small molecules

2026-09-21 | A Case of Leukemic Phase of Mantle Cell Lymphoma Diagnosed With Scarring Conjunctivitis and Bilateral Upper Palpebral Conjunctival Tumor.

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin's lymphoma. Ocular adnexal involvement is rare as the initial symptom, and conjunctival involvement is particularly rare. An 84-year-old man was referred to our hospital with chronic conjunctivitis of the bulbar and tarsal conjunctiva with bilateral symblepharon, as well as a reddish-brown, cobblestone-like tumor. Suspecting malignancy, a tumor biopsy and systemic examination revealed the neoplastic lesion to be MCL. Leukocytosis and abnormal cells in peripheral blood (53%) were observed, and diffuse tumor cell infiltration was observed in the bone marrow. Both the bone marrow and tumor cells were positive for CD5, CD20, and cyclin D1, while the bone marrow tissue was negative for SOX11, confirming leukemic conversion (leukemic phase of mantle cell lymphoma). PET/CT revealed accumulation in systemic lymph nodes and extranodal organs, leading to a diagnosis of Ann Arbor stage IV disease. TP53 deletion was not detected. Following treatment with acalabrutinib in combination with bendamustine and rituximab, as reported in 2025, the conjunctivitis and eyelid tumor resolved, with no recurrence observed during follow-up. We report a case of leukemia-type MCL diagnosed with bilateral chronic cicatricial conjunctivitis and elevated lesions on the upper eyelid conjunctiva as initial findings. When encountering such findings, early pathological diagnosis and thorough systemic examination are important, with systemic malignant lymphoma in mind.

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2026-09-09 | Preliminary study on efficacy and safety of pixantrone in relapsed/refractory aggressive B-cell lymphomas: multicenter, retrospective cohort study by Polish Lymphoma Research Group (PLRG).

Pixantrone (PIX) is an anthracycline derivative with reduced cardiotoxicity, registered in Poland for monotherapy in relapsed/refractory (R/R) aggressive B-cell non-Hodgkin lymphoma (B-NHL) in the third or fourth line of treatment. As R/R population is difficult to treat due to comorbidities including circulatory system pathologies we evaluate polish patients treated with PIX. This is the first real life study evaluating patients treated with PIX in Poland with emphasis on efficacy and cardiovascular toxicity. The retrospective study assessing safety and effectiveness of PIX administered in patients with aggressive de novo or transformed B-NHL [according to the Revised European American Lymphoma (REAL) and World Health Organization (WHO) classifications], who relapsed or were refractory to two or three previous lines of chemotherapy regimens, including at least one standard anthracycline-based regimen. Patients who did not remain sensitive to anthracyclines were excluded from this study. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), complete response (CR) rate, overall response rate (ORR) and safety. The data of 17 patients were collected in 6 study sites. The median age was 72 (range: 58-82) years old with male predominance (65%). In observed group10 patients had diffuse large B-cell lymphoma (DLBCL), 6 mantle cell lymphoma (MCL) and 1 patient had Richter syndrome. Five subjects responded to PIX (CR 2 and partial response 3)-ORR was 29%. The median of PFS was 12.9 months [standard error (SE) 2.2; 95% confidence interval (CI): 8.5, 17.2]. The median of survival time was 22.6 months (SE 7.3; 95% CI: 8.3, 36.8). The PIX compliance was good, with incidental dose omission or delay. The main reason for discontinuation was disease progression. Administration of PIX to patients with R/R aggressive B-NHL treated with multiple lines of chemotherapy containing maximal cumulative dose of anthracycline and with numerous concomitant diseases may be a potentially valuable therapeutic option but data from larger clinical studies will help in confirming PIX as an effective and safe option.

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2026-08-29 | Hepatitis C virus-associated B-cell non-Hodgkin lymphomas: immune evasion, multistep lymphomagenesis, and candidate biomarkers for risk stratification and disease monitoring.

Hepatitis C virus (HCV)-associated B-cell non-Hodgkin lymphomas represent a compelling model of virus-driven oncogenesis in which immune evasion and viral persistence sustain chronic antigenic stimulation, B-cell clonal expansion and progressive multistep lymphomagenesis. This minireview focuses on mechanisms that connect HCV immune escape with B-cell lymphomagenesis, antiviral treatment responses, and emerging biomarkers for risk stratification and disease monitoring. HCV persistence is sustained by extensive viral genetic variability (quasispecies formation) and by interference with innate and adaptive immune responses, including RIG-I/TLR3 pathway inhibition, suppression of interferon signaling, dendritic cell and natural killer cell dysfunction, and T-cell exhaustion. These mechanisms are relevant to lymphomagenesis because they maintain a persistent antigenic and inflammatory niche that supports chronic antigenic stimulation, clonal B-cell expansion, cytokine and chemokine dysregulation (e.g., BAFF/BLyS axis), apoptotic escape, and the progressive accumulation of genetic alterations and chromosomal aberrations. Lymphomagenesis thus emerges as a complex process consistent with a multistep model. Antiviral therapy provides a clinical indicator of this model, in which regression of some indolent HCV-associated lymphomas after viral eradication supports virus dependence, whereas incomplete lymphoproliferative response and the need for immunochemotherapy in aggressive lymphomas indicate partial independence from the viral trigger at advanced stages. Emerging biomarkers, including B-cell activation markers, immune-inflammatory mediators, immunogenetic susceptibility factors, microRNAs, and genomic alterations, show promise for risk stratification, and disease monitoring, but require further validation. Integrating antiviral and antitumor strategies with biomarker-guided patient stratification may improve early cancer diagnosis and treatment prioritization.

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2026-08-15 | SOHO State of the Art Updates and Next Questions| Mediastinal Gray-zone Lymphoma: Novel Biologic Insights and Updates on How Best to Approach This Rare Entity.

Mediastinal gray zone lymphoma (MGZL) is a very rare aggressive B-cell non-Hodgkin lymphoma characterized by clinical, pathologic, and molecular features that overlap between nodular sclerosis Hodgkin lymphoma (NSHL) and primary mediastinal B-cell lymphoma (PMBL). While these are clinically related lymphomas, recent molecular profiling studies demonstrated similarities between these 3 entities, including alterations in the nuclear factor-κB pathway, JAK2/STAT signaling, copy number alterations in 9p24.1, and immune evasion. In the most recent WHO-5 and ICC classifications, the definition of GZL was restricted to mediastinal GZL (MGZL), which remains as a separate entity between NSHL and PMBL; however, non-mediastinal GZL was classified under diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS). Given the rarity of the disease, evolving definition, and diagnostic challenges, few prospective studies have been undertaken to evaluate treatment outcomes. Response rates and survival with frontline chemotherapy are inferior compared to PMBL, and retrospective studies suggest superiority of dose-intensive regimens compared to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in MGZL. Despite recent therapeutic advancements in PMBL and classical Hodgkin lymphoma (cHL), most clinical trials have excluded patients with MGZL, leading to uncertainty regarding the best therapeutic strategy in both the frontline and relapsed/refractory settings.

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2026-08-13 | The Role of Direct-Acting Antivirals (DAAs) in Hepatitis C Virus-Associated Lymphoproliferative Disorders.

Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis, affecting approximately 50 million people worldwide. An estimated 15-30% of individuals with chronic HCV infection progress to cirrhosis, which may subsequently develop into hepatocellular carcinoma. Beyond liver disease, HCV is associated with a broad spectrum of extrahepatic manifestations, particularly mixed cryoglobulinemia (MC) and B-cell non-Hodgkin lymphoma (B-NHL). Persistent viral infection induces chronic antigenic stimulation of B lymphocytes, a key pathogenic mechanism underlying the progression from MC to overt B-NHL. These observations have important therapeutic implications and support the use of antiviral therapy as a cornerstone of treatment. The efficacy of direct-acting antivirals (DAAs) has been well established in patients with HCV-related MC and cryoglobulinemic vasculitis. Several studies have shown that DAAs achieve sustained virologic response rates exceeding 90%, often approaching 100% in contemporary cohorts. Viral eradication is frequently associated with clinical and immunological improvement, as well as regression of cryoglobulinemia. Encouraging outcomes have also been reported in patients with HCV-associated indolent B-NHL, particularly marginal zone lymphoma, although confirmation in larger studies with longer follow-up is needed. In patients with HCV-positive aggressive lymphomas, DAAs have been safely administered in combination with immunochemotherapy, yielding promising results. This review summarizes the current evidence on HCV-associated MC and B-NHL and discusses the impact of DAA therapy on the clinical course and management of these disorders.

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cell therapies

2026-08-28 | CD19 CAR T-cell therapy (GLPG5101) for relapsed or refractory B-cell non-Hodgkin lymphoma (ATALANTA-1): phase 1 results from a single-arm, multicentre, phase 1/2 study.

Chimeric antigen receptor (CAR) T-cell therapies have transformed the treatment of B-cell non-Hodgkin lymphoma, but centralised manufacturing-with its complex logistics and long vein-to-vein times-drives up costs and restricts access. We aimed to evaluate the safety of GLPG5101, a fresh, CD19 CAR T-cell product manufactured through a decentralised process, and determine the recommended phase 2 dose. This phase 1 dose-escalation part of the ATALANTA-1 phase 1/2, single-arm study, was executed in five hospitals in the Netherlands and Belgium. Patients aged 18 years or older, with histologically confirmed diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, marginal zone lymphoma (MZL), or mantle cell lymphoma (MCL) after two or more lines of therapy, measurable disease according to the Lugano classification, Eastern Cooperative Oncology Group Performance Status 0-2, and adequate organ function were enrolled. Patients were treated with a single intravenous infusion at one of three dose levels of GLPG5101 (dose level 1 [35-50 × 106 viable CAR+ T-cells], dose level 2 [85-110 × 106 viable CAR+ T-cells], and dose level 3 [200-250 × 106 viable CAR+ T-cells]). The phase 1 part of the study applied a Bayesian Optimal Interval design and the primary endpoints were safety (incidence of adverse events and serious adverse events until end of treatment [week 14], and dose-limiting toxicities [DLTs] until day 28) in patients who received fresh GLPG5101 at any dose (excluding recipients of non-conforming product [not meeting prespecified release criteria other than dose]) and determination of the recommended phase 2 dose. The study was registered with ClinicalTrials.gov (NCT06561425) and is closed for recruitment. From March 15, 2022, to Sept 10, 2024, 27 patients were screened for eligibility, 24 of whom were enrolled, underwent leukapheresis and lymphodepleting chemotherapy and received GLPG5101. Data cutoff was June 1, 2025. In the intention-to-treat population (n=24), the median age was 66·5 years (IQR 59·0-71·5), 15 (63%) patients were male, nine (38%) were female, and 21 (88%) were White. One of the 24 patients received a non-conforming product and was excluded from the safety analysis population. Median follow-up was 24·0 months (IQR 20·7-24·9). Five DLTs were reported: grade 3 thrombocytopenia (n=1, dose level 1), death from intra-abdominal haemorrhage (n=1, dose level 2), and grade 4 prolonged neutropenia not resolving to grade 2 or lower within 28 days (n=1 at dose level 1 and n=2 at dose level 2). All 23 patients in the safety analysis population had grade 3 or higher treatment-emergent adverse events; the most common were neutropenia (22 [96%]), leukopenia (nine [39%]), lymphopenia (seven [30%]), anaemia (six [26%]), and thrombocytopenia (five [22%]). Treatment-related deaths occurred in four patients: one during the 14-week treatment period due to intra-abdominal haemorrhage, and three after the treatment period due to Escherichia coli sepsis (n=1), immune-effector cell-associated haemophagocytic lymphohistiocytic syndrome (n=1), and COVID-19 (n=1). The safety review committee selected 110 × 106 (range 50-110 × 106) viable CAR T-cells as the recommended phase 2 dose. The results of this study showed the feasibility of rapid multicentre decentralised manufacturing and delivery of fresh CAR T-cell therapy in heavily pretreated B-cell non-Hodgkin lymphoma. The phase 2 part of ATALANTA-1 will provide further information on clinical activity and safety. CellPoint, Lakefront Biotherapeutics.

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2026-07-17 | Enabling access to talicabtagene autoleucel in relapsed/refractory B-cell malignancies; multicenter real-world evidence on delivery, efficacy and safety.

Talicabtagene autoleucel (tali-cel) is the first humanized CD19-directed CAR-T cell therapy approved in India for relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) and B-cell non-Hodgkin lymphoma (B-NHL). Here, we integrated clinical and manufacturing operations through a centralized coordination unit (CCU) and evaluated tali-cel implementation. Patients with r/r B-ALL (n = 105) and r/r B-NHL (n = 145) who underwent leukapheresis between 15 November 2023 and 31 January 2025 across 56 treatment centers were included. The CCU enabled timely delivery, with manufacturing slot allocation within one week of slot request and a median vein-to-vein time of 29 days (range, 16-102), independent of geographic location. In r/r B-ALL patients, the median follow-up was 14 months, and the median overall survival (OS) not reached, and progression-free survival (PFS) was 18 months (range: 9-NR). The 12-month OS and PFS were 64% (95% CI: 53-72) and 55% (95% CI: 45-65). In r/r B-NHL, the median follow-up was 13 months and the median PFS was 11 months (range:7-16) and OS was not reached. The 12-month OS and PFS were 63% (95% CI: 54-71) and 47% (95% CI: 38-56). No patients underwent consolidative stem cell transplantation. Grade 3/4 cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and Immune Effector Cell-associated Hemophagocytic Lymphohistiocytosis-like Syndrome (IEC-HS) occurred in 6%, 4%, and 23% of r/r B-ALL and 6%, 3%, and 18% of r/r B-NHL patients, respectively. These findings demonstrate the successful implementation of tali-cel across multiple centers in a large cohort, which might contribute towards improving CAR-T access globally.

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2026-07-05 | Efficacy and safety of CD19 CAR T-cell therapy in relapsed/refractory follicular lymphoma: A systematic review and meta-analysis.

Follicular lymphoma (FL) is an indolent B-cell non-Hodgkin lymphoma characterized by frequent relapses despite initial responsiveness to chemoimmunotherapy. CD19-directed chimeric antigen receptor (CAR) T-cell therapy has shown promising efficacy in relapsed or refractory disease, though safety concerns such as cytokine release syndrome (CRS) and neurological events remain. This study aimed to evaluate the efficacy and safety of CD19 CAR T-cell therapy in relapsed or refractory FL. A comprehensive search using six databases, including PubMed, Scopus, and Embase, was performed to identify relevant studies. Data on overall response rate (ORR), complete response rate (CRR), progression-free survival (PFS), duration of response (DOR), overall survival (OS), and adverse events, including CRS and neurological events, were extracted. Pooled estimates were calculated using the quality effects model. This review was registered in PROSPERO (CRD420251133655). Out of 2303 records initially identified, 6 studies met the inclusion criteria. The pooled efficacy analysis demonstrated an ORR of 93.5% (95% CI: 86.3-98.3%) and a CRR of 84.5% (95% CI: 72.6-93.6%). Regarding safety outcomes, the pooled estimate for CRS of any grade was 61.4% (95% CI: 45.0-76.6%). For neurological events, it was 33.6% (95% CI: 13.4-57.1%). Subgroup analyses identified prior therapy lines and CAR construct design as sources of heterogeneity. In conclusion, CD19 CAR T-cell therapy demonstrates high efficacy with a generally acceptable safety in relapsed or refractory FL, supporting its consideration for patients with limited treatment options while highlighting the need for further research on long-term outcomes.

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2026-07-02 | A novel dose-dense strategy for CD19-directed CAR T-cell therapy is associated with durable responses without increased toxicity in patients with B-cell non-Hodgkin lymphoma.

CD19-directed chimeric antigen receptor (CAR) T-cell therapy induces durable remissions in only 30-40% of patients with relapsed or refractory (R/R) B-cell non- Hodgkin lymphoma (B-NHL), highlighting a major need to improve outcomes. In dose-escalation studies, higher CAR T-cell doses improved tumor control but caused prohibitive toxicities. Having established the maximum tolerated JCAR014 dose in patients with B-NHL at 2 x 106 CAR+ cells/kg, we hypothesized that a second infusion at day 14 ("dose-dense") at the same dose and without repeat lymphodepletion, would be safe and enhance antitumor efficacy. We report outcomes from the pilot dose-dense cohort of a phase 1/2 trial (ClinicalTrials.gov identifier: NCT01865617) with 8-year follow-up. Two CAR T-cell products, each containing 2 x 106 CAR+ cells/kg, were manufactured for all 20 treated patients; 17 received both infusions. Any-grade cytokine release syndrome (CRS) and neurotoxicity (NT) occurred in 10 (59%) and 3 (18%) of dose-dense patients, respectively, and-except for one grade 2 CRS-events followed the first infusion only. Despite no additional lymphodepletion, CAR T-cell re-expansion after the second infusion occurred in 16 (94%) patients. By Lugano criteria, overall and complete response rates were 47% (8/17) and 41% (7/17), respectively. Among responders, the 8-year durationof- response rate was 63% (95% CI: 37-100), comparing favorably with the 26% (95% CI: 14-48) observed in patients treated with a single infusion. In conclusion, early redosing on day 14 was feasible, safe and led to durable responses in patients with R/R B-NHL.

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2026-06-29 | Resistance mechanisms and overcoming strategies for CAR T-cell therapy in B-cell hematologic malignancies.

Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment landscape for relapsed/refractory (R/R) B-cell malignancies, including B-cell non-Hodgkin lymphoma (B-NHL), B-cell acute lymphoblastic leukemia (B-ALL), and related diseases. However, treatment failure caused by primary or secondary resistance remains a major clinical challenge, thereby limiting long-term efficacy and patient survival. Recent studies have systematically clarified the multidimensional mechanisms underlying resistance to CAR T-cell therapy, which can be broadly classified into tumor-intrinsic factors, CAR T-cell dysfunction, and an immunosuppressive tumor microenvironment (TME). At the same time, innovative strategies to overcome these barriers have rapidly emerged, including multitarget CAR design, metabolic and epigenetic modulation, and microenvironment remodeling. This review summarizes the latest advances in the mechanisms of resistance to CAR T-cell therapy and corresponding therapeutic strategies in B-cell malignancies, and further discusses future perspectives to provide a theoretical basis for optimizing CAR T-cell therapy.

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proteins

2026-07-28 | Peptide-Drug Conjugates for Targeted Delivery in Hematological Malignancies: From Design Principles to Clinical Application.

Hematological malignancies account for over 1.3 million new cases and approximately 700,000 deaths annually. Despite advances in targeted therapies, immunotherapies, and antibody-drug conjugates, relapse, refractory disease, and acquired drug resistance remain critical challenges. Peptide-drug conjugates (PDCs) have emerged as a promising targeted delivery platform, combining peptide-mediated specificity with potent cytotoxic payloads. In this review, we summarized the fundamental design principles of PDCs, including targeting peptide selection, linker engineering, and payload optimization, with emphasis on the biological characteristics of hematological malignancies. We then examined current preclinical and clinical progress across multiple myeloma, acute myeloid leukemia, myelodysplastic syndromes, B-cell non-Hodgkin lymphoma, and chronic myeloid leukemia. We further discussed emerging strategies such as cathepsin B-responsive PROTAC-PDC hybrids, nanotechnology-assisted delivery, and artificial intelligence-guided molecular design. Finally, we addressed key translational challenges, including tumor heterogeneity, payload resistance, and pharmacokinetic constraints, and proposed future directions toward biomarker-driven precision PDC therapy for hematological malignancies.

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2026-07-17 | Englumafusp alfa plus glofitamab in B cell non-Hodgkin lymphoma: a phase 1 trial.

There is an unmet need for effective, off-the-shelf therapies for relapsed or refractory aggressive B cell non-Hodgkin lymphoma (B-NHL). Part 2 of the current study was an open-label, nonrandomized, phase 1 study of escalating doses of the CD19-4-1BBL co-stimulatory molecule, englumafusp alfa, in combination with glofitamab in patients with relapsed or refractory B-NHL. Obinutuzumab pretreatment was administered 7 days before the first glofitamab dose. Glofitamab step-up dosing in cycle 1 was followed by 11 cycles of glofitamab plus englumafusp alfa. Englumafusp alfa was administered at escalating doses, with the initial dose on cycle 2 day 8 (C2D8) or cycle 1 day 10 (C1D10). Primary objectives were to establish the maximum tolerated dose, and safety and tolerability. A total of 134 patients were enrolled, including 109 with aggressive B-NHL and 25 with indolent B-NHL. The maximum tolerated dose of englumafusp alfa was not reached; one dose-limiting toxicity occurred (grade 5 Pneumocystis jirovecii pneumonia). Adverse events were reported in 98.5% of all patients, with grade 3/4 adverse events in 59.0%. Grade 5 adverse events occurred in ten patients. In the subgroup of C2D8 patients with aggressive B-NHL (n = 83), overall response and complete metabolic response rates were 68.7% and 56.6%, respectively; among those without previous exposure to chimeric antigen receptor T cell therapy (n = 41), the corresponding rates were 73.2% and 65.9%. Pharmacodynamic changes following englumafusp alfa administration supported its co-stimulatory mode of action. These data demonstrate that the addition of englumafusp alfa to glofitamab is associated with encouraging efficacy and robust pharmacodynamic modulation, as well as a safety profile consistent with glofitamab monotherapy, in patients with relapsed or refractory B-NHL. CTIS identifier: 2022-502616-37-00 ; ClinicalTrials.gov identifier: NCT04077723 .

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2026-06-18 | Real-World Assessment of Prophylactic Anakinra on Neurotoxicity and Cytokine Release Syndrome after CD19 Chimeric Antigen Receptor T-Cell Therapy in Relapsed and Refractory B-Cell Lymphoma: An Inverse Probability of Treatment Weighting Analysis.

CD19-directed chimeric antigen receptor T-cell (CAR T) therapy has significantly improved outcomes for patients with relapsed or refractory B-cell non-Hodgkin lymphoma (R/R B-NHL) but is frequently complicated by immune effector cell-associated neurotoxicity syndrome (ICANS), a major cause of morbidity and mortality. Preclinical and early-phase clinical studies suggest that interleukin-1 blockade with anakinra may mitigate ICANS without impairing CAR T efficacy. However, real-world data evaluating the efficacy and safety of prophylactic anakinra remain limited. We performed a retrospective analysis comparing CAR T toxicities and clinical outcomes among patients treated with prophylactic anakinra versus controls using inverse probability of treatment weighting (IPTW), hypothesizing that anakinra prophylaxis would be associated with decreased severe ICANS. In 2023, our institution implemented a policy for anakinra prophylaxis for high-risk patients based on promising early-phase data. We conducted a single-center retrospective cohort study of 176 adult patients with R/R B-NHL who received CD19 CAR T therapy between 2018 and 2025. The analysis was restricted to patients meeting institutional criteria for anakinra prophylaxis (age ≥65 yr or receipt of a CD28 costimulatory domain CAR T product), excluding those with baseline ICE score <8. Patients treated with anakinra in the postpolicy era were compared with patients treated prior to the implementation of the policy. IPTW was used to balance baseline clinical and disease-related covariates between groups. After IPTW, patients receiving prophylactic anakinra had a higher incidence of any-grade ICANS compared with those who did not (40.0% versus 23.0%, P = .03), while rates of grade ≥3 ICANS were similar between groups (P = .62). In multivariate regression, anakinra prophylaxis was associated with increased odds of any-grade ICANS (aOR 3.22; 95% CI 1.39 to 7.46) but not grade ≥3 ICANS (aOR 1.84; 95% CI 0.61 to 5.5). Rates of all-grade cytokine release syndrome (CRS) were comparable (P = .74); however, in multivariate regression, anakinra prophylaxis was associated with increased odds of grade ≥3 CRS (aOR 17.83; 95% CI 1.30 to 245.21), though the estimate was imprecise due to sparse events. Grade ≥3 infections were more common in the anakinra cohort (21.5% versus 7.3%; P = .01) by day 30 and by day 90 (27.1% versus 10.4%; P = .01). Grade ≥3 infections remained associated with use of anakinra in multivariate regression (day 30: aOR 7.08; 95% CI 1.90 to 26.30, P = .004) (day 90: aOR 5.59; 95% CI 1.83 to 17.04; P = .003). No differences in response rates, event-free or overall survival were observed between groups. In this single-center historical comparison of high-risk patients receiving CD19 CAR T cells, prophylactic anakinra did not reduce severe ICANS and was associated with increased immune-mediated toxicities and infectious complications. Causal inference is limited by policy-driven treatment assignment, residual temporal confounding, and limited practical overlap. These findings suggest the need for caution in routine use of anakinra prophylaxis outside of clinical trials and underscore the importance of prospective studies to better define optimal toxicity mitigation strategies.

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2026-01-28 | Recurrent Urinary Tract Infections in a Patient with Diffuse Large B-Cell Lymphoma and Severe COVID-19: A Single Case of Suspected Immunosuppression Where Antibacterial Therapy Was Not Enough.

Background: Non-Hodgkin lymphoma (NHL) is a malignancy of the immune system that includes several subtypes, most commonly diffuse large B-cell lymphoma and follicular lymphoma. Its etiology is multifactorial, with risk factors such as immunosuppressive therapy, infections, chemical exposure, and advanced age. A key aspect is the bidirectional relationship between lymphoma and immunodeficiency, which increases susceptibility to recurrent infections and complicates disease management. Case presentation: One particularly challenging case during the COVID-19 pandemic involved a patient with a personal history of diffuse B-cell non-Hodgkin lymphoma, diagnosed 5 years earlier, who had undergone eight cycles of rituximab-based chemotherapy. The patient tested positive for SARS-CoV-2 for three consecutive months and experienced repeated urinary tract infections warranting more in-depth investigations. The uniqueness of this case lies in the rare association of non-Hodgkin lymphoma, suspected post-rituximab immunodeficiency, severe COVID-19 infection, and recurrent urinary tract infections, which complicated clinical management. Despite appropriate treatment for both respiratory and urinary infections, as well as eight cycles of chemotherapy, the patient's condition continued to deteriorate significantly, ultimately requiring intravenous immunoglobulin replacement therapy. Following the treatment, the patient presented a remarkable clinical improvement, with resolution of the signs and symptoms, and an absence of further recurrent infections. The patient remained clinically stable under regular immunoglobulin replacement therapy, with sustained infection control and improved quality of life. Conclusions: This case highlights the importance of assessing immune status in patients with a hematological malignancy, especially when recurrent infections persist.

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2025-11-03 | CHN1 suppresses B-cell non-Hodgkin lymphoma progression via akt/mTOR pathway

Abstract Introduction B-cell non-Hodgkin lymphoma (B-NHL) is the most prevalent NHL subtype, exhibiting high heterogeneity. Chimerin 1 (CHN1), a rac guanosine triphosphatase activating protein (racGAP), is predominantly expressed in neurons, especially in the cerebral cortex, and plays an important role in axon guidance. The previous study has estimated that CHN1 was associated with B-NHL aggressiveness, showing higher expression in indolent follicular lymphoma (FL) compared to aggressive Burkitt lymphoma (BL). In silico analysis also linked high CHN1 expression with favorable outcomes in diffuse large B-cell lymphoma (DLBCL) patients, though this prognostic value requires validation. The functional role of CHN1 in B-NHL remains unclear. Therefore, we aimed to validate the prognostic value of CHN1 in DLBCL and elucidate its biological functions and signaling pathways in B-NHL cells. Methods We retrospectively collected pathological specimens from 52 DLBCL patients. CHN1 expression was assessed by immunohistochemical (IHC) staining. Kaplan-Meier analysis evaluated the correlation between CHN1 expression levels and the prognosis of DLBCL patients. Stable CHN1-overexpressing human DLBCL cell line OCI-LY3 and human Burkitt lymphoma cell line Raji were established via lentiviral transduction. Cell proliferation was measured by direct cell counting. Migration and invasion were assessed using Transwell assays. Protein expression was analyzed by Western blotting. Transcriptome sequencing of OCI-LY3^OE^ cells, followed by GO, KEGG, and GSEA enrichment analyses, identified downstream pathways. Results IHC analysis classified DLBCL patients into CHN1-high and CHN1-low groups (cut-off value: 10% positivity). The CHN1-high group exhibited significantly higher objective response (OR: 86.2% vs. 39.1%, p=0.001) and complete response (CR: 65.5% vs. 21.7%, p=0.002) rates compared to the CHN1-low group. The disease progression (PD) rate was significantly lower in the CHN1-high group (10.3% vs. 52.2%, p=0.001). Kaplan-Meier analysis demonstrated that high CHN1 expression was significantly correlated with prolonged overall survival (OS, p=0.036) and progression-free survival (PFS, p=0.002). Successful establishment of CHN1-overexpressing RajiOE and OCI-LY3OE cells was confirmed. CHN1 overexpression significantly inhibited proliferation (p&lt;0.001) and promoted apoptosis in both cell lines (Raji: p&lt;0.001; OCI-LY3: p=0.002). Western blot demonstrated that CHN1 downregulated the anti-apoptotic protein BCL-2 (OCI-LY3OE: p=0.029; RajiOE: p=0.036) and upregulated the pro-apoptotic protein Bax (OCI-LY3OE: p=0.047; RajiOE: p=0.029). Furthermore, CHN1 suppressed migration (OCI-LY3: p=0.004; Raji: p=0.008) and invasion (OCI-LY3: p=0.012; Raji: p=0.007). Transcriptome sequencing of CHN1-overexpressing OCI-LY3 cells identified 867 upregulated and 1,035 downregulated genes. Enrichment analyses suggested that CHN1 involvement in cell adhesion, metabolism, vesicle formation, and cell junctions, and modulate pathways including PI3K/Akt, IL6/JAK/STAT3, and IL2/STAT5 signaling. Consistently, western blot revealed that CHN1 suppressed the phosphorylation of Akt and mTOR. Treatment with the Akt activator Sc79 partially restored Akt/mTOR phosphorylation and rescued the proliferative, migratory, and invasive capacities by CHN1 overexpression. Conclusions High CHN1 expression is a favorable prognostic marker in DLBCL, associated with higher OR/CR rates, lower PD, and prolonged OS and PFS. CHN1 suppresses B-NHL progression by inhibiting proliferation, migration, and invasion in B-NHL cells. Mechanistically, the Akt/mTOR signaling pathway may be a downstream mechanism of CHN1 in B-NHL cells.

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antibodies

2026-09-15 | Radiotherapy in Combination with CD20×CD3 Bispecific Antibodies for B-Cell Lymphoma: Biological Rationale, Current Evidence, and Open Questions.

Background/Objectives: CD20×CD3 bispecific antibodies (BsAbs) have changed the management of relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma. Whether and how radiotherapy (RT) can be safely and usefully combined with BsAb therapy remains undefined. This Perspective reviews the biological rationale and the available clinical evidence, distinguishing the established findings from the hypotheses. Methods: We conducted a targeted, non-systematic review of RT combined with CD20×CD3 BsAbs in B-cell lymphoma, searching PubMed/MEDLINE, the Cochrane Library, and ClinicalTrials.gov, supplemented by conference abstracts and a post hoc verification search. Given the immaturity and heterogeneity of the field, we used a narrative synthesis rather than a systematic search. Sources were classified as direct evidence, mixed/indirect (non-disaggregable) evidence, or registered trials without results; only the first category was used to support clinical claims. Results: Direct evidence comprises three case reports, a 7-patient lymphoma subgroup, and a 29-patient cohort with disaggregated CRS/neurotoxicity data. Additional mixed/indirect evidence comes from a 12-patient series. Three registered trials have not yet reported results. Five partially overlapping rationales are proposed: cytoreduction, the modulation of the tumour microenvironment, the management of tumour flare, the consolidation of residual disease, and urgent local control during BsAb step-up dosing. The potential antagonistic effects, including CD20 loss and T-cell depletion, have received comparatively little study. Whether RT-induced lymphopenia could blunt BsAb efficacy remains a key open question. Conclusions: The available evidence indicates only that RT has occasionally been delivered around BsAb therapy in small, non-comparative series, without a consistent toxicity signal. It does not establish the benefit, synergy, or optimal sequencing. Prospective studies are needed to define the role of RT in this setting.

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2026-09-09 | Protocol and Cohort Profile of a Prospective Multicenter Lymphoma Cohort in South Korea.

Real-world data are increasingly used to support pragmatic clinical trials. However, most existing oncology cohorts lack high-frequency symptom data and standardized infrastructures required for longitudinal outcome assessment. To describe the design of a prospective multicenter lymphoma cohort integrating patient-reported outcomes (PRO) to support future pragmatic trials. This ongoing cohort integrates data from institutional lymphoma registries established in 2010 and a multicenter prospective expansion initiated in April 2023. All participants provided written informed consent under the registry or multicenter cohort protocol applicable at the time of enrollment. Standardized electronic case report forms capture demographic, clinical, laboratory, and treatment information. PRO are collected using a mobile web-based platform. High-frequency symptom assessments are conducted using the PRO-CTCAE system at seven predefined time points per chemotherapy cycle. Data quality is maintained through predefined coding schemes, automated validation checks, and regular audits. Vital status is ascertained through linkage with national mortality data. Among 2,370 enrolled patients, 143 had Hodgkin lymphoma, 1,726 had B-cell non-Hodgkin lymphoma, and 501 had T- or NK-cell non-Hodgkin lymphoma. The high-frequency symptom data enable longitudinal assessment of treatment-related symptom trajectories across chemotherapy cycles. This cohort integrates standardized clinical data with high-frequency patient-reported outcomes in a real-world setting. The data structure and prospective design may support future pragmatic trials by enabling longitudinal outcome assessment and patient-centered monitoring.

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2026-08-26 | Safety and efficacy of bispecific antibodies in hematologic neoplasms: a systematic review.

Hematologic neoplasms remain a growing global burden, with relapse, resistance, and limited treatment options persisting. Bispecific antibodies (BsAbs) offer a novel multi-antigen targeting strategy. This systematic review assesses their efficacy and safety, offering an in-depth appraisal of their therapeutic potential and the unmet medical needs. We conducted this systematic review following the PRISMA 2020 guidelines. Articles published up to 20 June 2026 were searched across PubMed, Scopus, Web of Science, and Embase. Efficacy outcomes such as measurable residual disease (MRD), overall response rate (ORR), complete response (CR), overall survival (OS), and progression-free survival (PFS), as well as safety outcomes such as severe adverse events (SAEs), grade ≥3 adverse events (≥3 AEs), hematologic and non-hematologic toxicities were systematically evaluated. Thirty-six studies evaluating nineteen different BsAbs were included. Blinatumomab (CD3-CD19) remains the most extensively studied bispecific antibody in relapsed or refractory B-cell precursor acute lymphoblastic leukemia (R/R BCP-ALL). CD3-CD20 BsAbs (Glofitamab, Epcoritamab) demonstrated durability in non-Hodgkin lymphoma (NHL). In multiple myeloma (MM), BCMA- and GPRC5D-targeting BsAbs achieved MRD negativity and deep responses including very good partial response (VGPR) and stringent complete response (sCR). BsAbs in acute myeloid leukemia (AML) and Hodgkin/T-cell lymphoma (HL/TCL) remained early-phase with limited efficacy and no approvals to date. Cytokine release syndrome (CRS) and neurotoxicity were the dominant toxicities of CD3-engaging agents (neurologic events >50% in several Blinatumomab studies). Teclistamab (CD3-BCMA) and Talquetamab (CD3-GPRC5D) were associated with frequent CRS, with neurotoxicity also reported. However, hematologic toxicity and infections remain major challenges in multiple myeloma treatment. BsAbs demonstrate established clinical activity in BCP-ALL, B-cell NHL, and MM but remain under investigation in AML, HL, and T-cell lymphoma. CRS, neurotoxicity, cytopenias, and infections remain key safety considerations. Further studies should optimize treatment strategies and evaluate emerging targets and non-CD3-engaging bispecific antibodies.The protocol was prospectively registered in PROSPERO (CRD42023467556). https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023467556.

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2026-07-31 | Mosunetuzumab: A bispecific CD20 × CD3 antibody for follicular lymphoma with promising evidence in other B-NHL subtypes.

Mosunetuzumab is a bispecific antibody targeting CD20 x CD3 re-directing T cells to target and destroy CD20-positive B cells. T-cell-based therapies including bispecific antibodies have revolutionized B-cell NHL treatment. Mosunetuzumab is approved for follicular lymphoma with at least 2 prior lines of therapy. There are also NCCN recommendations for its use in diffuse large B-cell lymphoma and in combination with polatuzumab vedotin in relapsed/refractory mantle cell lymphoma with prior BTK inhibitor therapy. Published trials show low rates of severe CRS and support outpatient administration in appropriate settings. Utilizing a search of PubMed, conference abstracts, and clinicaltrials.gov between 2020 and 2026, prospective trial data as well as retrospective real-world evidence and ongoing studies were included for a more complete picture of available data. This review summarizes the molecular design, mechanism of action, clinical efficacy, and safety of mosunetuzumab, an agent representative of immunotherapeutic advancement in lymphoma.

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2026-07-22 | Glofitamab in the sequential treatment of relapsed/refractory B-Cell lymphoma: a single-center real-world study.

Glofitamab is a bispecific antibody (BsAb), and has good efficacy in relapsed or refractory B-cell non-Hodgkin lymphoma (r/r B-NHL), especially in relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). This study explored its sequential treatment strategies and efficacy in the real world, including rescue therapy after chimeric antigen receptor T cell (CAR-T) therapy failure, bridging CAR-T therapy and monotherapy. This was a single-center retrospective cohort analysis of 24 patients with clearly diagnosed relapsed/refractory B-cell lymphoma, including primary diffuse large B-cell lymphoma (DLBCL), diffuse large B-cell lymphoma with Richter transformation (DLBCL-RT), and Burkitt lymphoma (BL). Patients were divided into three groups according to the treatment sequence: Group 1 (Glofitamab rescue therapy after progression of CAR-T therapy), group 2 (Glofitamab bridging subsequent CAR-T therapy), and group 3 (Glofitamab monotherapy), who received Glofitamab at our center between September 2024 and December 2025. In the single-center real-world experience, Glofitamab demonstrated controllable safety and durable anti-tumor activity in three clinical scenarios. Especially, it could still bring clinical benefits even after CAR-T therapy failed, and it explored the sequential treatment strategy of Glofitamab and CAR-T.

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2025-10-31 | TIMAP downregulation in Burkitt's lymphoma reveals key molecules and signaling pathways in B-cell lymphomagenesis.

Burkitt's lymphoma (BL) is an aggressive subtype of B-cell non-Hodgkin's lymphoma, known for its rapid tumor growth and poor prognosis. Transforming growth factor beta-inhibited membrane-associated protein (TIMAP) is a regulatory subunit of protein phosphatase 1 catalytic subunit, enriched in lymphoid tissues, and upregulated in various cancers. Despite suggestions that TIMAP promotes lymphomagenesis in a c-myc-driven model, its precise role remains unclear. This study aimed to investigate the contribution of TIMAP to B-cell lymphomagenesis by examining transcriptomic changes upon TIMAP downregulation in BL cells. Raji BL cells were transfected with 2'Fluoro Arabinonucleic acid (FANA)-antisense oligonucleotides (ASO) targeting TIMAP (FANA-ASO-TIMAP) or a scramble control (FANA-ASO-Scramble). TIMAP expression was significantly reduced at the mRNA (0.70 ± 0.04, p = 0.001) and protein levels (median = 0.73, IQR = 0.13, p = 0.002). RNA sequencing identified 2,368 differentially expressed genes (DEGs), of which 1,326 were upregulated, and 1,042 were downregulated. Gene Ontology analysis revealed that the DEGs were primarily involved in cellular processes, DNA replication, intracellular signal transduction, and apoptosis. Pathways related to lymphoma progression, such as B-cell receptor signaling, p53 signaling, and mTOR signaling, were notably affected. Key genes such as PAK3, LINC00487, AID, PURPL, and BCL2 were among the most dysregulated, highlighting TIMAP's role in critical oncogenic pathways in B-cell Lymphoma. These findings suggest that TIMAP is a key regulator of gene expression and signaling pathways in B-cell lymphomagenesis and could serve as a potential therapeutic target for novel treatments.

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2025-07-30 | Liquid-liquid phase separation of ZHX2 protects DLBCL cells against ferroptosis through induction of SLC3A2.

Diffuse large B-cell lymphoma (DLBCL), the most common B-cell non-Hodgkin lymphoma (B-NHL), is characterized by strong aggression, high heterogeneity, and poor prognosis. Consequently, there is an urgent need to identify crucial therapeutic targets. Here, we found that the transcription factor zinc-finger and homeobox 2 (ZHX2) was highly expressed in DLBCL. Subsequently, ZHX2 was proven to be critical for promoting DLBCL cell proliferation by inhibiting ferroptosis. Mechanistically, ZHX2 bound to the promoter region of the solute carrier family 3-member 2 (SLC3A2) gene through liquid-liquid phase separation (LLPS) and activated its function to negatively regulate ferroptosis. Furthermore, we constructed lipid nanoparticles ZHX2-siRNA@LNP targeting DLBCL, which effectively inhibited the growth of the tumors in vivo. In summary, our study indicated that the LLPS of ZHX2 protected DLBCL against ferroptosis through induction of SLC3A2, and disturbing it with ZHX2-siRNA@LNP could significantly repress DLBCL, providing a promising therapeutic strategy for DLBCL.

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2023-11-16 | Alternative splicing of its 5′-UTR limits CD20 mRNA translation and enables resistance to CD20-directed immunotherapies

Abstract Aberrant skipping of coding exons in CD19 and CD22 compromises the response to immunotherapy in B-cell malignancies. Here, we showed that the MS4A1 gene encoding human CD20 also produces several messenger RNA (mRNA) isoforms with distinct 5′ untranslated regions. Four variants (V1-4) were detected using RNA sequencing (RNA-seq) at distinct stages of normal B-cell differentiation and B-lymphoid malignancies, with V1 and V3 being the most abundant. During B-cell activation and Epstein-Barr virus infection, redirection of splicing from V1 to V3 coincided with increased CD20 positivity. Similarly, in diffuse large B-cell lymphoma, only V3, but not V1, correlated with CD20 protein levels, suggesting that V1 might be translation-deficient. Indeed, the longer V1 isoform contained upstream open reading frames and a stem-loop structure, which cooperatively inhibited polysome recruitment. By modulating CD20 isoforms with splice-switching morpholino oligomers, we enhanced CD20 expression and anti-CD20 antibody rituximab-mediated cytotoxicity in a panel of B-cell lines. Furthermore, reconstitution of CD20-knockout cells with V3 mRNA led to the recovery of CD20 positivity, whereas V1-reconstituted cells had undetectable levels of CD20 protein. Surprisingly, in vitro CD20-directed chimeric antigen receptor T cells were able to kill both V3- and V1-expressing cells, but the bispecific T-cell engager mosunetuzumab was only effective against V3-expressing cells. To determine whether CD20 splicing is involved in immunotherapy resistance, we performed RNA-seq on 4 postmosunetuzumab follicular lymphoma relapses and discovered that in 2 of them, the downregulation of CD20 was accompanied by a V3-to-V1 shift. Thus, splicing-mediated mechanisms of epitope loss extend to CD20-directed immunotherapies.

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2023-08-29 | TESOGENASE, An Engineered Nuclease Editor for Enhanced Targeted Genome Integration

Summary/Abstract Non-viral DNA donor template has been widely used for targeted genomic integration by homologous recombination (HR). This process has become more efficient with RNA guided endonuclease editor system such as CRISPR/Cas9. Circular single stranded DNA (cssDNA) has been harnessed previously as a g enome engineering c atalyst (GATALYST) for efficient and safe targeted gene knock-in. However, the engineering efficiency is bottlenecked by the nucleoplasm trafficking and genomic tethering of cssDNA donor, especially for extra-large transgene integration. Here we developed enGager, en hanced G ATALYST a ssociated g enome e ditor system by fusion of nucleus localization signal (NLS) peptide tagged Cas9 with various single stranded DNA binding protein modules through a GFP reporter Knock-in screening. The enGager system assembles an integrative genome integration machinery by forming tripartite complex for engineered nuclease editors, sgRNA and ssDNA donors, thereby facilitate the nucleus trafficking of DNA donors and increase their active local concentration at the targeted genomic site. When applied for genome integration with cssDNA donor templates to diverse genomic loci in various cell types, these enGagers outperform unfused editors. The enhancement of integration efficiency ranges from 1.5- to more than 6-fold, with the effect being more prominent for > 4Kb transgene knock-in in primary cells. We further demonstrated that enGager mediated enhancement for genome integration is ssDNA, but less dsDNA dependent. Using one of the mini-enGagers, we demonstrated large chimeric antigen receptor (CAR) transgene integration in primary T cells with exceptional efficiency and anti-tumor function. These tripartite e ditors with s sDNA o ptimized g enome en gineering system (TESOGENASE TM ) add a set of novel endonuclease editors into the gene-editing toolbox for potential cell and gene therapeutic development based on ssDNA mediated non-viral genome engineering. Highlight A reporter Knock-in screening establishes enGager system to identify TESOGENASE editor to improving ssDNA mediated genome integration Mini-TESOGENASEs developed by fusing Cas9 nuclease with novel ssDNA binding motifs mRNA mini-TESOGENASEs enhance targeted genome integration via various non-viral delivery approaches Efficient functional CAR-T cell engineering by mini-TESOGENASE

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2023-07-06 | Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine Immunogenicity among Chimeric Antigen Receptor T Cell Therapy Recipients.

Patients receiving chimeric antigen receptor T cell (CAR-T) therapy may have impaired humoral responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccinations owing to their underlying hematologic malignancy, prior lines of therapy, and CAR-T-associated hypogammaglobulinemia. Comprehensive data on vaccine immunogenicity in this patient population are limited. A single-center retrospective study of adults receiving CD19 or BCMA-directed CAR-T therapy for B cell non-Hodgkin lymphoma or multiple myeloma was conducted. Patients received at least 2 doses of SARS-CoV-2 vaccination with BNT162b2 or mRNA-1273 or 1 dose of Ad26.COV2.S and had SARS-CoV-2 anti-spike antibody (anti-S IgG) levels measured at least 1 month after the last vaccine dose. Patients were excluded if they received SARS-CoV-2 monoclonal antibody therapy or immunoglobulin within 3 months of the index anti-S titer. The seropositivity rate (assessed by an anti-S assay cutoff of ≥.8 U/mL in the Roche assay) and median anti-S IgG titers were analyzed. Fifty patients were included in the study. The median age was 65 years (interquartile range [IQR], 58 to 70 years), and the majority were male (68%). Thirty-two participants (64%) had a positive antibody response, with a median titer of 138.5 U/mL (IQR, 11.61 to 2541 U/mL). Receipt of ≥3 vaccines was associated with a significantly higher anti-S IgG level. Our study supports current guidelines for SARS-CoV-2 vaccination among recipients of CAR-T therapy and demonstrates that a 3-dose primary series followed by a fourth booster increases antibody levels. However, the relatively low magnitude of titers and low percentage of nonresponders demonstrates that further studies are needed to optimize vaccination timing and determine predictors of vaccine response in this population.

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