiple sclerosis (MS). Rituximab (RTX), a monoclonal anti-CD20 antibody, effectively decreases inflammatory disease processes in patients with MS by specifically removing B cells. Neutropenia is an uncommon side effect of CD20-depleting treatment and may require the administration of granulocyte-colony stimulating factors. We report the case of a patient with MS who experienced severe neutropenia during RTX treatment.

NSGO-OV-UMB1/ENGOT-OV30: A phase II study of durvalumab in combination with the anti-CD73 monoclonal antibody Oleclumab in patients with relapsed ovarian cancer

ObjectivesIn patients with epithelial ovarian cancer (EOC), the clinical efficacy of monotherapy with immune checkpoint inhibitors (ICIs) against PD-1/PD-L1 is modest. To enhance response rates to these immunotherapeutic agents and broaden the indications for their use, new approaches involving combinational therapy are needed. The immune regulator CD73 is a potential target, as it promotes tumor escape by producing immunosuppressive extracellular adenosine in the tumor microenvironment. Here, we present the results from the NSGO-OV-UMB1/ENGOT-OV-30 trial evaluating the activity of combining the anti-CD73 antibody oleclumab with the anti-PD-L1 checkpoint inhibitor durvalumab in patients with recurrent EOC. MethodsIn this phase II open-label non-randomized study, patients with CD73-positive relapsed EOC were intravenously administered oleclumab (3000 mg, Q2W) and durvalumab (1500 mg, Q4W). The primary endpoint was disease control rate (DCR) at 16 weeks. The expression of PD-L1 and CD8 was assessed by immunohistochemistry of archival tumors. ResultsThis trial included 25 patients with a median age of 66 years (47–77 years). Twenty-two patients were evaluable for treatment activity analysis. The DCR was 27%, the median progression-free survival was 2.7 months (95% CI: 2.2–4.2) and the median overall survival was 8.4 months (95% CI: 5.0–13.4). Infiltration of CD8+ cells and PD-L1 expression on tumor cells were observed in partially overlapping sets of 74% of the tumor samples. Neither CD8- nor PD-L1-positivity were significantly associated with better DCR. ConclusionsCombined treatment with oleclumab and durvalumab was safe and demonstrated limited anti-tumor activity in patients with recurrent EOC.

The role of autologous stem-cell transplantation in classical Hodgkin lymphoma in the modern era

Despite excellent cure rates with modern front-line regimens, up to 20% of patients with Hodgkin lymphoma will progress through front-line therapy or experience disease relapse. Worldwide, salvage chemotherapy followed by high-dose chemotherapy with autologous stem cell transplantation (HDT/ASCT) is considered the standard of care for these patients and can cure approximately 50% of relapsed or refractory (R/R) patients in the second line. Brentuximab vedotin (BV), an anti-CD30 antibody drug conjugate, and PD1 inhibitors like nivolumab and pembrolizumab, have high response rates in patients who recur after HDT/ASCT. When used prior to HDT/ASCT, BV and PD1 inhibitors appear to dramatically increase the effectiveness of salvage therapies with complete response rates often double those seen with historic chemotherapy-based regimens and durable progression free survival (PFS) post-HDT/ASCT. Emerging data in adults and from pediatric trials showing a durable PFS in a subset of relapsed patients raises the question of whether HDT/ASCT is essential for cure in R/R patients after PD1 based salvage. Future studies will help clarify if ASCT can omitted PD1 based salvage to avoid the potential toxicity of HDT/ASCT without compromising cure.

Blockade of the CD47/SIRPα checkpoint axis potentiates the macrophage-mediated anti-tumor efficacy of tafasitamab.

Macrophages are one of the key mediators of the therapeutic effects exerted by monoclonal antibodies, such as the anti-CD19 antibody tafasitamab, approved in combination with lenalidomide for the treatment of relapsed or refractory (r/r) diffuse large B cell lymphoma (DLBCL). However, antibody-dependent cellular phagocytosis (ADCP) in the tumor microenvironment can be counteracted by increased expression of the inhibitory receptor SIRPα on macrophages and its ligand, the immune checkpoint molecule CD47 on tumor cells. The aim of this study was to investigate the impact of the CD47-SIRPα axis on tafasitamabmediated phagocytosis and explore the potential of anti-CD47 blockade to enhance its antitumor activity. Elevated expression of both SIRPα and CD47 was observed in DLBCL patient-derived lymph node biopsies compared to healthy controls. CRISPR-mediated CD47 overexpression impacted tafasitamab-mediated ADCP in vitro and increased expression of SIRPα on macrophages correlated with decreased ADCP activity of tafasitamab against DLBCL cell lines. Combination of tafasitamab and an anti-CD47 blocking antibody enhanced ADCP activity of in vitro generated macrophages. Importantly, tafasitamab-mediated phagocytosis was elevated in combination with CD47 blockade using primary DLBCL cells and patient-derived lymphoma-associated macrophages (LAMs) in an autologous setting. Furthermore, lymphoma cells with low CD19 expression were efficiently eliminated by the combination treatment. Finally, combined treatment of tafasitamab and an anti-CD47 antibody resulted in enhanced tumor volume reduction and survival benefit in lymphoma xenograft mouse models. These findings provide evidence that CD47 blockade can enhance the phagocytic potential of tumor targeting immunotherapies such as tafasitamab and suggest there is value in exploring the combination in the clinic.

Rituximab as a Therapeutic Strategy in Hemophagocytic Lymphohistiocytosis: Efficacy, Outcomes, and Survival-Insights From a Systematic Review.

Hemophagocytic lymphohistiocytosis (HLH) is a severe immunologic disorder that can be fatal if left untreated. The condition is characterized by excessive immune system activation and is often triggered by infections such as Epstein-Barr virus (EBV). Rituximab, an anti-CD20 monoclonal antibody, has been suggested as a treatment, particularly for EBV-associated HLH. A systematic review was conducted using PRISMA guidelines, with a literature search spanning PubMed, Scopus, Web of Science, and the Cochrane Library. The inclusion criteria focused on studies that assessed rituximab's efficacy in treating HLH. Quality assessment was performed using the Joanna Briggs Institute Critical Appraisal Checklist for Case Reports. Of 783 identified records, 24 studies were included in the final analysis. Rituximab was typically administered at 375mg/m2, with varying doses and treatment frequency. Clinical response, often seen within 1 month, was assessed by improvements in clinical symptoms and laboratory findings. Survival rates posttreatment displayed a wide range, with instances of complete remission and disease-free periods, as well as reports of relapse and mortality. Rituximab demonstrates the potential for significant clinical benefit in treating HLH, particularly when associated with EBV, showing promise in reducing disease activity and contributing to remission. These findings encourage further research and clinical trials to refine the therapeutic protocols and better understand the long-term effects of rituximab in HLH management.

A multi-centre longitudinal study analysing multiple sclerosis disease-modifying therapy prescribing patterns during the COVID-19 pandemic

BackgroundThe COVID-19 pandemic raised concern amongst clinicians that disease-modifying therapies (DMT), particularly anti-CD20 monoclonal antibodies (mAb) and fingolimod, could worsen COVID-19 in people with multiple sclerosis (pwMS). This study aimed to examine DMT prescribing trends pre- and post-pandemic onset.MethodsA multi-centre longitudinal study with 8,771 participants from MSBase was conducted. Two time periods were defined: pre-pandemic (March 11 2018–March 10 2020) and post-pandemic onset (March 11 2020–11 March 2022). The association between time and prescribing trends was analysed using multivariable mixed-effects logistic regression. DMT initiation refers to first initiation of any DMT, whilst DMT switches indicate changing regimen within 6 months of last use.ResultsPost-pandemic onset, there was a significant increase in DMT initiation/switching to natalizumab and cladribine [(Natalizumab-initiation: OR 1.72, 95% CI 1.39–2.13; switching: OR 1.66, 95% CI 1.40–1.98), (Cladribine-initiation: OR 1.43, 95% CI 1.09–1.87; switching: OR 1.67, 95% CI 1.41–1.98)]. Anti-CD20mAb initiation/switching decreased in the year of the pandemic, but recovered in the second year, such that overall odds increased slightly post-pandemic (initiation: OR 1.26, 95% CI 1.06–1.49; Switching: OR 1.15, 95% CI 1.02–1.29. Initiation/switching of fingolimod, interferon-beta, and alemtuzumab significantly decreased [(Fingolimod-initiation: OR 0.55, 95% CI 0.41–0.73; switching: OR 0.49, 95% CI 0.41–0.58), (Interferon-gamma-initiation: OR 0.48, 95% CI 0.41–0.57; switching: OR 0.78, 95% CI 0.62–0.99), (Alemtuzumab-initiation: OR 0.27, 95% CI 0.15–0.48; switching: OR 0.27, 95% CI 0.17–0.44)].ConclusionsPost-pandemic onset, clinicians preferentially prescribed natalizumab and cladribine over anti-CD20 mAbs and fingolimod, likely to preserve efficacy but reduce perceived immunosuppressive risks. This could have implications for disease progression in pwMS. Our findings highlight the significance of equitable DMT access globally, and the importance of evidence-based decision-making in global health challenges.

Reconstituted CD74+ NK cells trigger chronic graft versus host disease after allogeneic bone marrow transplantation

Chronic graft-versus-host disease (cGVHD) is the most common long-term complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The patients with pulmonary cGVHD in particular have a very poor prognosis. NK cells are the first reconstituted lymphocyte subset after allo-HSCT; however, the impact of reconstituted NK cells on cGVHD is unclear. Here, we found allogeneic recipients showed obvious pulmonary cGVHD. Surprisingly, deletion of reconstituted NK cells resulted in maximal relief of pulmonary cGVHD. Mechanistically, reconstituted NK cells with donor profiles modulated the pulmonary inflammatory microenvironment to trigger cGVHD. Reconstituted NK cells secreted IFN-γ and TNF-α to induce CXCL10 production by epithelial cells, which recruited macrophages and CD4+ T cells to the lungs. Then macrophages and CD4+ T cells were activated by the inflammatory microenvironment, thereby mediating lung injury. Through assessment of differences in cellular energy, we found that CD74+ NK cells with high mitochondrial potential and pro-inflammatory activity triggered pulmonary cGVHD. Furthermore, targeted elimination of CD74+ NK cells using the anti-CD74 antibody significantly alleviated pulmonary cGVHD but preserved the CD74− NK cells to exert graft-versus-leukemia (GVL) effects. Data from human samples corroborated our findings in mouse models. Collectively, our results reveal that reconstituted CD74+ NK cells trigger pulmonary cGVHD and suggest that administration of CD74 antibody was a potential therapeutic for patients with cGVHD.

Combining CD38 antibody with CD47 blockade is a promising strategy for treating hematologic malignancies expressing CD38.

CD38 and CD47 are expressed in many hematologic malignancies, including multiple myeloma (MM), B-cell non-Hodgkin lymphoma (NHL), B-cell acute lymphoblastic leukemia (ALL), and B-cell chronic lymphocytic leukemia (CLL). Here, we evaluated the antitumor activities of CD38/CD47 bispecific antibodies (BsAbs). Five suitable anti-CD38 antibodies for co-targeting CD47 and CD38 BsAb were developed using a 2 + 2 "mAb-trap" platform. The activity characteristics of the CD38/CD47 BsAbs were evaluated using in vitro and in vivo systems. Using hybridoma screening technology, we obtained nine suitable anti-CD38 antibodies. All anti-CD38 antibodies bind to CD38+ tumor cells and kill tumor cells via antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Five anti-CD38 antibodies (4A8, 12C10, 26B4, 35G5, and 65A7) were selected for designing CD38/CD47 BsAbs (IMM5605) using a "mAb-trap" platform. BsAbs had higher affinity and binding activity to the CD38 target than those to the CD47 target, decreasing the potential on-target potential and off-tumor effects. The CD38/CD47 BsAbs did not bind to RBCs and did not induce RBC agglutination; thus, BsAbs had much lower blood toxicity. The CD38/CD47 BsAbs had a greater ability to block the CD47/SIRPα signal in CD38+/CD47+ tumor cells than IMM01 (SIRPα Fc fusion protein). Through Fc domain engineering, CD38/CD47 BsAbs were shown to kill tumors more effectively by inducing ADCC and ADCP. IMM5605-26B4 had the strongest inhibitory effect on cellular CD38 enzymatic activity. IMM5605-12C10 had the strongest ability to directly induce the apoptosis of tumor cells. The anti-CD38 antibody 26B4 combined with the SIRPα-Fc fusion proteins showed strong antitumor effects, which were better than any of the mono-therapeutic agents used alone in the NCI-H929 cell xenograft model. The CD38/CD47 BsAbs exhibited strong antitumor effects; specifically, IMM5605-12C10 efficiently eradicated all established tumors in all mice. A panel of BsAbs targeting CD38 and CD47 developed based on the "mAb-tarp" platform showed potent tumor-killing ability in vitro and in vivo. As BsAbs had lower affinity for binding to CD47, higher affinity for binding to CD38, no affinity for binding to RBCs, and did not induce RBC agglutination, we concluded that CD38/CD47 BsAbs are safe and have a satisfactory tolerability profile.

Local radiotherapy and measurable residual disease-driven immunotherapy in patients with early-stage follicular lymphoma (FIL MIRO): final results of a prospective, multicentre, phase 2 trial

The mainstay of treatment for early-stage follicular lymphoma is local radiotherapy, with a possible role for anti-CD20 monoclonal antibody (mAb). We aimed to evaluate the effect of these treatments using a measurable residual disease (MRD)-driven approach. This prospective, multicentre, phase 2 trial was conducted at 27 centres of the Fondazione Italiana Linfomi (FIL) in Italy. Eligible participants were adults (≥18 years) with newly diagnosed, histologically confirmed follicular lymphoma (stage I or II; grade I-IIIa). Patients were initially treated with 24 Gy involved-field radiotherapy over 12 days; those who were MRD-positive after radiotherapy or during follow-up received eight intravenous doses (1000 mg per dose; one dose per week) of the anti-CD20 mAb ofatumumab. The primary endpoint was the proportion of patients who were MRD-positive after involved-field radiotherapy and became MRD-negative after ofatumumab treatment. Patients were included in the primary endpoint analysis population if they were positive for BCL2::IGH rearrangement at enrolment in peripheral blood or bone marrow samples. MRD positivity was defined as the persistence of BCL2::IGH rearrangement in peripheral blood or bone marrow, assessed centrally by laboratories of the FIL MRD Network. The trial was registered with EudraCT, 2012-001676-11. Between May 2, 2015, and June 1, 2018, we enrolled 110 participants, of whom 106 (96%) were eligible and received involved-field radiotherapy. Of these, 105 (99%) were White, one (1%) was Black, 50 (47%) were male, and 56 (53%) were female. Of 105 participants in whom BCL2::IGH status was evaluable, 32 (30%) had a detectable BCL2::IGH rearrangement at baseline. After radiotherapy, 12 (40%) of 30 patients reached MRD-negative status, which was long-lasting (at least 36 or 42 months) in three (25%). In those who were MRD-positive after radiotherapy, ofatumumab induced MRD-negativity in 23 (92%; 95% CI 74-99) of 25 evaluable patients. After a median follow-up of 46·1 months (IQR 42·8-50·8), 14 (61%) of these 23 patients remain in complete response and are MRD-negative. The most common grade 3-4 adverse events were infusion-related reactions, observed in four patients. Local radiotherapy is frequently not associated with the eradication of follicular lymphoma. An MRD-driven, anti-CD20 monoclonal antibody consolidation enables molecular remission to be reached in almost all patients and is associated with a reduced incidence of relapse over time. A clinical advantage of an MRD-driven consolidation is therefore suggested. AIRC Foundation for Cancer Research in Italy, Novartis International, and GlaxoSmithKline.

Efficacy and safety of MIL62, a novel glycoengineered type Ⅱ anti-CD20 monoclonal antibody, combined with lenalidomide in patients with relapsed/refractory follicular lymphoma or marginal zone lymphoma: a multicentre, single-arm, phase 1b/2 trial

MIL62, a novel glycoengineered type Ⅱ anti-CD20 monoclonal antibody, with a nearly completely afucosylated N-glycans in Fc region, has demonstrated superior activity compared with rituximab and obinutuzumab invitro and invivo, respectively. This multicentre, single-arm, phase 1b/2 trial aimed to explore the efficacy, pharmacokinetics, and safety of MIL62 combined with lenalidomide in patients with relapsed/refractory (R/R) follicular lymphoma (FL) or marginal zone lymphoma (MZL). Eligible patients included those who had histopathologically confirmed CD20 positive FL (grade 1-3a) or MZL and failed to be treated with rituximab. Patients received intravenously infused MIL62 1000mg (cycle 1: day 1, 15; cycles 2-8: day 1, cycles 10 and 12: day 1) combined with oral lenalidomide (once a day, days 2-22, the initial dose was 10mg, and the maximum dose was 20mg) for 12 cycles, 28 days as a cycle. The primary endpoint was objective response rate (ORR) assessed by investigator per Lugano 2014 criteria every 3 cycles. This study was registered in ClinicalTrials.gov (NCT04110301). Between November 22, 2019 and December 22, 2020, 54 patients were enrolled from 11 hospitals in China and received study treatment. Fifty patients were included in the efficacy analysis set, and 43 patients (86%, 95% CI: 73, 94) achieved objective response, meeting the pre-specified primary endpoint. Disease control rate was 96% (48/50, 95% CI: 86, 100), proportion of patients with duration of response (DoR) > 6 months was 77% (33/43). The median follow-up for survival was 12.3 months (IQR 12.0-12.6). The 1-year progression-free survival rate was 72% (95% CI: 57, 83), 9-month DoR rate was 74% (95% CI: 58, 85), and 1-year overall survival rate was 98% (95% CI: 85, 100). Most common TRAEs were neutropenia (93%, 50/54), leukopenia (85% 46/54), thrombocytopenia (61% 33/54), lymphopenia (32% 17/54), and alanine aminotransferase increased (20% 11/54). MIL62 combined with lenalidomide showed promising efficacy in patients with R/R FL and MZL. A multicentre, randomized, open-label, phase Ⅲ trial of MIL62 combined with lenalidomide versus lenalidomide in anti-CD20 monoclonal antibody refractory FL patients is ongoing (NCT04834024). Beijing Mabworks Biotech Co. Ltd, Beijing China and the National Science and Technology Major Project for Key New Drug Development (2017ZX09304015).

A novel anti-CD47 protein antibody and toll-like receptor agonist complex detects tumor surface CD-47 changes in early stage lung cancer by in vivo imaging

CD47, a cell surface protein known for inhibiting phagocytosis, plays a critical role in the tumor microenvironment (TME) and is a potential biomarker for cancer. However, directly applying αCD47, a hydrophilic macromolecular antibody that targets CD47, in vivo for cancer detection can have adverse effects on normal cells, cause systemic toxicities, and lead to resistance against anti-cancer therapies. In this study, we developed a novel complex incorporating aluminum-based metal-organic frameworks (Al-MOF) loaded with indocyanine green (ICG), αCD47, and resiquimod (R848), a hydrophobic small molecule Toll-like receptor 7/8 (TLR7/8) agonist. Upon activation with an infrared 808 nm laser, the nanocomposites exhibited photothermal effects that triggered the release of the loaded reagents, induced ROS production, and induced changes in the TME. This led to the polarization of immune-suppressive M2 macrophages towards an immune-stimulatory M1 phenotype, promoted dendritic cell (DC) maturation, and enabled mature DCs to facilitate antigen presentation, T-cell activation, and critical roles in tumor immunity. Furthermore, in vivo imaging successfully detected the specific binding of αCD47 with CD47 on tumor cells. Overall, the complex composed of αCD47 antibody and toll-like receptor agonist showed promising efficacy in both tumor diagnosis and therapy, providing a potential strategy for detecting early lung cancer and modulating the tumor microenvironment for improved treatment outcomes.

Omicron SARS-CoV-2 infection management and outcomes in patients with hematologic disease and recipients of cell therapy.

Scarce real-life data exists for COVID-19 management in hematologic disease (HD) patients in the Omicron era. To assess the current clinical management and outcome of SARS-CoV-2 infection diagnosed, identify the risk factors for severe outcomes according to the HD characteristics and cell therapy procedures in a real-world setting. A retrospective observational registry led by the Spanish Transplant Group (GETH-TC) with 692 consecutive patients with HD from December 2021 to May 2023 was analyzed. Nearly one-third of patients (31%) remained untreated and presented low COVID-19-related mortality (0.9%). Nirmatrelvir/ritonavir was used mainly in mild COVID-19 cases in the outpatient setting (32%) with a low mortality (1%), while treatment with remdesivir was preferentially administered in moderate-to-severe SARS-CoV-2 infection cases during hospitalization (35%) with a mortality rate of 8.6%. The hospital admission rate was 23%, while 18% developed pneumonia. COVID-19-related mortality in admitted patients was 14%. Older age, autologous hematopoietic stem cell transplantation (SCT), chimeric antigen receptor T-cell therapy, corticosteroids and incomplete vaccination were factors independently associated with COVID-19 severity and significantly related with higher rates of hospital admission and pneumonia. Incomplete vaccination status, treatment with prior anti-CD20 monoclonal antibodies, and comorbid cardiomyopathy were identified as independent risk factors for COVID-19 mortality. The results support that, albeit to a lower extent, COVID-19 in the Omicron era remains a significant problem in HD patients. Complete vaccination (3 doses) should be prioritized in these immunocompromised patients. The identified risk factors may help to improve COVID-19 management to decrease the rate of severe disease, ICU admissions and mortality.

Abstract PO-038: Unbiased discovery of novel antibody therapies that stimulate macrophage-mediated destruction of B-cell lymphoma

Abstract Monoclonal antibodies are among the most effective treatments for patients with blood cancers, and they primarily function by marking cells for destruction by the innate immune system. Macrophages are critical innate effectors of antibody therapies for lymphoma, but their anti-tumor capacity is limited by the CD47/SIRPa interaction. CD47 acts a “don’t eat me” signal that is highly expressed on the surface of many lymphomas, and it prevents phagocytosis by binding to the inhibitory receptor SIRPa expressed on macrophages. In multiple clinical trials, CD47-blocking therapies have demonstrated encouraging signs of efficacy for B-cell lymphomas, particularly when used in combination with rituximab, an opsonizing anti-CD20 antibody. However, the best antibodies and combination strategies to activate macrophages remains unknown. Here, we sought to define the repertoire of cell surface antigens that can be targeted to stimulate macrophage-mediated destruction of B-cell lymphomas. To achieve this goal, we developed a high-throughput functional screening platform to measure the ability of primary macrophages to attack B-cell lymphoma cells. We successfully applied this system to screen monoclonal antibody libraries targeting hundreds of distinct cell surface antigens across both mouse and human systems. We conducted screens using each antibody as a single agent, in combination with anti-CD20, or in combination with anti-CD47. From these efforts, we identified CD24, CD38, CXCR4, CD71, and multiple other novel and unique antigens that could be targeted alone or in combination to exert maximal macrophage-mediated destruction of B-cell lymphoma. Of note, some of the identified targets are predominantly expressed by the lymphoma cells, whereas others are expressed by the macrophages and act as unappreciated immune checkpoints. In validation studies, we defined a multitude of new antibody combinations that robustly stimulate macrophages to attack and eliminate lymphoma cells. Since some anti-CD47-antibodies have been limited by on-target hematologic toxicity, we also used the identified targets to engineer a collection of novel bispecific antibodies that induce macrophage phagocytosis without causing hematologic toxicity. We generated 156 bispecific antibodies, produced them recombinantly, and demonstrated they can maximize macrophage-mediated cytotoxicity of human B-cell lymphoma cells while minimizing binding to healthy blood cells. In mouse xenograft models, these bispecific antibodies exhibited significant single-agent activity in a model of aggressive B-cell lymphoma. Thus, our study has led to the development of a multitude of novel therapeutic candidates and combination strategies that can be developed further to maximize anti-tumor function and benefit patients with lymphoma. Furthermore, our approach can be rapidly applied to other hematologic malignancies to create innovative bispecific agents that maximize anti-tumor responses by macrophages or other innate immune cells. Citation Format: Juliano Ribeiro, Carlota Pages Geli, José Velarde, Anna Meglan, Jasmine Blandin, Kyle Vaccaro, Marta Crespo, Kipp Weiskopf. Unbiased discovery of novel antibody therapies that stimulate macrophage-mediated destruction of B-cell lymphoma [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-038.

Obinutuzumab in Refractory Membranous Nephropathy: A Case Series

Rationale & ObjectiveMembranous nephropathy (MN), recognized as an autoimmune kidney disease, responds well to anti-CD20 monoclonal antibodies. Obinutuzumab, a type Ⅱ humanized anti-CD20 and immunoglobulin G1 Fc-optimized monoclonal antibody, compared to rituximab, has demonstrated superior efficacy in B cell leukemia and lymphoma, especially in rituximab-resistant cases. However, the efficacy and safety of obinutuzumab in MN remain unclear. Study DesignRetrospective cohort study. Setting & ParticipantsA total of 18 patients who were diagnosed as MN and received obinutuzumab at our center, without secondary MN, undergoing dialysis, history of kidney transplantation, or infections requiring treatment. ExposureObinutuzumab treatment. OutcomesPrimary outcomes included remission rate, time to first remission, and first relapse-free survival time during the follow-up period. Analytical ApproachSurvival analysis was conducted with Cox proportional hazards models, Log-rank test, and Kaplan–Meier survival analysis. ResultsMN patients (median age 52.5 years, 83% males) received an average dose of 2.1 ± 0.8 g obinutuzumab during a median follow-up period of 13.6 months. During follow-up, 17 patients (94.4%) achieved remission, with 12 patients (66.7%) achieving partial remission (PR) and 5 patients (27.8%) achieving complete remission (CR). The median time to first remission and first relapse-free survival time was 2.7 (1.0, 6.1) months and 9.8 (2.6, 11.2) months, respectively. Of 12 patients with previous rituximab treatment, all achieved remission successfully, with 8 (66.7%) achieving PR and 4 (33.3%) achieving CR. Adverse events were mostly mild, and no severe treatment-related adverse events were observed. LimitationsLimited or missing data, risks of selection bias, or recall bias; underestimated first relapse-free survival time due to limited follow-up period; unmonitored counts of CD19+ B cells and other lymphocyte subsets. ConclusionsObinutuzumab demonstrated promising efficacy and safety in inducing remission in MN, particularly in patients with an unsatisfactory response to rituximab.

Linvoseltamab for Treatment of Relapsed/Refractory Multiple Myeloma.

We present a phase I/II first-in-human trial evaluating the safety and efficacy of 50 mg and 200 mg doses of linvoseltamab, a B-cell maturation antigen × CD3 bispecific antibody in relapsed/refractory multiple myeloma (RRMM). Phase II eligible patients had RRMM that either progressed on/after ≥three lines of therapy including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody or was triple-class (PI/IMiD/anti-CD38) refractory. Phase II treatment was once a week through week 14 and then once every 2 weeks. Phase II 200 mg patients who achieved a ≥very good partial response by week 24 received linvoseltamab once every 4 weeks. The primary end point in phase II was overall response rate (ORR). Among the 117 patients treated with 200 mg, the median age was 70 years, 39% had high-risk cytogenetics, and 28% had penta-refractory disease. At a median follow-up of 14.3 months, the ORR was 71%, with 50% achieving ≥complete response (CR). In 104 patients treated with 50 mg at a median follow-up of 7.4 months, the ORR was 48%, with 21% achieving ≥CR. The median duration of response (DOR) for 200 mg patients (n = 83) was 29.4 months (95% CI, 19.2 to not evaluable). Among 200 mg patients, the most common adverse events included cytokine release syndrome (35.0% Gr1, 10.3% Gr2, 0.9% Gr3), neutropenia (0.9% Gr2, 18.8% Gr3, 23.1% Gr4), and anemia (3.4% Gr1, 4.3% Gr2, 30.8% Gr3). Immune effector cell-associated neurotoxicity syndrome occurred in 7.7% of patients (2.6% each Gr1, Gr2, Gr3). Infections were reported in 74.4% of patients (33.3% Gr3, 2.6% Gr4); infection frequency and severity declined over time. Linvoseltamab 200 mg induced deep and durable responses, with a median DOR of 29.4 months, in patients with RRMM with an acceptable safety profile.

Epcoritamab monotherapy in patients with relapsed or refractory follicular lymphoma (EPCORE NHL-1): a phase 2 cohort of a single-arm, multicentre study

A standard of care and optimal duration of therapy have not been established for patients with multiply relapsed or refractory follicular lymphoma. The aim of this study was to evaluate epcoritamab, a novel CD3 × CD20 bispecific antibody, in the third-line and later setting of follicular lymphoma. EPCORE NHL-1 is a multicohort, single-arm, phase 1-2 trial conducted at 88 sites across 15 countries. Here, we report the primary analysis of patients with relapsed or refractory follicular lymphoma in the phase 2 part of the trial, which included the pivotal (dose expansion) cohort and the cycle 1 optimisation cohort. Eligible patients were aged 18 years or older, had relapsed or refractory CD20+ follicular lymphoma (grade 1-3A), an Eastern Cooperative Oncology Group performance status of up to 2, and had received at least two previous lines of therapy (including an anti-CD20 monoclonal antibody and an alkylating agent or lenalidomide). Patients were treated with subcutaneous epcoritamab 48 mg in 28-day cycles: weekly in cycles 1-3, biweekly in cycles 4-9, and every 4 weeks until disease progression or unacceptable toxicity. To mitigate the risk and severity of cytokine release syndrome, in the pivotal cohort, cycle 1 consisted of a step-up dosing regimen of a 0·16-mg priming dose on day 1 and a 0·80-mg intermediate dose on day 8, followed by subsequent 48-mg full doses and prophylactic prednisolone 100 mg; in the cycle 1 optimisation cohort, a second intermediate dose of 3 mg on day 15, adequate hydration, and prophylactic dexamethasone 15 mg were evaluated during cycle 1 to further reduce risk and severity of cytokine release syndrome. Primary endpoints were independently reviewed overall response rate for the pivotal cohort and the proportion of patients with grade 2 or worse and any-grade cytokine release syndrome for the cycle 1 optimisation cohort. Analyses were done in all enrolled patients who had received at least one dose of epcoritamab. This study is registered with ClinicalTrials.gov, NCT03625037, and is ongoing. Between June 19, 2020, and April 21, 2023, 128 patients (median age 65 years [IQR 55-72]; 49 [38%] female and 79 [62%] male) were enrolled and treated in the pivotal cohort (median follow-up 17·4 months [IQR 9·1-20·9]). The overall response rate was 82·0% (105 of 128 patients; 95% CI 74·3-88·3), with a complete response rate of 62·5% (80 of 128; 95% CI 53·5-70·9). The most common grade 3-4 treatment-emergent adverse event was neutropenia in 32 (25%) of 128 patients. Grade 1-2 cytokine release syndrome was reported in 83 (65%) of 128 patients; grade 3 cytokine release syndrome was reported in two (2%). Immune effector cell-associated neurotoxicity syndrome was reported in eight (6%) of 128 patients (five [4%] grade 1; three [2%] grade 2). Between Oct 25, 2022, and Jan 8, 2024, 86 patients (median age 64 years [55-71]; 37 [43%] female and 49 [57%] male) were enrolled and treated in the cycle 1 optimisation cohort. The incidence of cytokine release syndrome was 49% (42 of 86 patients; eight [9%] grade 2; none of grade 3 or worse), with no reported immune effector cell-associated neurotoxicity syndrome. Epcoritamab monotherapy showed clinically meaningful activity in patients with multiply relapsed or refractory follicular lymphoma, and had a manageable safety profile. Genmab and AbbVie.

A Glimpse into Humoral Response and Related Therapeutic Approaches of Takayasu's Arteritis.

Takayasu's arteritis (TAK) manifests as an insidiously progressive and debilitating form of granulomatous inflammation including the aorta and its major branches. The precise etiology of TAK remains elusive, with current understanding suggesting an autoimmune origin primarily driven by T cells. Notably, a growing body of evidence bears testimony to the widespread effects of B cells on disease pathogenesis and progression. Distinct alterations in peripheral B cell subsets have been described in individuals with TAK. Advancements in technology have facilitated the identification of novel autoantibodies in TAK. Moreover, emerging data suggest that dysregulated signaling cascades downstream of B cell receptor families, including interactions with innate pattern recognition receptors such as toll-like receptors, as well as co-stimulatory molecules like CD40, CD80 and CD86, may result in the selection and proliferation of autoreactive B cell clones in TAK. Additionally, ectopic lymphoid neogenesis within the aortic wall of TAK patients exhibits functional characteristics. In recent decades, therapeutic interventions targeting B cells, notably utilizing the anti-CD20 monoclonal antibody rituximab, have demonstrated efficacy in TAK. Despite the importance of the humoral immune response, a systematic understanding of how autoreactive B cells contribute to the pathogenic process is still lacking. This review provides a comprehensive overview of the biological significance of B cell-mediated autoimmunity in TAK pathogenesis, as well as insights into therapeutic strategies targeting the humoral response. Furthermore, it examines the roles of T-helper and T follicular helper cells in humoral immunity and their potential contributions to disease mechanisms. We believe that further identification of the pathogenic role of autoimmune B cells and the underlying regulation system will lead to deeper personalized management of TAK patients. We believe that further elucidation of the pathogenic role of autoimmune B cells and the underlying regulatory mechanisms holds promise for the development of personalized approaches to managing TAK patients.

Single-cell profiling indicates a high similarity between immune cells in the cerebrospinal fluid and in meningeal ectopic lymphoid tissue in experimental autoimmune encephalomyelitis.

B cell depleting anti-CD20 monoclonal antibodies (aCD20 mAbs) are highly effective in treatment of multiple sclerosis (MS) but fail to halt the formation of meningeal ectopic lymphoid tissue (mELT) in the murine model experimental autoimmune encephalomyelitis (EAE). While mELT can be examined in EAE, it is not accessible in vivo in MS patients. Our key objectives were to compare the immune cells in cerebrospinal fluid (CSF), which is accessible in patients, with those in mELT, and to study the effects of aCD20 mAbs on CSF and mELT in EAE. Applying single cell RNA sequencing, we compared gene expression profiles in immune cells from (1) CSF with mELT and (2) aCD20 mAbs treated with control treated mice in a spontaneous 2D2xTh EAE model. The immune cell composition in CSF and mELT was very similar. Gene expression profiles and pathway enrichment analysis revealed no striking differences between the two compartments. aCD20 mAbs led not only to a virtually complete depletion of B cells in the CSF but also to a reduction of naïve CD4+ T cells and marked increase of macrophages. No remarkable differences in regulated genes or pathways were observed. Our results suggest that immune cells in the CSF may serve as a surrogate for mELT in EAE. Future studies are required to confirm this in MS patients. The observed increase of macrophages in B cell depleted CSF is a novel finding and requires verification in CSF of aCD20 mAbs treated MS patients. Due to unresolved technical challenges, we were unable to study the effects of aCD20 mAbs on mELT. This should be addressed in future studies.

Rituximab Therapy for Immune-Mediated Neurological Diseases: Our Experience at a Tertiary Care Centre.

Rituximab (RTX) is a monoclonal anti-CD20 chimeric antibody that inhibits B cell activity. However, it is an appealing substitute for traditional immunomodulatory drugs as a swiftly acting, targeted therapy with mounting evidence of efficacy and tolerance in numerous neuroinflammatory conditions. We discuss the scientific evidence for the use of RTX in neurological illnesses, as well as the dose, safety, and other practical elements of prescription. This study aims to assess and correlate the effects of RTX on immune-mediated neurological disorders. The primary objective of this study is to determine the outcomes in patients treated with RTX for the following conditions: myasthenia gravis (MG), autoimmune encephalitis, multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein antibody disease (MOGAD), immune-mediated peripheral neuropathy, and inflammatory muscle disease. The secondary objective is to assess adverse drug reactions in patients treated with RTX. This is a prospective observational study conducted at a tertiary care centre. The data were analyzed for the period from May 2022 to May 2024. Approval was obtained from the institutional ethics committee before commencing the study, andwritten informed consent was obtained from all patients. A total of 56 patients were included in the study. The distribution of patients according to diseases is as follows: MG (17), MS (11), NMOSD (10), MOGAD (7), immune-mediated peripheral neuropathy (6), autoimmune encephalitis (3), and inflammatory muscle disease (2). However, one patient was lost to follow-up in the autoimmune encephalitis group. All patients experienced improvements in symptoms, and no relapse episodes have been reported except for one patient who had a relapse in the inflammatory muscle disease group. During the infusion process, some adverse drug reactions, such as chills and rigors, were observed, and two patients experienced major side effects, such as Pott's disease and cryptogenic organizing pneumonia. Nevertheless, overall, rituximab shows promise as an off-labelimmunosuppressive treatment for the aforementioned neurological immune-mediated diseases.

The TRIM28/miR133a/CD47 axis acts as a potential therapeutic target in pancreatic necrosis by impairing efferocytosis

Efferocytosis, the clearance of apoptotic cells by macrophages, plays a crucial role in inflammatory responses and effectively prevents secondary necrosis. However, the mechanisms underlying efferocytosis in acute pancreatitis (AP) remain unclear. In this study, we demonstrated the presence of efferocytosis in injured human and mouse pancreatic tissues. We also observed significant upregulation of CD47, an efferocytosis-related the "do not eat me" molecule in injured acinar cells. Subsequently, we used CRISPR-Cas9 gene editing, anti-adeno-associated virus (AAV) gene modification, and anti-CD47 antibody to investigate the potential therapeutic role of AP. CD47 expression was negatively regulated by upstream miR133a, which is controlled by the transcription factor TRIM28. To further investigate the regulation of efferocytosis and reduction of pancreatic necrosis in AP, we used miR-133a-agomir and pancreas-specific AAV-shTRIM28 to modulate CD47 expression. Our findings confirmed that CD47-mediated efferocytosis is critical for preventing pancreatic necrosis and suggest that targeting the TRIM28-miR133a-CD47 axis is clinically relevant for the treatment of AP.