RARE DISEASE
T-cell non-Hodgkin lymphoma
T-cell non-Hodgkin lymphoma
T-cell non-Hodgkin lymphoma
Synonyms: T-cell NHL
Synonyms: T-cell NHL
Synonyms: T-cell NHL
Drug discovery
34
drugs
With orphan designations
Overview
T-cell non-Hodgkin lymphoma (T-NHL) comprises 10–15% of NHL cases and includes aggressive malignancies originating from mature T-cells, such as peripheral T-cell lymphoma (PTCL) and anaplastic large cell lymphoma (ALCL). Diagnosis relies on histopathological evaluation, often presenting with advanced-stage disease. First-line treatment involves anthracycline-based chemotherapy (e.g., CHOP regimen), but relapse rates remain high. Targeted therapies (e.g., brentuximab vedotin for CD30+ ALCL) and stem cell transplantation are reserved for refractory cases. Prognosis is poorer than B-cell NHL, with 5-year survival rates of 30–40% [5][6][11][16].
Therapies
First-line: CHOP chemotherapy ± consolidative autologous/allogeneic stem cell transplant [6][18].
Targeted therapies: Brentuximab vedotin (CD30+ ALCL), pralatrexate, and histone deacetylase inhibitors (e.g., romidepsin) [3][6][13].
Emerging options: CAR T-cell therapy and checkpoint inhibitors in clinical trials [6][13][18].
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
427 drug discovery papers about T-cell non-Hodgkin lymphoma, with 1 first-in-class and 12 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
427 drug discovery papers about T-cell non-Hodgkin lymphoma, with 1 first-in-class and 12 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-16 | Malignancy-Associated Hemophagocytic Lymphohistiocytosis: Clinical Characteristics, Treatment Patterns, and Survival Outcomes in a Tertiary Care Center Cohort.
Malignancy-associated hemophagocytic lymphohistiocytosis (M-HLH) carries a poor prognosis and is often complicated by overlapping infection, cytopenias, organ failure, and progressive disease. We retrospectively analyzed 49 adults with M-HLH at a single tertiary cancer center (2013-2026), summarizing malignancy spectrum, diagnostic features, treatment, and survival outcomes. HLH probability was assessed by HScore and modified HLH-2004 criteria. Lymphoma was the main underlying disease (34/49; 69.4%), led by aggressive B-cell (17/49; 34.7%) and T-cell NHL (12/49; 24.5%). HLH coincided with initial malignancy recognition in 17 of 49 patients (34.7%). The median HScore was 231 (IQR 202-256); 44 of 49 patients (89.8%) met the ≥ 169 threshold, and 42 of 49 patients (85.7%) fulfilled ≥ 5 of 7 modified HLH-2004 criteria. HLH-directed therapy included corticosteroids (41/49; 83.7%), etoposide (21/49; 42.9%), and anakinra (16/49; 32.7%); 21 of 49 patients (42.9%) received concurrent malignancy-directed chemotherapy. Mortality was 59.2% (29/49) with a median overall survival of 56 days (median follow-up 612 days for the cohort; 574 days among survivors, n = 20). De novo presentation carried substantially lower mortality than HLH in previously known malignancy (23.5% vs. 78.1%; hazard ratio [HR] 5.38, 95% confidence interval [CI], 1.85-15.61; P = .002). Malignancy-directed chemotherapy was associated with lower mortality than HLH-directed therapy alone (HR 3.11, 95% CI, 1.36-7.09; P = .007). All 6 patients with invasive mold infection died. M-HLH was predominantly lymphoma-associated, met diagnostic criteria with high probability, and carried poor short-term survival. De novo presentation had better outcomes, likely because lymphoma-directed chemotherapy can simultaneously address the underlying malignant trigger and the hyperinflammatory state. Invasive mold infection was uniformly fatal, illustrating the lethal combination of profound immunosuppression and uncontrolled opportunistic infection in this setting.
2026-06-23 | Bendamustine-based lymphodepletion prior to CAR T-cell therapy: a systematic review.
Lymphodepletion (LD) is a critical prerequisite for successful chimeric antigen receptor T-cell (CAR-T) therapy. While fludarabine and cyclophosphamide (Flu/Cy) remain the standard LD regimen, bendamustine has emerged as a potential alternative due to its distinct immunomodulatory properties and more favorable toxicity profile. This systematic review evaluates the safety, efficacy, and feasibility of bendamustine-based LD in patients undergoing CAR-T therapy for hematologic malignancies. A comprehensive literature search was conducted through January 2026 across PubMed, Embase, Web of Science, and clinical trial registries. Studies were eligible if they reported clinical outcomes following bendamustine-based lymphodepletion prior to CD19-, CD30-, or BCMA-directed CAR-T therapy. Extracted endpoints included overall response rate (ORR), complete response rate (CRR), progression-free survival (PFS), overall survival (OS), and treatment-related toxicities. Eighteen studies comprising over 1400 patients were included. Across disease indications-including B- and T-cell non-Hodgkin lymphoma, Hodgkin lymphoma (HL), and multiple myeloma (MM)-ORRs ranged from 50% to 88%, with CRRs up to 74%. Compared with Flu/Cy, bendamustine-based LD demonstrated comparable efficacy while being associated with significantly lower rates of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and grade ≥3 cytopenias. Additionally, bendamustine facilitated outpatient CAR-T delivery, with reduced hospitalization and intensive care unit (ICU) utilization. However, prior exposure to bendamustine before leukapheresis was associated with inferior CAR-T outcomes. Bendamustine-based LD represents a safe and effective alternative to Flu/Cy, particularly in outpatient settings and in patients at higher risk of treatment-related toxicity. However, the current evidence is largely derived from retrospective and non-randomized studies. Prospective, comparative trials are warranted to validate these findings and to better define the optimal LD strategy across disease types and CAR-T platforms.
2025-12-31 | Subcutaneous Panniculitis-like T-cell Non-Hodgkin Lymphoma Associated with Cushing Syndrome: An Introspection
Background: Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) accounts for less than 1% of non-Hodgkin lymphoma cases and is characterized by malignant lymphocyte infiltration into adipose tissues. The term “panniculitis-like T -cells” refers to the histological similarity of the lymphoma cells to the T-cells found in chronic or granulomatous panniculitis. This type of lymphoma is responsible for an ectopic ACTH secretion which leads to excessive cortisol secretion causing Cushing syndrome. Case: A 45-year-old patient diagnosed with SPTCL in 2022 underwent six cycles of cyclophosphamide, epirubicin, vincristine, and prednisone (CHOP regimen). Due to iatrogenic Cushing syndrome, CHOP was discontinued, and two cycles of rituximab-ifosphamide-carboplatin-etoposide (R-ICE) were administered. In 2023, the patient presented with scleral jaundice and dark urine. Laboratory findings revealed a total bilirubin of 11.2 mg/dL, leukopenia, thrombocytopenia, hyperfibrinogenemia, and elevated D-dimers. A CT scan showed hepatic and iliopsoas muscle lesions, indicating systemic dissemination and relapse of the lymphoma. Conclusion: Corticosteroid-based regimens are standard treatment options for SPTCL. However, paraneoplastic syndromes such as ectopic ACTH secretion by malignant cells may lead to excessive cortisol levels, exacerbated by corticosteroids. Due to iatrogenic Cushing syndrome induced by the first-line therapy and relapse following second-line options, off-label venetoclax, an apoptosis inducer, was initiated in combination with ropeginterferon alfa-2b. The patient achieved complete remission. No SPTCL cases treated with venetoclax have been published in the literature. We report high efficacy of off-label venetoclax in a relapsed SPTCL with no other available therapeutic option.
2025-12-13 | Fucoidan potentiates anti-tumor efficacy of CAR-T cells against non-Hodgkin lymphoma by activation of STAT3 pathway
BACKGROUND: Despite advances in chimeric antigen receptor T-cell (CAR-T) therapy, significant challenges remain, including progressive T-cell exhaustion and poor in vivo persistence. Current strategies to enhance CAR-T function-such as cytokine co-expression-often lead to severe adverse effects, most notably cytokine release syndrome (CRS). Therefore, there is a pressing need to develop safer and more sustainable approaches, particularly through nutritional interventions, to improve the antitumor efficacy of CAR-T therapy. Fucoidan (FO), a bioactive polysaccharide derived from marine plants, has demonstrated immunomodulatory properties and synergistic potential in combination with conventional chemotherapy. However, its role in cellular immunotherapy, including CAR-T therapy, has not yet been explored. This study aims to elucidate the function of FO in CAR-T therapy for non-Hodgkin lymphoma (NHL) and to provide a foundational basis for its clinical translation in the field of cellular immunotherapy. METHODS: The current study used a combination of in vitro and in vivo assays to explore the role of FO in CAR T therapy. The anti-CD19 CAR-T cells were constructed by lentivirus containing CAR-CD19 structure. For phenotype analysis of CAR T cells, different cell populations, such as memory and exhausted CAR T cells, were stained by cell marker and identified by flow cytometry. CAR-T cells from different treatment groups were co-cultured with target cells with different E: T ratio to detect the cytotoxicity and cytokine release of CAR-T cells. We also evaluate FO's supportive role for function of CAR-T cells in the tumor-bearing mouse models. The underlying mechanism of activated signaling pathway were also investigated and confirmed by the inhibitor. RESULTS: In this study, we systematically investigated the role of FO in anti-CD19 CAR-T cell-mediated treatment of NHL. Specifically, CAR-T cells' memory maintenance and exhaustion resistance were enhanced by FO. FO not only improved CAR-T cell's antioxidant capacity and proliferation, but also prevented apoptosis of activated CAR-T cells, collectively contributing to the improved and sustained anti-tumor efficacy in both in vitro assays and xenograft models. Our mechanistic studies also revealed FO served as a potentiator for CAR-T cells' function through enhancing the activation of STAT3 signaling pathway. CONCLUSIONS: These findings elucidate the supportive role of FO in enhancing CAR-T cell function, which indicates FO's clinical potential as immunomodulatory supplement to potentiate CAR-T therapy against NHL.
2025-11-13 | The Potential of the Gut Microbiota and Butyrate to Enhance CAR T-cell Therapy in Non-Hodgkin Lymphoma
Our results support the relationship between microbiota and CAR T-cell therapy major outcomes. Analysis of microbiota led to the identification of SCFAs, especially butyrate, as a prognostic factor, and also provides the basis for considering them as chemical modifiers of CAR T cells to improve their efficacy.
cell therapies
2026-05-27 | Novel transposon BAFF CAR-T cells (LMY-920) for non-Hodgkin lymphoma (NHL).
2563 Background: CAR-T cells targeting CD19 using scFv-based CARs have been effective and approved to treat lymphoma. Response rates are high, but a significant number of patients fail to respond or relapse. This has been linked to T cell exhaustion, immune dysregulation, and/or epitope loss. To overcome this, we developed a CAR-T cell product expressing a BAFF-ligand (LMY-920). The CAR consists of truncated human BAFF on a 3rd generation CAR backbone with CD28, OX40, and CD3z intracellular signaling domains. The BAFF-ligand domain confers ability to bind the 3 BAFF receptors (BAFFR/BR3, TACI and BCMA). These are attractive tumor-associated antigens being variably expressed in all B-lineage malignancies such as B cell NHL, chronic lymphocytic leukemia (CLL), hairy cell leukemia and multiple myeloma (MM), and are important for B-cell survival, reducing the chance of antigen escape. Additionally, they are expressed on B-lineage cells involved in antibody-mediated autoimmune diseases. BAFF ligand interactions are lower affinity than scFv interactions, potentially reducing T-cell exhaustion. The novel TcBuster transposon system is used to improve manufacturing time, efficiency, cost, and safety. Methods: Patients with refractory B cell NHL are treated in this study (NCT05312801). Autologous LMY-920 CAR-T cells are manufactured, then patients receive 3 days of fludarabine (30 mg/m 2 /d) and cyclophosphamide (500 mg/m 2 /d) lymphodepletion. LMY-920 is administered intravenously in a 3+3 dose escalation design from 1-8 x 10 6 BAFF-CAR-T cells/kg. Response is assessed using the Lugano criteria. CAR-T expansion and biologic characteristics are assessed. Results: Five patients have been treated with 1-2 x 10 6 BAFF-CAR-T cells/kg in this study, 2 patients each with mantle cell lymphoma (MCL), diffuse large B cell lymphoma (DLBCL), and one with marginal zone lymphoma (MZL). Patients had received 2 – 6 prior lines of therapy and all were refractory. One patient experienced grade 1 CRS (fever), but no ICANS was reported. All patients experienced grade 3 or higher hematologic toxicity that recovered prior to day 28, and grade 1-2 fatigue. There have been no dose limiting toxicities and dose escalation continues. Responses included 2 complete responses (CR) (DLBCL), a partial response (MZL), a mixed response (MCL) and one stable disease (MCL). Of note, one of the DLBCL patients in CR had received prior axicabtagene ciloleucel (anti-CD19) CAR-T cells as well as anti-CD20 bispecific antibodies, with lymphoma cells resulting in CD19 and CD20 antigen loss. Conclusions: The successful use of a novel transposon-engineered BAFF ligand-based CAR-T cell product demonstrates the potential of a new direction in CAR-T cell development. Safety and efficacy were seen, including patients with prior CAR-T failure and epitope loss, as hypothesized. This product is also being evaluated in patients with CLL, MM and systemic lupus erythematosus. Clinical trial information: NCT05312801 .
2026-05-08 | CAR-T cell therapy in non-Hodgkin lymphoma: a clinical trial landscape review
Background: Chimeric antigen receptor T cell (CAR-T) therapy has emerged as a transformative treatment modality for selected subtypes of non-Hodgkin lymphoma (NHL). While multiple CAR-T products have demonstrated remarkable clinical activity, the overall clinical development landscape remains heterogeneous, with substantial variation in trial design, target selection, geographic distribution, and endpoint prioritization. A comprehensive analysis of the global clinical trial landscape is essential to contextualize current progress and identify unmet needs in this rapidly evolving field. Methods: We conducted a systematic landscape analysis of CAR-T-related clinical trials for NHL using the Trialtrove database. Interventional trials registered up to December 18, 2025, were retrieved using predefined search criteria. Eligible studies were screened according to standardized inclusion and exclusion criteria. Key trial characteristics, including trial status, phase, geographic location, sponsor type, molecular targets, and reported clinical endpoints, were extracted and analyzed descriptively. Results: A total of 360 eligible clinical trials were included in the final analysis. The global CAR-T clinical trial landscape in NHL is characterized by rapid expansion and a predominant focus on early-phase development. Trial activity is highly concentrated in a limited number of countries, with academic institutions serving as the primary drivers of clinical investigation. CD19-directed CAR-T therapies dominate the current landscape, although emerging diversification toward alternative targets is evident. Reported study endpoints largely emphasize safety and short-term efficacy, whereas durable clinical outcomes remain less frequently assessed, reflecting the exploratory nature of most trials. Conclusion: CAR-T therapy development in NHL continues to advance rapidly, driven by academic innovation and expanding preclinical insights. However, persistent challenges related to antigen escape, treatment durability, and trial design remain. Future progress will require the integration of next-generation CAR engineering strategies, broader incorporation of long-term clinical endpoints, and alignment with evolving regulatory and policy frameworks to support sustainable clinical translation.
2026-04-21 | Targeting CAR-T cell exhaustion in non-Hodgkin lymphoma: mechanistic insights and emerging clinical strategies
Although the response rates to chimeric antigen receptor T (CAR-T) therapy in patients with treatment-resistant lymphoma are high, the majority of patients relapse. CAR-T cell exhaustion, characterized by the progressive loss of T-cell effector functions due to several molecular and epigenetic pathways, is a major mediator of CAR-T cell failure. Strategies to prevent CAR-T cell exhaustion, including modifications to the CAR structure, addition of adjunctive agents, and alternative product manufacturing strategies have shown promise. In this review, we discuss the mechanisms of CAR-T cell exhaustion and describe strategies for its mitigation, with the aim of supporting further research in this critical area.
2026-02-14 | Outcomes of point-of-care manufactured CAR T cell therapy for B cell acute lymphoblastic leukemia and non-Hodgkin lymphoma in Vietnam
Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of relapsed/refractory (R/R) B cell acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL), but access remains limited in resource-constrained settings. This phase I study evaluated the safety and feasibility of point-of-care (PoC) manufactured CD19-targeted CAR T cell therapy in Vietnamese patients. Between August 2023 and June 2025, 16 patients, eight with R/R ALL and eight with R/R NHL, were enrolled. All received fresh CAR T cells produced on-site using the CliniMACS Prodigy system, with a median dose of 1.9 × 106 CAR T cells/kg (range, 0.83-2.17 × 106). Cytokine release syndrome (CRS) occurred in 13 patients (12 with grade 1-2, one with grade 3), and grade 1 neurotoxicity was observed in two patients. In ALL, the complete remission (CR) rates were 100% on day 30, 75% on day 90, and 62.5% on day 180. Patients with NHL showed CR rates of 87.5% on both day 90 and day 180. The estimated 1-year progression-free survival rates were 62.5% (95% confidence interval [CI]: 36.5%-100%) for ALL and 87.5% (95% CI: 67.3%-100%) for NHL. PoC manufactured CD19 CAR T cells demonstrated manageable toxicity and encouraging early efficacy in Vietnamese patients with R/R ALL and NHL. This model offers a cost-effective strategy for delivering advanced therapy in resource-limited settings.
2026-01-01 | Outcomes of CAR T-Cell Therapy in transformed indolent Non-Hodgkin Lymphomas and de novo DLBCL: A comparative analysis from the Italian CAR T-SIE study
Background Transformed indolent non-Hodgkin lymphoma (TiNHL) generally has poorer outcomes than de novo diffuse large B-cell lymphoma (dnDLBCL). Although anti-CD19 CAR T-cell therapy is standard for relapsed/refractory (R/R) large B-cell lymphoma (LBCL), its prognostic role across histologies remains unclear. Methods We conducted a multicenter, retrospective/prospective observational study comparing R/R TiNHL and R/R dnDLBCL patients treated with commercial CAR T-cell therapy and enrolled in the Italian CART-SIE study. Findings Among 438 patients, 107 had TiNHL (96 transformed follicular lymphoma [tFL], 11 transformed marginal zone lymphoma [tMZL]) and 331 had dnDLBCL. Baseline characteristics were comparable. TiNHL patients showed superior overall (83% vs 69%) and complete response rates (62% vs 53%) (both p ' 0·01), with better 2-year progression-free survival (PFS: 44% vs 31%) and overall survival (OS: 61% vs 48%) (both p ' 0·01). CAR-HEMATOTOX score predicted worse outcomes (PFS HR=2·10; OS HR=3·57). No significant differences were found between tFL and tMZL. Two-year relapse/progression incidence was lower in TiNHL (28% vs 47%, p ' 0·01), with similar non-relapse mortality (11% vs 4%, p = 0·12). Safety profiles, including cytokine release syndrome and ICANS rates, were comparable. Conclusion TiNHL patients receiving CAR T-cell therapy achieved better outcomes than dnDLBCL patients, with comparable safety, supporting its use as a standard treatment in TiNHL.
proteins
2025-11-24 | Retrospective analysis of clinical characteristics, treatment outcomes and prognosis of patients with natural killer/T-cell lymphoma.
Natural killer/T-cell lymphoma (NKTCL) is the most common T-cell non-Hodgkin lymphoma in China; however, the clinical characteristics and optimal treatment remain unclear. The present study aimed to retrospectively assess the clinical features of patients with NKTCL and to determine treatment strategies. A total of 200 patients who were diagnosed with NKTCL and admitted to the Cancer Center, Union Hospital (Wuhan, China) between June 2013 and June 2022 were identified. Clinical data from these patients were collected and analyzed to evaluate the clinical features, treatment outcomes and prognostic factors. A total of 171 patients diagnosed with NKTCL were ultimately enrolled. Patients were diagnosed at a median age of 45 years and had a male-to-female ratio of 2:1. Out of the 171 patients, 117 were in the early stage (stage I/II; 68.4%) and 54 were in the advanced stage (stage III/IV; 31.6%) of NKTCL. Among these patients, B symptoms were present in 60.2% of patients (103/171) and the Eastern Cooperative Oncology Group performance status was scored as 0-1 in 93.6% of patients (160/171). Most patients had a low-to-moderate risk of international prognostic index (147/171; 86.0%), prognostic index for NKTCL (PINK; 122/171; 71.3%) and PINK with extended features (112/171; 65.5%). At baseline, it was demonstrated that Epstein-Barr virus DNA was positive in the serum of 166/171 patients (2.9%). Combined chemotherapy and radiotherapy at 54 Gy revealed a promising effect with the highest overall response rate (ORR) of 98.2%, a 4-year progression-free survival (PFS) rate of 82.5% [95% confidence interval (CI), 75.1-89.9%] and an overall survival (OS) rate of 92.2% (95% CI, 86.9-97.5%) for the early-stage group. Pegasparase-based chemotherapy was used to treat advanced-stage patients, resulting in a 4-year PFS rate of 62.3% (95% CI, 47.4-77.2%) and an OS rate of 63.5% (95% CI, 48.2-78.8%). The regimen containing the programmed cell death protein 1 inhibitor camrelizumab demonstrated an ORR of 100% in both the early- and advanced-stage cohorts. Moreover, stage and an age of >60 years were independent prognostic factors for poor PFS, whilst stage and elevated lactate dehydrogenase were independent prognostic factors for poor OS. In conclusion, the results indicated promising efficacy for pegaspargase-based chemotherapy in terms of response rates and survival outcomes for both early- and advanced-stage patients. However, further refinement of treatment strategies is needed.
2024-12-09 | Chemo-free salvage treatment outperforms traditional chemotherapy in advanced lines of relapsed/refractory subcutaneous panniculitis-like T-cell lymphoma
Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare subtype of non-Hodgkin lymphoma with a good prognosis, but the optimal treatment for relapsed/refractory (R/R) SPTCL has been rarely discussed. This study aims to compare the efficacy of conventional chemotherapy and chemo-free immunomodulatory regimen for R/R SPTCL. We retrospectively reviewed the patients with first relapse or primary refractory SPTCL between September 1997 and October 2020. A total of 19 patients with R/R SPTCL with a median age of 34 were included. All patient received the first-line chemotherapy-based treatment with a median PFS of 1.8 months. In these patients, 16 received salvage second-line treatment with an ORR of 31.3% and a median TTNT of 3.0 months. 13 of these 16 patients received chemotherapy-based treatment, resulting in a median TTNT of 2.4 months. 2 of these 16 patients received allogeneic hematopoietic stem cell transplantation and achieved long term complete remission (CR). In third-line treatment, 7 patients received chemotherapy-based regimen and 6 received chemo-free regimen such as VRMP (bortezomib, lenadomide and methylprednisolone) regimen and CsA plus IFNα regimen. The median TTNT of chemotherapy and chemo-free group were 3.2 months and not reached, respectively. Chemo-free group had a better TTNT than chemotherapy group (p=0.007). The use of chemotherapy-free regimens for R/R SPTCL appears promising and warrants further validation.
2024-12-08 | Spontaneous regression in mature T-cell non-Hodgkin lymphoma.
Spontaneous regression (SR) is observed in some patients with mature T-cell non-Hodgkin lymphoma (MTCL), including adult T-cell leukemia/lymphoma (ATL), although the incidence is rare. We extracted 31 cases with MTCL who experienced SR based on a literature search and summarized the patient characteristics and clinical outcomes. MTCL with SR included various subtypes, the most common being ATL (n = 17). Five of 24 cases (21%) maintained SR for more than 5 years, and the median duration of SR was 2 years. Sixteen of 31 cases (52%) experienced tumor relapse after SR. Two retrospective studies including ATL cases showed SR rates of 18% and 4%, respectively. Representative triggers are infection and surgical biopsies, and possible mechanisms include immunological mechanisms such as cross-reactivity of virus-specific T cells with tumor antigens. The diagnostic criteria for SR are not standardized among reports, and the clinical outcomes are not fully described. Practically, observation is the only accepted strategy after SR was achieved. In the era of molecular targeted therapy or immunotherapy, new strategies including maintenance therapy after SR could be discussed, although clinical data are lacking.
2024-09-19 | Comprehensive analysis of constitutional mismatch repair deficiency‐associated non‐Hodgkin lymphomas in a global cohort
Abstract Background Constitutional mismatch repair deficiency syndrome (CMMRD) is a rare childhood cancer predisposition syndrome associated with a broad spectrum of malignancies, including non‐Hodgkin lymphomas (NHL). Most patients die due to cancer before the age of 20 years. Limited data exist on CMMRD‐associated lymphomas and their outcome. Methods We conducted a retrospective study including all CMMRD‐associated NHL patients registered before 2020 in the European and North American databases or reported by members of the European Intergroup for Childhood Non‐Hodgkin Lymphoma (EICNHL). Events considered to define event‐free survival included relapse/progression, second malignancy (SML), or death, whichever occurred first. Findings The analysis included 74 patients, with 20 having multiple metachronous NHL. The median age at diagnosis was 9.4 years. Previous malignancies were reported in 36% of the patients, café au lait spots in 96%, and consanguinity in 54%. The initial lymphoma subtypes were 53 T‐cell lymphoblastic lymphomas (T‐LBL), four B‐lymphoblastic lymphomas, and 17 mature B‐cell non‐Hodgkin lymphoma (B‐NHL). All patients were treated with curative intent, with current chemotherapy regimens adapted to their subtype. The median follow‐up was 8.7 years. After the first lymphoma, the 5‐year event‐free and overall survival rates were, respectively, 23.5% [95% confidence interval (CI): 14.9–35.1] and 61.5% [95% CI: 49.6–72.1]. The 5‐year cumulative risk of progression/relapse, SML or death as a first event was 20.8%, 52.9%, and 2.7%. Interpretation Standard treatments for sporadic NHL are effective in most CMMRD‐associated NHL cases, but multiple malignancies, including lymphomas, impair prognosis. Future strategies should evaluate the potential of less genotoxic therapies, including immunotherapy, in preventing SMLs while maintaining effective control of NHL.
2022-12-21 | The fusion oncogene VAV1‐MYO1F triggers aberrant T‐cell receptor signaling in vivo and drives peripheral T‐cell lymphoma in mice
Abstract VAV1‐MYO1F is a recently identified gain‐of‐function fusion protein of the proto‐oncogene Vav guanine nucleotide exchange factor 1 ( VAV1 ) that is recurrently detected in T‐cell non‐Hodgkin's lymphoma (T‐NHL) patients. However, the pathophysiological functions of VAV1‐MYO1F in lymphomagenesis are insufficiently defined. Therefore, we generated transgenic mouse models to conditionally express VAV1‐MYO1F in T‐cells in vivo. We demonstrate that VAV1‐MYO1F triggers cell autonomous activation of T‐cell signaling with an activation of the ERK, JNK, and AKT pathways. VAV1‐MYO1F expression induces a T‐cell activation phenotype with high surface expression of CD25, ICOS, CD44, PD‐1, and decreased CD62L as well as aberrant T‐cell differentiation, proliferation, and neoplastic transformation. Consequently, the VAV1‐MYO1F expressing T‐cells induce a malignant T lymphoproliferative disease with 100% penetrance in vivo that mimics key aspects of human peripheral T‐cell lymphoma. These results demonstrate that the human T‐cell oncogene VAV1‐MYO1F is sufficient to trigger oncogenic T‐cell signaling and neoplastic transformation, and moreover, it provides a new clinically relevant mouse model to explore the pathogenesis of and treatment concepts for human T‐cell lymphoma.
antibodies
2026-06-15 | A rare collision tumor of lymphoepithelioma-like carcinoma and t-cell lymphoma: a case report.
We report a rare case of a collision tumor in a patient concurrently diagnosed with lymphoepithelioma-like carcinoma (LELC) and T-cell non-Hodgkin lymphoma (NHL-T). The patient was a 61-year-old male presenting with a one-week history of low back pain. Positron emission tomography-computed tomography (PET-CT) revealed hypermetabolic masses in the anterior mediastinum, adjacent to right cardiophrenic angle, in the retroperitoneum, and adjacent to the left iliac vessels in the pelvis. The puncture biopsy of the mass adjacent to the cardiophrenic angle suggested LELC coexisting with NHL-T. The patient was treated with a combination regimen of a PD-1 inhibitor and platinum-based chemotherapy, but disease progression was observed. Subsequent biopsy of the pelvic mass confirmed the presence of NHL-T. The treatment regimen was then modified to include a PD-1 inhibitor, bortezomib, and ICE (ifosfamide, carboplatin, etoposide) chemotherapy. After two cycles, the response was assessed as partial remission. The patient remains on ongoing therapy. This case highlights diagnostic challenges and provides insights into the management of such rare collision tumors.
2026-04-16 | Targeting cutaneous T-cell lymphoma in non-Hodgkin lymphoma: what’s new for investigational agents?
INTRODUCTION: Cutaneous T-cell lymphomas (CTCLs) are a rare group of T-cell lymphomas originating from skin-homing T-lymphocytes. While patients with early-stage disease may have an indolent disease course and excellent survival rates, patients with advanced-stage disease and the aggressive leukemic variant Sézary syndrome (SS) have poor outcomes with poor responses to therapy and short durations of response. New and better treatments are urgently needed for these patients. AREAS COVERED: This review describes the current treatment landscape including underlying disease biology, diagnosis and staging, approaches to therapy with novel FDA-approved agents including brentuximab vedotin, mogamulizumab, and denileukin diftitiox-cdxl. Novel and upcoming biomarkers, drugs, and therapeutic strategies are additionally covered in detail with a focus on safety, efficacy, and compartment-specific effects. EXPERT OPINION: Recent years have seen a shift away from chemotherapy with the approval of targeted therapies like mogamulizumab, brentuximab vedotin, and denileukin diftitox-cxdl. Though these novel agents have improved outcomes for patients with advanced-stage CTCL, most patients will continue to experience relapses. Emerging agents, including lacutamab, resminostat, and immune checkpoint inhibitors and biomarkers including CD5, CD70, and CD47/Sirpα represent the next frontier in maintaining durable remissions and improving quality of life (QoL) for these patients.
2025-12-25 | Anaplastic Lymphoma Kinase (ALK)-Positive Anaplastic Large Cell Lymphoma Presenting as an Axillary Breast Abscess in a Young Woman: A Case Report.
Malignant tumours - both lymphoid and epithelial - have been reported to present clinically and radiologically as abscesses, leading to significant diagnostic delays. Anaplastic large cell lymphoma (ALCL) is a rare subtype of T cell non-Hodgkin lymphoma (NHL) characterised by CD30 positivity and, in some cases, anaplastic lymphoma kinase (ALK) expression. Although nodal involvement is most common, extranodal or soft-tissue disease may present with abscess-like features, resulting in diagnostic delay. A 31-year-old woman presented with right axillary pain and swelling, initially diagnosed as an abscess. Despite multiple courses of antibiotics and repeat imaging, the lesion enlarged and became indurated. An initial biopsy showed only chronic inflammation. Surgical incision and drainage were later performed, and histopathological analysis of tissue fragments revealed atypical lymphoid proliferation. Immunohistochemistry confirmed CD30-positive, ALK-positive ALCL. Staging CT demonstrated a necrotic right axillary mass measuring 6 × 5.6 × 5.4 cm with splenomegaly (15 cm), but no mediastinal, retroperitoneal, or pelvic disease, as such findings were consistent with stage III(S) disease. The patient received brentuximab vedotin plus cyclophosphamide, doxorubicin and prednisone (BV-CHP) chemotherapy following multidisciplinary review and showed marked improvement. This case illustrates the diagnostic challenge of ALK-positive ALCL presenting as a recurrent axillary abscess. Early recognition and histopathological evaluation of atypical or non-resolving abscesses are essential for timely diagnosis and effective treatment, ultimately improving patient outcomes.
2025-11-20 | Beyond monotherapy: multimodal strategies integrating immune checkpoint inhibitors in lymphoma management
The advent of immune checkpoint inhibitors (ICIs) has revolutionized lymphoma therapy, though efficacy varies markedly between Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). ICIs targeting the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) pathway show significant efficacy in HL, but limited benefit in NHL subtypes including diffuse large B-cell lymphoma; in T-cell lymphomas and natural killer (NK) cell lymphomas, PD-1 inhibitors demonstrate significant efficacy in extranodal NK/T-cell lymphoma, but response rates remain limited for most peripheral T-cell lymphoma subtypes. The PD-1/PD-L1 axis is central to lymphoma immunotherapy: PD-1/PD-L1 blockade counters tumor immune evasion, whereas CTLA-4 inhibition enhances early T-cell activation in lymphoid tissues. Additional checkpoints also contribute to disease progression by mediating T-cell exhaustion, underscoring their therapeutic relevance. This review delineates the mechanistic rationale and clinical implications of combining ICIs with conventional therapies (chemotherapy, radiotherapy), targeted agents, and emerging modalities. Synergistic combinations have shown promise in overcoming resistance and amplifying antitumor immunity. Clinical trials highlight PD-1 inhibitor-chemotherapy/radiotherapy regimens improving response and survival rates in select lymphomas. Immuno-combination therapies achieve superior efficacy in specific subtypes despite heightened immune-related adverse events. By synthesizing evidence across different combination approaches, this perspective provides clinicians with an integrative framework that transcends traditional disease subtype boundaries, offering broader insights for therapeutic decision-making in lymphoma immunotherapy. Current challenges include developing predictive biomarkers and optimizing management of immune-related adverse events. Collectively, integrating ICIs with complementary modalities offers transformative potential, yet requires rigorous mechanistic exploration and clinical validation to maximize therapeutic index and durability of responses.
2025-11-03 | Favorable Outcomes of Bridging Glofitamab Prior to anti-CD19 CAR-T cell Therapy in patients with non-Hodgkin lymphoma
Abstract Introduction: Chimeric antigen receptor (CAR) T-cells have improved outcomes of patients (pts) with relapsed/refractory Non-Hodgkin Lymphoma (R/R NHL). However, 20% to 40% of those pts did not benefit from CAR-T therapies according to real-world study. Glofitamab, a CD20xCD3 bispecific antibody, was proven viable as salvage therapy following CAR-T treatment failure in the LYSA study, but its potential role as a CAR-T bridging therapy to improve patients' prognosis has yet to be investigated. Here we report the efficacy and safety of glofitamab bridging CAR-T therapies in pts with R/R NHL. Methods: Pts with R/R NHL who underwent leukapheresis received pre-treatment with obinutuzumab prior to the first dose of glofitamab. Based on disease progression status, pts received glofitamab monotherapy or glofitamab combined with gemcitabine + oxaliplatin/ BTK inhibitor/ methotrexate regimens prior to CAR-T infusion. Response rates are evaluated after bridging therapies and CAR-T therapies based on Lugano criteria. Adverse events were assessed according to American Society for Transplantation and Cellular Therapy consensus. Results: As of May 2025, 10 NHL pts who received glofitamab bridging CD19 CAR-T therapy in Wuhan Union Hospital were enrolled, among which 8 pts had a biopsy proven diffuse large B-cell lymphoma (DLBCL) whereas others had mantle cell lymphoma (n=1) and Burkitt lymphoma (n=1). The median age was 61.5 years (range: 20-79) and 70% of pts had Ann Arbor stage III/IV. Median lines of prior therapies was 2 (range: 2-5; ≥3 prior therapies: 60%) with two cases of autologous hematopoietic stem cell transplantation and 1 case of CAR-T therapy. All pts were refractory to their last line of therapy, including two with primary central nervous system lymphoma (PCNSL), two with secondary CNS involvement, one with bulky extramedullary disease (>7 cm), and four harboring TP53 mutations. During glofitamab bridging therapy, grade 1 cytokine release syndrome (CRS) occurred in 4 pts and grade 2 immune effector cell-associated neurotoxicity syndrome (ICANS) in 1 patient. Viral infections developed in 4 pts. The overall response rate (ORR) was 66.7% (6/9 pts), with a complete metabolic response (CMR) rate of 22.2% (2/9 pts), excluding one patient unevaluable for response. The median interval between first glofitamab dose and CAR-T infusion was 31 (25-67) days. Seven pts (70%) experienced grade 1 CRS and 1 pts with PCNSL experienced grade 2 ICANS. Four pts experienced grade 3 infection. 100% pts responded to CAR-T therapies and 80% (8/10 pts) achieved CMR with PET-CT/PET-MRI at day+30 post-infusion. All subjects exhibited peripheral blood CAR-T expansion detectable via flow cytometry, reaching a median peak level of 13.57 CAR-T cells/μL (range: 3.2-403.4) at median peak time of day+11. CAR-T persistence (>50 copies/μg DNA by ddPCR) was sustained in 80% pts at month 1. At a median follow-up of 6.0 months (range: 4-15.5), all pts remained treatment-free except one receiving regular glofitamab maintenance therapy. Disease relapse occurred in one patient at 3.5 months, while others were under active surveillance. Conclusion: Glofitamab bridging therapy prior to CAR-T demonstrated promising efficacy in pts with high-risk NHL, without significant safety concerns or detrimental impact on CAR-T cell kinetics. This study provides preliminary evidence for redefining therapeutic paradigms in non-Hodgkin lymphoma, particularly PCNSL, supporting further investigation through expanded validation cohorts and longitudinal outcomes assessment.
other
2025-05-12 | Rapid and direct discovery of functional tumor specific neoantigens by high resolution mass spectrometry and novel algorithm prediction
While immune cell therapies have transformed cancer treatment, achieving comparable success in solid tumors remains a significant challenge compared to hematologic malignancies like non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). Over the past four decades, various immunotherapeutic strategies, including tumor vaccines, tumor-infiltrating lymphocyte (TIL) therapies, and T-cell receptor (TCR) therapies, have demonstrated clinical efficacy in select solid tumors, suggesting potential advantages over CAR-T and CAR-NK cell therapies in specific contexts. The dynamic nature of the cancer-immunity cycle, characterized by the continuous evolution of tumor-specific neoantigens, enables tumors to evade immune surveillance. This highlights the urgent need for rapid and accurate identification of functional tumor neoantigens to inform the design of personalized tumor vaccines. These vaccines can be based on mRNA, dendritic cells (DCs), or synthetic peptides. In this study, we established a novel platform integrating immunoprecipitation with mass spectrometry (IP-MS) for efficient and direct identification of tumor-specific neoantigen peptides. By combining this approach with our proprietary AI-based prediction algorithm and high-throughput in vitro functional validation, we can generate patient-specific neoantigen candidates within six weeks, accelerating personalized tumor vaccine development.
2021-12-29 | BRG1 and NPM-ALK Are Co-Regulated in Anaplastic Large-Cell Lymphoma; BRG1 Is a Potential Therapeutic Target in ALCL
Anaplastic large-cell lymphoma (ALCL) is a T-cell malignancy driven in many cases by the product of a chromosomal translocation, nucleophosmin–anaplastic lymphoma kinase (NPM-ALK). NPM-ALK activates a plethora of pathways that drive the hallmarks of cancer, largely signalling pathways normally associated with cytokine and/or T-cell receptor-induced signalling. However, NPM-ALK is also located in the nucleus and its functions in this cellular compartment for the most part remain to be determined. We show that ALCL cell lines and primary patient tumours express the transcriptional activator BRG1 in a NPM-ALK-dependent manner. NPM-ALK regulates expression of BRG1 by post-translational mechanisms dependent on its kinase activity, protecting it from proteasomal degradation. Furthermore, we show that BRG1 drives a transcriptional programme associated with cell cycle progression. In turn, inhibition of BRG1 expression with specific shRNA decreases cell viability, suggesting that it may represent a key therapeutic target for the treatment of ALCL.
small molecules
2026-07-16 | Malignancy-Associated Hemophagocytic Lymphohistiocytosis: Clinical Characteristics, Treatment Patterns, and Survival Outcomes in a Tertiary Care Center Cohort.
Malignancy-associated hemophagocytic lymphohistiocytosis (M-HLH) carries a poor prognosis and is often complicated by overlapping infection, cytopenias, organ failure, and progressive disease. We retrospectively analyzed 49 adults with M-HLH at a single tertiary cancer center (2013-2026), summarizing malignancy spectrum, diagnostic features, treatment, and survival outcomes. HLH probability was assessed by HScore and modified HLH-2004 criteria. Lymphoma was the main underlying disease (34/49; 69.4%), led by aggressive B-cell (17/49; 34.7%) and T-cell NHL (12/49; 24.5%). HLH coincided with initial malignancy recognition in 17 of 49 patients (34.7%). The median HScore was 231 (IQR 202-256); 44 of 49 patients (89.8%) met the ≥ 169 threshold, and 42 of 49 patients (85.7%) fulfilled ≥ 5 of 7 modified HLH-2004 criteria. HLH-directed therapy included corticosteroids (41/49; 83.7%), etoposide (21/49; 42.9%), and anakinra (16/49; 32.7%); 21 of 49 patients (42.9%) received concurrent malignancy-directed chemotherapy. Mortality was 59.2% (29/49) with a median overall survival of 56 days (median follow-up 612 days for the cohort; 574 days among survivors, n = 20). De novo presentation carried substantially lower mortality than HLH in previously known malignancy (23.5% vs. 78.1%; hazard ratio [HR] 5.38, 95% confidence interval [CI], 1.85-15.61; P = .002). Malignancy-directed chemotherapy was associated with lower mortality than HLH-directed therapy alone (HR 3.11, 95% CI, 1.36-7.09; P = .007). All 6 patients with invasive mold infection died. M-HLH was predominantly lymphoma-associated, met diagnostic criteria with high probability, and carried poor short-term survival. De novo presentation had better outcomes, likely because lymphoma-directed chemotherapy can simultaneously address the underlying malignant trigger and the hyperinflammatory state. Invasive mold infection was uniformly fatal, illustrating the lethal combination of profound immunosuppression and uncontrolled opportunistic infection in this setting.
2026-06-23 | Bendamustine-based lymphodepletion prior to CAR T-cell therapy: a systematic review.
Lymphodepletion (LD) is a critical prerequisite for successful chimeric antigen receptor T-cell (CAR-T) therapy. While fludarabine and cyclophosphamide (Flu/Cy) remain the standard LD regimen, bendamustine has emerged as a potential alternative due to its distinct immunomodulatory properties and more favorable toxicity profile. This systematic review evaluates the safety, efficacy, and feasibility of bendamustine-based LD in patients undergoing CAR-T therapy for hematologic malignancies. A comprehensive literature search was conducted through January 2026 across PubMed, Embase, Web of Science, and clinical trial registries. Studies were eligible if they reported clinical outcomes following bendamustine-based lymphodepletion prior to CD19-, CD30-, or BCMA-directed CAR-T therapy. Extracted endpoints included overall response rate (ORR), complete response rate (CRR), progression-free survival (PFS), overall survival (OS), and treatment-related toxicities. Eighteen studies comprising over 1400 patients were included. Across disease indications-including B- and T-cell non-Hodgkin lymphoma, Hodgkin lymphoma (HL), and multiple myeloma (MM)-ORRs ranged from 50% to 88%, with CRRs up to 74%. Compared with Flu/Cy, bendamustine-based LD demonstrated comparable efficacy while being associated with significantly lower rates of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and grade ≥3 cytopenias. Additionally, bendamustine facilitated outpatient CAR-T delivery, with reduced hospitalization and intensive care unit (ICU) utilization. However, prior exposure to bendamustine before leukapheresis was associated with inferior CAR-T outcomes. Bendamustine-based LD represents a safe and effective alternative to Flu/Cy, particularly in outpatient settings and in patients at higher risk of treatment-related toxicity. However, the current evidence is largely derived from retrospective and non-randomized studies. Prospective, comparative trials are warranted to validate these findings and to better define the optimal LD strategy across disease types and CAR-T platforms.
2025-12-31 | Subcutaneous Panniculitis-like T-cell Non-Hodgkin Lymphoma Associated with Cushing Syndrome: An Introspection
Background: Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) accounts for less than 1% of non-Hodgkin lymphoma cases and is characterized by malignant lymphocyte infiltration into adipose tissues. The term “panniculitis-like T -cells” refers to the histological similarity of the lymphoma cells to the T-cells found in chronic or granulomatous panniculitis. This type of lymphoma is responsible for an ectopic ACTH secretion which leads to excessive cortisol secretion causing Cushing syndrome. Case: A 45-year-old patient diagnosed with SPTCL in 2022 underwent six cycles of cyclophosphamide, epirubicin, vincristine, and prednisone (CHOP regimen). Due to iatrogenic Cushing syndrome, CHOP was discontinued, and two cycles of rituximab-ifosphamide-carboplatin-etoposide (R-ICE) were administered. In 2023, the patient presented with scleral jaundice and dark urine. Laboratory findings revealed a total bilirubin of 11.2 mg/dL, leukopenia, thrombocytopenia, hyperfibrinogenemia, and elevated D-dimers. A CT scan showed hepatic and iliopsoas muscle lesions, indicating systemic dissemination and relapse of the lymphoma. Conclusion: Corticosteroid-based regimens are standard treatment options for SPTCL. However, paraneoplastic syndromes such as ectopic ACTH secretion by malignant cells may lead to excessive cortisol levels, exacerbated by corticosteroids. Due to iatrogenic Cushing syndrome induced by the first-line therapy and relapse following second-line options, off-label venetoclax, an apoptosis inducer, was initiated in combination with ropeginterferon alfa-2b. The patient achieved complete remission. No SPTCL cases treated with venetoclax have been published in the literature. We report high efficacy of off-label venetoclax in a relapsed SPTCL with no other available therapeutic option.
2025-12-13 | Fucoidan potentiates anti-tumor efficacy of CAR-T cells against non-Hodgkin lymphoma by activation of STAT3 pathway
BACKGROUND: Despite advances in chimeric antigen receptor T-cell (CAR-T) therapy, significant challenges remain, including progressive T-cell exhaustion and poor in vivo persistence. Current strategies to enhance CAR-T function-such as cytokine co-expression-often lead to severe adverse effects, most notably cytokine release syndrome (CRS). Therefore, there is a pressing need to develop safer and more sustainable approaches, particularly through nutritional interventions, to improve the antitumor efficacy of CAR-T therapy. Fucoidan (FO), a bioactive polysaccharide derived from marine plants, has demonstrated immunomodulatory properties and synergistic potential in combination with conventional chemotherapy. However, its role in cellular immunotherapy, including CAR-T therapy, has not yet been explored. This study aims to elucidate the function of FO in CAR-T therapy for non-Hodgkin lymphoma (NHL) and to provide a foundational basis for its clinical translation in the field of cellular immunotherapy. METHODS: The current study used a combination of in vitro and in vivo assays to explore the role of FO in CAR T therapy. The anti-CD19 CAR-T cells were constructed by lentivirus containing CAR-CD19 structure. For phenotype analysis of CAR T cells, different cell populations, such as memory and exhausted CAR T cells, were stained by cell marker and identified by flow cytometry. CAR-T cells from different treatment groups were co-cultured with target cells with different E: T ratio to detect the cytotoxicity and cytokine release of CAR-T cells. We also evaluate FO's supportive role for function of CAR-T cells in the tumor-bearing mouse models. The underlying mechanism of activated signaling pathway were also investigated and confirmed by the inhibitor. RESULTS: In this study, we systematically investigated the role of FO in anti-CD19 CAR-T cell-mediated treatment of NHL. Specifically, CAR-T cells' memory maintenance and exhaustion resistance were enhanced by FO. FO not only improved CAR-T cell's antioxidant capacity and proliferation, but also prevented apoptosis of activated CAR-T cells, collectively contributing to the improved and sustained anti-tumor efficacy in both in vitro assays and xenograft models. Our mechanistic studies also revealed FO served as a potentiator for CAR-T cells' function through enhancing the activation of STAT3 signaling pathway. CONCLUSIONS: These findings elucidate the supportive role of FO in enhancing CAR-T cell function, which indicates FO's clinical potential as immunomodulatory supplement to potentiate CAR-T therapy against NHL.
2025-11-13 | The Potential of the Gut Microbiota and Butyrate to Enhance CAR T-cell Therapy in Non-Hodgkin Lymphoma
Our results support the relationship between microbiota and CAR T-cell therapy major outcomes. Analysis of microbiota led to the identification of SCFAs, especially butyrate, as a prognostic factor, and also provides the basis for considering them as chemical modifiers of CAR T cells to improve their efficacy.
cell therapies
2026-05-27 | Novel transposon BAFF CAR-T cells (LMY-920) for non-Hodgkin lymphoma (NHL).
2563 Background: CAR-T cells targeting CD19 using scFv-based CARs have been effective and approved to treat lymphoma. Response rates are high, but a significant number of patients fail to respond or relapse. This has been linked to T cell exhaustion, immune dysregulation, and/or epitope loss. To overcome this, we developed a CAR-T cell product expressing a BAFF-ligand (LMY-920). The CAR consists of truncated human BAFF on a 3rd generation CAR backbone with CD28, OX40, and CD3z intracellular signaling domains. The BAFF-ligand domain confers ability to bind the 3 BAFF receptors (BAFFR/BR3, TACI and BCMA). These are attractive tumor-associated antigens being variably expressed in all B-lineage malignancies such as B cell NHL, chronic lymphocytic leukemia (CLL), hairy cell leukemia and multiple myeloma (MM), and are important for B-cell survival, reducing the chance of antigen escape. Additionally, they are expressed on B-lineage cells involved in antibody-mediated autoimmune diseases. BAFF ligand interactions are lower affinity than scFv interactions, potentially reducing T-cell exhaustion. The novel TcBuster transposon system is used to improve manufacturing time, efficiency, cost, and safety. Methods: Patients with refractory B cell NHL are treated in this study (NCT05312801). Autologous LMY-920 CAR-T cells are manufactured, then patients receive 3 days of fludarabine (30 mg/m 2 /d) and cyclophosphamide (500 mg/m 2 /d) lymphodepletion. LMY-920 is administered intravenously in a 3+3 dose escalation design from 1-8 x 10 6 BAFF-CAR-T cells/kg. Response is assessed using the Lugano criteria. CAR-T expansion and biologic characteristics are assessed. Results: Five patients have been treated with 1-2 x 10 6 BAFF-CAR-T cells/kg in this study, 2 patients each with mantle cell lymphoma (MCL), diffuse large B cell lymphoma (DLBCL), and one with marginal zone lymphoma (MZL). Patients had received 2 – 6 prior lines of therapy and all were refractory. One patient experienced grade 1 CRS (fever), but no ICANS was reported. All patients experienced grade 3 or higher hematologic toxicity that recovered prior to day 28, and grade 1-2 fatigue. There have been no dose limiting toxicities and dose escalation continues. Responses included 2 complete responses (CR) (DLBCL), a partial response (MZL), a mixed response (MCL) and one stable disease (MCL). Of note, one of the DLBCL patients in CR had received prior axicabtagene ciloleucel (anti-CD19) CAR-T cells as well as anti-CD20 bispecific antibodies, with lymphoma cells resulting in CD19 and CD20 antigen loss. Conclusions: The successful use of a novel transposon-engineered BAFF ligand-based CAR-T cell product demonstrates the potential of a new direction in CAR-T cell development. Safety and efficacy were seen, including patients with prior CAR-T failure and epitope loss, as hypothesized. This product is also being evaluated in patients with CLL, MM and systemic lupus erythematosus. Clinical trial information: NCT05312801 .
2026-05-08 | CAR-T cell therapy in non-Hodgkin lymphoma: a clinical trial landscape review
Background: Chimeric antigen receptor T cell (CAR-T) therapy has emerged as a transformative treatment modality for selected subtypes of non-Hodgkin lymphoma (NHL). While multiple CAR-T products have demonstrated remarkable clinical activity, the overall clinical development landscape remains heterogeneous, with substantial variation in trial design, target selection, geographic distribution, and endpoint prioritization. A comprehensive analysis of the global clinical trial landscape is essential to contextualize current progress and identify unmet needs in this rapidly evolving field. Methods: We conducted a systematic landscape analysis of CAR-T-related clinical trials for NHL using the Trialtrove database. Interventional trials registered up to December 18, 2025, were retrieved using predefined search criteria. Eligible studies were screened according to standardized inclusion and exclusion criteria. Key trial characteristics, including trial status, phase, geographic location, sponsor type, molecular targets, and reported clinical endpoints, were extracted and analyzed descriptively. Results: A total of 360 eligible clinical trials were included in the final analysis. The global CAR-T clinical trial landscape in NHL is characterized by rapid expansion and a predominant focus on early-phase development. Trial activity is highly concentrated in a limited number of countries, with academic institutions serving as the primary drivers of clinical investigation. CD19-directed CAR-T therapies dominate the current landscape, although emerging diversification toward alternative targets is evident. Reported study endpoints largely emphasize safety and short-term efficacy, whereas durable clinical outcomes remain less frequently assessed, reflecting the exploratory nature of most trials. Conclusion: CAR-T therapy development in NHL continues to advance rapidly, driven by academic innovation and expanding preclinical insights. However, persistent challenges related to antigen escape, treatment durability, and trial design remain. Future progress will require the integration of next-generation CAR engineering strategies, broader incorporation of long-term clinical endpoints, and alignment with evolving regulatory and policy frameworks to support sustainable clinical translation.
2026-04-21 | Targeting CAR-T cell exhaustion in non-Hodgkin lymphoma: mechanistic insights and emerging clinical strategies
Although the response rates to chimeric antigen receptor T (CAR-T) therapy in patients with treatment-resistant lymphoma are high, the majority of patients relapse. CAR-T cell exhaustion, characterized by the progressive loss of T-cell effector functions due to several molecular and epigenetic pathways, is a major mediator of CAR-T cell failure. Strategies to prevent CAR-T cell exhaustion, including modifications to the CAR structure, addition of adjunctive agents, and alternative product manufacturing strategies have shown promise. In this review, we discuss the mechanisms of CAR-T cell exhaustion and describe strategies for its mitigation, with the aim of supporting further research in this critical area.
2026-02-14 | Outcomes of point-of-care manufactured CAR T cell therapy for B cell acute lymphoblastic leukemia and non-Hodgkin lymphoma in Vietnam
Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of relapsed/refractory (R/R) B cell acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL), but access remains limited in resource-constrained settings. This phase I study evaluated the safety and feasibility of point-of-care (PoC) manufactured CD19-targeted CAR T cell therapy in Vietnamese patients. Between August 2023 and June 2025, 16 patients, eight with R/R ALL and eight with R/R NHL, were enrolled. All received fresh CAR T cells produced on-site using the CliniMACS Prodigy system, with a median dose of 1.9 × 106 CAR T cells/kg (range, 0.83-2.17 × 106). Cytokine release syndrome (CRS) occurred in 13 patients (12 with grade 1-2, one with grade 3), and grade 1 neurotoxicity was observed in two patients. In ALL, the complete remission (CR) rates were 100% on day 30, 75% on day 90, and 62.5% on day 180. Patients with NHL showed CR rates of 87.5% on both day 90 and day 180. The estimated 1-year progression-free survival rates were 62.5% (95% confidence interval [CI]: 36.5%-100%) for ALL and 87.5% (95% CI: 67.3%-100%) for NHL. PoC manufactured CD19 CAR T cells demonstrated manageable toxicity and encouraging early efficacy in Vietnamese patients with R/R ALL and NHL. This model offers a cost-effective strategy for delivering advanced therapy in resource-limited settings.
2026-01-01 | Outcomes of CAR T-Cell Therapy in transformed indolent Non-Hodgkin Lymphomas and de novo DLBCL: A comparative analysis from the Italian CAR T-SIE study
Background Transformed indolent non-Hodgkin lymphoma (TiNHL) generally has poorer outcomes than de novo diffuse large B-cell lymphoma (dnDLBCL). Although anti-CD19 CAR T-cell therapy is standard for relapsed/refractory (R/R) large B-cell lymphoma (LBCL), its prognostic role across histologies remains unclear. Methods We conducted a multicenter, retrospective/prospective observational study comparing R/R TiNHL and R/R dnDLBCL patients treated with commercial CAR T-cell therapy and enrolled in the Italian CART-SIE study. Findings Among 438 patients, 107 had TiNHL (96 transformed follicular lymphoma [tFL], 11 transformed marginal zone lymphoma [tMZL]) and 331 had dnDLBCL. Baseline characteristics were comparable. TiNHL patients showed superior overall (83% vs 69%) and complete response rates (62% vs 53%) (both p ' 0·01), with better 2-year progression-free survival (PFS: 44% vs 31%) and overall survival (OS: 61% vs 48%) (both p ' 0·01). CAR-HEMATOTOX score predicted worse outcomes (PFS HR=2·10; OS HR=3·57). No significant differences were found between tFL and tMZL. Two-year relapse/progression incidence was lower in TiNHL (28% vs 47%, p ' 0·01), with similar non-relapse mortality (11% vs 4%, p = 0·12). Safety profiles, including cytokine release syndrome and ICANS rates, were comparable. Conclusion TiNHL patients receiving CAR T-cell therapy achieved better outcomes than dnDLBCL patients, with comparable safety, supporting its use as a standard treatment in TiNHL.
proteins
2025-11-24 | Retrospective analysis of clinical characteristics, treatment outcomes and prognosis of patients with natural killer/T-cell lymphoma.
Natural killer/T-cell lymphoma (NKTCL) is the most common T-cell non-Hodgkin lymphoma in China; however, the clinical characteristics and optimal treatment remain unclear. The present study aimed to retrospectively assess the clinical features of patients with NKTCL and to determine treatment strategies. A total of 200 patients who were diagnosed with NKTCL and admitted to the Cancer Center, Union Hospital (Wuhan, China) between June 2013 and June 2022 were identified. Clinical data from these patients were collected and analyzed to evaluate the clinical features, treatment outcomes and prognostic factors. A total of 171 patients diagnosed with NKTCL were ultimately enrolled. Patients were diagnosed at a median age of 45 years and had a male-to-female ratio of 2:1. Out of the 171 patients, 117 were in the early stage (stage I/II; 68.4%) and 54 were in the advanced stage (stage III/IV; 31.6%) of NKTCL. Among these patients, B symptoms were present in 60.2% of patients (103/171) and the Eastern Cooperative Oncology Group performance status was scored as 0-1 in 93.6% of patients (160/171). Most patients had a low-to-moderate risk of international prognostic index (147/171; 86.0%), prognostic index for NKTCL (PINK; 122/171; 71.3%) and PINK with extended features (112/171; 65.5%). At baseline, it was demonstrated that Epstein-Barr virus DNA was positive in the serum of 166/171 patients (2.9%). Combined chemotherapy and radiotherapy at 54 Gy revealed a promising effect with the highest overall response rate (ORR) of 98.2%, a 4-year progression-free survival (PFS) rate of 82.5% [95% confidence interval (CI), 75.1-89.9%] and an overall survival (OS) rate of 92.2% (95% CI, 86.9-97.5%) for the early-stage group. Pegasparase-based chemotherapy was used to treat advanced-stage patients, resulting in a 4-year PFS rate of 62.3% (95% CI, 47.4-77.2%) and an OS rate of 63.5% (95% CI, 48.2-78.8%). The regimen containing the programmed cell death protein 1 inhibitor camrelizumab demonstrated an ORR of 100% in both the early- and advanced-stage cohorts. Moreover, stage and an age of >60 years were independent prognostic factors for poor PFS, whilst stage and elevated lactate dehydrogenase were independent prognostic factors for poor OS. In conclusion, the results indicated promising efficacy for pegaspargase-based chemotherapy in terms of response rates and survival outcomes for both early- and advanced-stage patients. However, further refinement of treatment strategies is needed.
2024-12-09 | Chemo-free salvage treatment outperforms traditional chemotherapy in advanced lines of relapsed/refractory subcutaneous panniculitis-like T-cell lymphoma
Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare subtype of non-Hodgkin lymphoma with a good prognosis, but the optimal treatment for relapsed/refractory (R/R) SPTCL has been rarely discussed. This study aims to compare the efficacy of conventional chemotherapy and chemo-free immunomodulatory regimen for R/R SPTCL. We retrospectively reviewed the patients with first relapse or primary refractory SPTCL between September 1997 and October 2020. A total of 19 patients with R/R SPTCL with a median age of 34 were included. All patient received the first-line chemotherapy-based treatment with a median PFS of 1.8 months. In these patients, 16 received salvage second-line treatment with an ORR of 31.3% and a median TTNT of 3.0 months. 13 of these 16 patients received chemotherapy-based treatment, resulting in a median TTNT of 2.4 months. 2 of these 16 patients received allogeneic hematopoietic stem cell transplantation and achieved long term complete remission (CR). In third-line treatment, 7 patients received chemotherapy-based regimen and 6 received chemo-free regimen such as VRMP (bortezomib, lenadomide and methylprednisolone) regimen and CsA plus IFNα regimen. The median TTNT of chemotherapy and chemo-free group were 3.2 months and not reached, respectively. Chemo-free group had a better TTNT than chemotherapy group (p=0.007). The use of chemotherapy-free regimens for R/R SPTCL appears promising and warrants further validation.
2024-12-08 | Spontaneous regression in mature T-cell non-Hodgkin lymphoma.
Spontaneous regression (SR) is observed in some patients with mature T-cell non-Hodgkin lymphoma (MTCL), including adult T-cell leukemia/lymphoma (ATL), although the incidence is rare. We extracted 31 cases with MTCL who experienced SR based on a literature search and summarized the patient characteristics and clinical outcomes. MTCL with SR included various subtypes, the most common being ATL (n = 17). Five of 24 cases (21%) maintained SR for more than 5 years, and the median duration of SR was 2 years. Sixteen of 31 cases (52%) experienced tumor relapse after SR. Two retrospective studies including ATL cases showed SR rates of 18% and 4%, respectively. Representative triggers are infection and surgical biopsies, and possible mechanisms include immunological mechanisms such as cross-reactivity of virus-specific T cells with tumor antigens. The diagnostic criteria for SR are not standardized among reports, and the clinical outcomes are not fully described. Practically, observation is the only accepted strategy after SR was achieved. In the era of molecular targeted therapy or immunotherapy, new strategies including maintenance therapy after SR could be discussed, although clinical data are lacking.
2024-09-19 | Comprehensive analysis of constitutional mismatch repair deficiency‐associated non‐Hodgkin lymphomas in a global cohort
Abstract Background Constitutional mismatch repair deficiency syndrome (CMMRD) is a rare childhood cancer predisposition syndrome associated with a broad spectrum of malignancies, including non‐Hodgkin lymphomas (NHL). Most patients die due to cancer before the age of 20 years. Limited data exist on CMMRD‐associated lymphomas and their outcome. Methods We conducted a retrospective study including all CMMRD‐associated NHL patients registered before 2020 in the European and North American databases or reported by members of the European Intergroup for Childhood Non‐Hodgkin Lymphoma (EICNHL). Events considered to define event‐free survival included relapse/progression, second malignancy (SML), or death, whichever occurred first. Findings The analysis included 74 patients, with 20 having multiple metachronous NHL. The median age at diagnosis was 9.4 years. Previous malignancies were reported in 36% of the patients, café au lait spots in 96%, and consanguinity in 54%. The initial lymphoma subtypes were 53 T‐cell lymphoblastic lymphomas (T‐LBL), four B‐lymphoblastic lymphomas, and 17 mature B‐cell non‐Hodgkin lymphoma (B‐NHL). All patients were treated with curative intent, with current chemotherapy regimens adapted to their subtype. The median follow‐up was 8.7 years. After the first lymphoma, the 5‐year event‐free and overall survival rates were, respectively, 23.5% [95% confidence interval (CI): 14.9–35.1] and 61.5% [95% CI: 49.6–72.1]. The 5‐year cumulative risk of progression/relapse, SML or death as a first event was 20.8%, 52.9%, and 2.7%. Interpretation Standard treatments for sporadic NHL are effective in most CMMRD‐associated NHL cases, but multiple malignancies, including lymphomas, impair prognosis. Future strategies should evaluate the potential of less genotoxic therapies, including immunotherapy, in preventing SMLs while maintaining effective control of NHL.
2022-12-21 | The fusion oncogene VAV1‐MYO1F triggers aberrant T‐cell receptor signaling in vivo and drives peripheral T‐cell lymphoma in mice
Abstract VAV1‐MYO1F is a recently identified gain‐of‐function fusion protein of the proto‐oncogene Vav guanine nucleotide exchange factor 1 ( VAV1 ) that is recurrently detected in T‐cell non‐Hodgkin's lymphoma (T‐NHL) patients. However, the pathophysiological functions of VAV1‐MYO1F in lymphomagenesis are insufficiently defined. Therefore, we generated transgenic mouse models to conditionally express VAV1‐MYO1F in T‐cells in vivo. We demonstrate that VAV1‐MYO1F triggers cell autonomous activation of T‐cell signaling with an activation of the ERK, JNK, and AKT pathways. VAV1‐MYO1F expression induces a T‐cell activation phenotype with high surface expression of CD25, ICOS, CD44, PD‐1, and decreased CD62L as well as aberrant T‐cell differentiation, proliferation, and neoplastic transformation. Consequently, the VAV1‐MYO1F expressing T‐cells induce a malignant T lymphoproliferative disease with 100% penetrance in vivo that mimics key aspects of human peripheral T‐cell lymphoma. These results demonstrate that the human T‐cell oncogene VAV1‐MYO1F is sufficient to trigger oncogenic T‐cell signaling and neoplastic transformation, and moreover, it provides a new clinically relevant mouse model to explore the pathogenesis of and treatment concepts for human T‐cell lymphoma.
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2026-06-15 | A rare collision tumor of lymphoepithelioma-like carcinoma and t-cell lymphoma: a case report.
We report a rare case of a collision tumor in a patient concurrently diagnosed with lymphoepithelioma-like carcinoma (LELC) and T-cell non-Hodgkin lymphoma (NHL-T). The patient was a 61-year-old male presenting with a one-week history of low back pain. Positron emission tomography-computed tomography (PET-CT) revealed hypermetabolic masses in the anterior mediastinum, adjacent to right cardiophrenic angle, in the retroperitoneum, and adjacent to the left iliac vessels in the pelvis. The puncture biopsy of the mass adjacent to the cardiophrenic angle suggested LELC coexisting with NHL-T. The patient was treated with a combination regimen of a PD-1 inhibitor and platinum-based chemotherapy, but disease progression was observed. Subsequent biopsy of the pelvic mass confirmed the presence of NHL-T. The treatment regimen was then modified to include a PD-1 inhibitor, bortezomib, and ICE (ifosfamide, carboplatin, etoposide) chemotherapy. After two cycles, the response was assessed as partial remission. The patient remains on ongoing therapy. This case highlights diagnostic challenges and provides insights into the management of such rare collision tumors.
2026-04-16 | Targeting cutaneous T-cell lymphoma in non-Hodgkin lymphoma: what’s new for investigational agents?
INTRODUCTION: Cutaneous T-cell lymphomas (CTCLs) are a rare group of T-cell lymphomas originating from skin-homing T-lymphocytes. While patients with early-stage disease may have an indolent disease course and excellent survival rates, patients with advanced-stage disease and the aggressive leukemic variant Sézary syndrome (SS) have poor outcomes with poor responses to therapy and short durations of response. New and better treatments are urgently needed for these patients. AREAS COVERED: This review describes the current treatment landscape including underlying disease biology, diagnosis and staging, approaches to therapy with novel FDA-approved agents including brentuximab vedotin, mogamulizumab, and denileukin diftitiox-cdxl. Novel and upcoming biomarkers, drugs, and therapeutic strategies are additionally covered in detail with a focus on safety, efficacy, and compartment-specific effects. EXPERT OPINION: Recent years have seen a shift away from chemotherapy with the approval of targeted therapies like mogamulizumab, brentuximab vedotin, and denileukin diftitox-cxdl. Though these novel agents have improved outcomes for patients with advanced-stage CTCL, most patients will continue to experience relapses. Emerging agents, including lacutamab, resminostat, and immune checkpoint inhibitors and biomarkers including CD5, CD70, and CD47/Sirpα represent the next frontier in maintaining durable remissions and improving quality of life (QoL) for these patients.
2025-12-25 | Anaplastic Lymphoma Kinase (ALK)-Positive Anaplastic Large Cell Lymphoma Presenting as an Axillary Breast Abscess in a Young Woman: A Case Report.
Malignant tumours - both lymphoid and epithelial - have been reported to present clinically and radiologically as abscesses, leading to significant diagnostic delays. Anaplastic large cell lymphoma (ALCL) is a rare subtype of T cell non-Hodgkin lymphoma (NHL) characterised by CD30 positivity and, in some cases, anaplastic lymphoma kinase (ALK) expression. Although nodal involvement is most common, extranodal or soft-tissue disease may present with abscess-like features, resulting in diagnostic delay. A 31-year-old woman presented with right axillary pain and swelling, initially diagnosed as an abscess. Despite multiple courses of antibiotics and repeat imaging, the lesion enlarged and became indurated. An initial biopsy showed only chronic inflammation. Surgical incision and drainage were later performed, and histopathological analysis of tissue fragments revealed atypical lymphoid proliferation. Immunohistochemistry confirmed CD30-positive, ALK-positive ALCL. Staging CT demonstrated a necrotic right axillary mass measuring 6 × 5.6 × 5.4 cm with splenomegaly (15 cm), but no mediastinal, retroperitoneal, or pelvic disease, as such findings were consistent with stage III(S) disease. The patient received brentuximab vedotin plus cyclophosphamide, doxorubicin and prednisone (BV-CHP) chemotherapy following multidisciplinary review and showed marked improvement. This case illustrates the diagnostic challenge of ALK-positive ALCL presenting as a recurrent axillary abscess. Early recognition and histopathological evaluation of atypical or non-resolving abscesses are essential for timely diagnosis and effective treatment, ultimately improving patient outcomes.
2025-11-20 | Beyond monotherapy: multimodal strategies integrating immune checkpoint inhibitors in lymphoma management
The advent of immune checkpoint inhibitors (ICIs) has revolutionized lymphoma therapy, though efficacy varies markedly between Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). ICIs targeting the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) pathway show significant efficacy in HL, but limited benefit in NHL subtypes including diffuse large B-cell lymphoma; in T-cell lymphomas and natural killer (NK) cell lymphomas, PD-1 inhibitors demonstrate significant efficacy in extranodal NK/T-cell lymphoma, but response rates remain limited for most peripheral T-cell lymphoma subtypes. The PD-1/PD-L1 axis is central to lymphoma immunotherapy: PD-1/PD-L1 blockade counters tumor immune evasion, whereas CTLA-4 inhibition enhances early T-cell activation in lymphoid tissues. Additional checkpoints also contribute to disease progression by mediating T-cell exhaustion, underscoring their therapeutic relevance. This review delineates the mechanistic rationale and clinical implications of combining ICIs with conventional therapies (chemotherapy, radiotherapy), targeted agents, and emerging modalities. Synergistic combinations have shown promise in overcoming resistance and amplifying antitumor immunity. Clinical trials highlight PD-1 inhibitor-chemotherapy/radiotherapy regimens improving response and survival rates in select lymphomas. Immuno-combination therapies achieve superior efficacy in specific subtypes despite heightened immune-related adverse events. By synthesizing evidence across different combination approaches, this perspective provides clinicians with an integrative framework that transcends traditional disease subtype boundaries, offering broader insights for therapeutic decision-making in lymphoma immunotherapy. Current challenges include developing predictive biomarkers and optimizing management of immune-related adverse events. Collectively, integrating ICIs with complementary modalities offers transformative potential, yet requires rigorous mechanistic exploration and clinical validation to maximize therapeutic index and durability of responses.
2025-11-03 | Favorable Outcomes of Bridging Glofitamab Prior to anti-CD19 CAR-T cell Therapy in patients with non-Hodgkin lymphoma
Abstract Introduction: Chimeric antigen receptor (CAR) T-cells have improved outcomes of patients (pts) with relapsed/refractory Non-Hodgkin Lymphoma (R/R NHL). However, 20% to 40% of those pts did not benefit from CAR-T therapies according to real-world study. Glofitamab, a CD20xCD3 bispecific antibody, was proven viable as salvage therapy following CAR-T treatment failure in the LYSA study, but its potential role as a CAR-T bridging therapy to improve patients' prognosis has yet to be investigated. Here we report the efficacy and safety of glofitamab bridging CAR-T therapies in pts with R/R NHL. Methods: Pts with R/R NHL who underwent leukapheresis received pre-treatment with obinutuzumab prior to the first dose of glofitamab. Based on disease progression status, pts received glofitamab monotherapy or glofitamab combined with gemcitabine + oxaliplatin/ BTK inhibitor/ methotrexate regimens prior to CAR-T infusion. Response rates are evaluated after bridging therapies and CAR-T therapies based on Lugano criteria. Adverse events were assessed according to American Society for Transplantation and Cellular Therapy consensus. Results: As of May 2025, 10 NHL pts who received glofitamab bridging CD19 CAR-T therapy in Wuhan Union Hospital were enrolled, among which 8 pts had a biopsy proven diffuse large B-cell lymphoma (DLBCL) whereas others had mantle cell lymphoma (n=1) and Burkitt lymphoma (n=1). The median age was 61.5 years (range: 20-79) and 70% of pts had Ann Arbor stage III/IV. Median lines of prior therapies was 2 (range: 2-5; ≥3 prior therapies: 60%) with two cases of autologous hematopoietic stem cell transplantation and 1 case of CAR-T therapy. All pts were refractory to their last line of therapy, including two with primary central nervous system lymphoma (PCNSL), two with secondary CNS involvement, one with bulky extramedullary disease (>7 cm), and four harboring TP53 mutations. During glofitamab bridging therapy, grade 1 cytokine release syndrome (CRS) occurred in 4 pts and grade 2 immune effector cell-associated neurotoxicity syndrome (ICANS) in 1 patient. Viral infections developed in 4 pts. The overall response rate (ORR) was 66.7% (6/9 pts), with a complete metabolic response (CMR) rate of 22.2% (2/9 pts), excluding one patient unevaluable for response. The median interval between first glofitamab dose and CAR-T infusion was 31 (25-67) days. Seven pts (70%) experienced grade 1 CRS and 1 pts with PCNSL experienced grade 2 ICANS. Four pts experienced grade 3 infection. 100% pts responded to CAR-T therapies and 80% (8/10 pts) achieved CMR with PET-CT/PET-MRI at day+30 post-infusion. All subjects exhibited peripheral blood CAR-T expansion detectable via flow cytometry, reaching a median peak level of 13.57 CAR-T cells/μL (range: 3.2-403.4) at median peak time of day+11. CAR-T persistence (>50 copies/μg DNA by ddPCR) was sustained in 80% pts at month 1. At a median follow-up of 6.0 months (range: 4-15.5), all pts remained treatment-free except one receiving regular glofitamab maintenance therapy. Disease relapse occurred in one patient at 3.5 months, while others were under active surveillance. Conclusion: Glofitamab bridging therapy prior to CAR-T demonstrated promising efficacy in pts with high-risk NHL, without significant safety concerns or detrimental impact on CAR-T cell kinetics. This study provides preliminary evidence for redefining therapeutic paradigms in non-Hodgkin lymphoma, particularly PCNSL, supporting further investigation through expanded validation cohorts and longitudinal outcomes assessment.
other
2025-05-12 | Rapid and direct discovery of functional tumor specific neoantigens by high resolution mass spectrometry and novel algorithm prediction
While immune cell therapies have transformed cancer treatment, achieving comparable success in solid tumors remains a significant challenge compared to hematologic malignancies like non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). Over the past four decades, various immunotherapeutic strategies, including tumor vaccines, tumor-infiltrating lymphocyte (TIL) therapies, and T-cell receptor (TCR) therapies, have demonstrated clinical efficacy in select solid tumors, suggesting potential advantages over CAR-T and CAR-NK cell therapies in specific contexts. The dynamic nature of the cancer-immunity cycle, characterized by the continuous evolution of tumor-specific neoantigens, enables tumors to evade immune surveillance. This highlights the urgent need for rapid and accurate identification of functional tumor neoantigens to inform the design of personalized tumor vaccines. These vaccines can be based on mRNA, dendritic cells (DCs), or synthetic peptides. In this study, we established a novel platform integrating immunoprecipitation with mass spectrometry (IP-MS) for efficient and direct identification of tumor-specific neoantigen peptides. By combining this approach with our proprietary AI-based prediction algorithm and high-throughput in vitro functional validation, we can generate patient-specific neoantigen candidates within six weeks, accelerating personalized tumor vaccine development.
2021-12-29 | BRG1 and NPM-ALK Are Co-Regulated in Anaplastic Large-Cell Lymphoma; BRG1 Is a Potential Therapeutic Target in ALCL
Anaplastic large-cell lymphoma (ALCL) is a T-cell malignancy driven in many cases by the product of a chromosomal translocation, nucleophosmin–anaplastic lymphoma kinase (NPM-ALK). NPM-ALK activates a plethora of pathways that drive the hallmarks of cancer, largely signalling pathways normally associated with cytokine and/or T-cell receptor-induced signalling. However, NPM-ALK is also located in the nucleus and its functions in this cellular compartment for the most part remain to be determined. We show that ALCL cell lines and primary patient tumours express the transcriptional activator BRG1 in a NPM-ALK-dependent manner. NPM-ALK regulates expression of BRG1 by post-translational mechanisms dependent on its kinase activity, protecting it from proteasomal degradation. Furthermore, we show that BRG1 drives a transcriptional programme associated with cell cycle progression. In turn, inhibition of BRG1 expression with specific shRNA decreases cell viability, suggesting that it may represent a key therapeutic target for the treatment of ALCL.
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Drug Discovery Landscape
34 orphan drug designations for T-cell non-Hodgkin lymphoma, including 3 approved therapies.
34 orphan drug designations for T-cell non-Hodgkin lymphoma, including 3 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
cluster of differentiation (CD)5 knockout (KO) chimeric antigen receptor (CAR) T cells targeting CD5 (CART5) | cell therapies | FDA | 2026-07-31 | — | Vittoria Biotherapeutics, Inc. |
a small molecule inhibitor of Zeste homolog 2 (EZH2) | small molecules | FDA | 2026-04-13 | — | Evopoint Biosciences USA, Inc. |
Autologous T cells genetically modified to express a CD5 chimeric antigen receptor (CAR) | cell therapies | FDA | 2024-08-05 | — | March Biosciences, Inc. |
recombinant human interleukin-12 (rHuIL-12) | proteins | FDA | 2024-07-15 | — | Libo Pharma Corp. |
human anti-CD94 IgG1 monoclonal antibody (non-fucosylated) | antibodies | FDA | 2024-05-09 | — | Dren Bio, Inc |
antibody-drug conjugate of a humanized monoclonal antibody specific for CD6 conjugated to monomethyl auristatin E | antibodies | FDA | 2024-03-11 | — | Abcon Therapeutics, Inc. |
soquelitinib | small molecules | FDA | 2024-02-07 | — | Corvus Pharmaceuticals, Inc. |
4-[[[4-[5-chloro-2-[[trans-4-[[(1R)-2-methoxy-1-methyl ethyl] amino] cyclohexyl] amino] -4-pyridinyl]-2-thiazolyl] amino] methyl] tetrahydro-2H-pyran-4-carbonitrile dimaleate | small molecules | FDA | 2023-12-20 | — | SELLAS Life Sciences Group, Inc. |
autologous peripheral blood mononuclear cells manipulated ex vivo to produce macrophages with markedly reduced signal-regulatory protein alpha (SIRPalpha) expression | cell therapies | FDA | 2023-11-06 | — | SIRPant Immunotherapeutics |
heterologous swine glyco-humanized polyclonal antibody against T lymphocytes | antibodies | FDA | 2023-08-07 | — | Xenothera |
2-{[2-benzyl-4-(5-methyl-3H-imidazol-4-ylmethyl)-3-oxo-piperazine-1-carbonyl]- amino}-4methyl-pentanoic acid | small molecules | FDA | 2023-03-07 | — | Prescient Therapeutics, LTD |
(2S,4R)-1-((S)-2-(7-(4-((R)-3-((4-(N-(4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide | antibodies | FDA | 2022-03-09 | — | Dialectic Therapeutics, Inc. |
berbamine | small molecules | FDA | 2021-11-29 | — | IsoQ Therapeutics Inc. |
Hypericin | small molecules | FDA | 2021-09-02 | — | Soligenix, Inc. |
Allogeneic CRISPR/Cas9-mediated genetically modified CAR T cells targeting CD70 antigen | combination | FDA | 2021-06-08 | — | CRISPR Therapeutics, Inc. |
linperlisib | small molecules | FDA | 2021-05-26 | — | Shanghai Yingli Pharmaceutical Co., Ltd. |
Sugemalimab | antibodies | FDA | 2020-10-08 | — | CStone Pharmaceuticals (Suzhou) Co., Ltd. |
AZD4205, a potent ATP-competitive JAK1 kinase inhibitor | small molecules | FDA | 2020-09-10 | — | Dizal (Jiangsu) Pharmaceutical Co., Ltd. |
1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one, L-(+)-lactic acid salt | small molecules | FDA | 2020-08-28 | — | Astex Pharmaceuticals, Inc. |
cobomarsen | RNAs | FDA | 2020-07-21 | — | Viridian Therapeutics, Inc. |
nanatinostat and valganciclovir | small molecules | FDA | 2020-06-22 | — | Viracta Therapeutics, Inc. |
tipifarnib | small molecules | FDA | 2020-04-06 | — | Kura Oncology, Inc. |
tetravalent bispecific chimeric anti-human CD30 x anti-human CD16A recombinant antibody construct | antibodies | FDA | 2020-04-01 | — | Affimed GmbH |
sintilimab | antibodies | FDA | 2020-03-24 | — | Innovent Biologics (Suzhou) Co. Ltd |
Autologous modified RNA transfected myeloid cells that express a fusion protein composed of humanized scFv that recognizes human CD5, a CD8 alpha transmembrane domain, and Fc gamma and PI3K intracellular signaling domains (CD5-ATAK-Fcy-PI3K Myeloid Cells) | cell therapies | FDA | 2020-03-16 | — | Myeloid Therapeutics, Inc. |
duvelisib | small molecules | FDA | 2019-10-02 | — | Secura Bio, Inc. |
Panobinostat | small molecules | EMA | 2007-08-02 | — | Novartis Europharm Limited |
pralatrexate [Folotyn] | small molecules | FDA | 2006-07-20 | 2009-09-24 | Acrotech Biopharma LLC |
romidepsin [Istodax] | small molecules | FDA | 2004-09-30 | 2009-11-05 | Celgene Corporation |
vorinostat [Zolinza] | small molecules | FDA | 2004-03-16 | 2006-10-06 | Merck & Co., Inc. |
Chimeric monoclonal antibody to CD30 (anti-CD30 antibody) | antibodies | FDA | 2004-02-18 | — | Seattle Genetics, Inc. |
(1S)-1-(9-deazahypoxanthin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol-hydrochloride | small molecules | FDA | 2004-01-29 | — | Mundipharma Research Limited |
siplizumab | antibodies | FDA | 2003-07-15 | — | MedImmune, LLC |
Tretinoin | small molecules | FDA | 2003-04-11 | — | Antigenics, Inc. |
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