RARE DISEASE
Angioimmunoblastic T-cell lymphoma
Angioimmunoblastic T-cell lymphoma
Angioimmunoblastic T-cell lymphoma
Synonyms: AILT, Immunoblastic lymphadenopathy, Lymphogranulomatosis X, T-cell lymphoma, AILD type
Synonyms: AILT, Immunoblastic lymphadenopathy, Lymphogranulomatosis X, T-cell lymphoma, AILD type
Synonyms: AILT, Immunoblastic lymphadenopathy, Lymphogranulomatosis X, T-cell lymphoma, AILD type
Drug discovery
5
drugs
With orphan designations
Overview
Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive peripheral T-cell lymphoma derived from follicular helper T-cells, characterized by systemic symptoms, immune dysregulation, and frequent advanced-stage presentation at diagnosis. Histopathology reveals polymorphic infiltrates, proliferative vasculature, and CD10/CXCL13-positive malignant T-cells. Despite CHOP-based induction and autologous stem cell transplant consolidation, relapse rates remain high, with a 5-year survival of 30-35% [1][3][11][15].
Burden
Therapies
First-line: CHOP/CHOEP ± autologous transplant; CD30-positive cases may use brentuximab vedotin combinations [1][3][16].
Relapsed/refractory: Epigenetic agents (HDAC inhibitors, hypomethylating agents), PI3K inhibitors, or allogeneic transplant [3][8][15].
Emerging options: Lenalidomide-CHOEP trials (#NCT02561273) and targeted immunotherapy [1][3].
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
734 drug discovery papers about Angioimmunoblastic T-cell lymphoma, with 3 first-in-class and 10 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
734 drug discovery papers about Angioimmunoblastic T-cell lymphoma, with 3 first-in-class and 10 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-21 | Long-Lasting and Well-Tolerated Response after Belinostat Treatment as Part of a Maintenance-Like Approach in a Case of Relapsed AITL
Among Peripheral T-cell lymphomas (PTCLs), T-follicular helper (TFH)-PTCLs are characterized by a common genetic profile and immunophenotype in their malignant cells. Notably, TFH-PTCLs harbor variants in genes involved in epigenetic regulation, suggesting that these entities may be sensitive to Histone Deacetylase Inhibitors (HDACis). This report presents the case of a 79-year-old woman diagnosed with TFH-PTCL of Angioimmunoblastic-Type (AITL). The diagnosis was based solely on histopathological findings from a cervical lymph node biopsy. The expression of three TFH markers (PD-1, BCL6 and CXCL13), together with the typical morphological hallmarks of AITL, was identified in the patient’s biopsy. After receiving six cycles of a combination of 5-Azacitidine (5-AZA) and CHOP, the patient achieved a Complete Metabolic Response (CMR), which was not sustained. Treatment with belinostat, a pan-HDACi, assecond-line therapy resulted in a long-lasting and well-tolerated response. Interestingly, administering belinostat for 22 months after the patient reached a CMR proved successful as a maintenance-like strategy.
2026-08-11 | Multi-omics analysis identifies GAA as an independent poor prognostic biomarker and candidate therapeutic target in angioimmunoblastic T-cell lymphoma
Background Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive subtype of peripheral T-cell lymphoma with poor clinical outcomes and limited therapeutic options. The contribution of metabolic reprogramming and immune microenvironmental alterations to AITL progression remains insufficiently defined. Methods We conducted integrative transcriptomic and proteomic analyses of AITL samples compared with reactive lymphoid hyperplasia to identify molecules associated with treatment response and prognosis. Immune infiltration and pathway enrichment analyses were performed, and findings were validated in independent GEO cohorts (GSE19069 and GSE58445). Key protein expression was confirmed by immunohistochemistry and multiplex immunofluorescence. Results Differential expression analyses revealed that lysosomal alpha-glucosidase (GAA), a key enzyme involved in glycogen metabolism, was significantly upregulated at both the RNA and protein levels in patients who failed to respond to standard chemotherapy. Elevated GAA expression was associated with inferior overall survival in multivariate analysis. Immunohistochemistry staining and multiplex immunofluorescence further confirmed the spatial expression pattern of GAA in AITL tissues. Immune deconvolution and pathway enrichment analyses suggested that GAA-high tumors exhibited increased CD8 + T-cell infiltration accompanied by transcriptional features of T-cell exhaustion, as well as transcriptionally inferred metabolic alterations characterized by enhanced glycolysis-related signatures and reduced oxidative phosphorylation-related signatures. These findings were further validated in an independent AITL cohort from the GEO database. Conclusions Our study identifies GAA as a candidate biomarker associated with adverse clinical outcomes, immune microenvironmental features, and metabolic pathway alterations in AITL, highlighting glycogen metabolism as a previously underexplored biological axis and a potential therapeutic vulnerability warranting further functional investigation.
2026-07-18 | Chidamide‑augmented BEAM conditioning and maintenance in first-remission T‑cell lymphoma: a single‑arm phase 2 experience
T‑cell lymphoma (TCL) is a rare subset of non‑Hodgkin lymphoma (NHL), accounting for 5–10% of cases in Western countries and 15–20% in Asia [ 1 ]. TCL encompasses multiple pathological subtypes, including nodal T‑follicular helper cell lymphoma, angioimmunoblastic‑type (nTFHL‑AI), peripheral T‑cell lymphoma‑not otherwise specified (PTCL‑NOS), and anaplastic large‑cell lymphoma (ALCL) [ 2 ]. First‑line CHOP‑based regimens yield unsatisfactory outcomes [ 2 ]. Autologous stem cell transplantation (ASCT) is a standard consolidation strategy for TCL in first remission, yet the 2‑year progression‑free survival (PFS) with BEAM conditioning is only 52.9% [ 3 ]. Chidamide, an oral HDAC1/2/3/10 inhibitor, has demonstrated efficacy in relapsed/refractory TCL [ 4 ]. Preclinical studies suggest synergistic effects with chemotherapeutic agents such as cytarabine and etoposide [ 5 ]. However, no study has systematically integrated chidamide into the BEAM (carmustine, etoposide, cytarabine, and melphalan) backbone to improve transplant outcomes.
2026-06-29 | Multiple subcutaneous nodules as the primary presentation of angioimmunoblastic T-cell lymphoma: a case report and literature review.
Angioimmunoblastic T-cell lymphoma (AITL) frequently involves the skin, typically presenting as rash or pruritus. However, AITL presenting primarily with multiple subcutaneous nodules is exceedingly rare and poses significant diagnostic challenges, often leading to misdiagnosis. We reported a 53-year-old man who presented with widespread subcutaneous nodules. He had a 1-month history of multiple painless subcutaneous nodules on the trunk and upper limbs. Physical examination revealed multiple firm nodules measuring 0.5-2 cm, accompanied by dark red plaques. Laboratory investigations showed mild anemia, elevated inflammatory markers, decreased IgA levels, and increased IgE levels. Imaging findings demonstrated generalized lymphadenopathy. Histopathological examination revealed effacement of the lymph node architecture with atypical lymphoid cells; immunohistochemistry was positive for CD3, CD4, PD-1, and EBER. A diagnosis of AITL of stage III was established. The patient achieved complete remission (CR) after 6 cycles of chidamide plus CHOP chemotherapy, with no evidence of recurrence at 6 months. This case broadens the recognized cutaneous spectrum of AITL and underscores the importance of considering lymphoma in the differential diagnosis of unexplained subcutaneous nodules.
2026-06-09 | TFH phenotype and response to tucidinostat in relapsed/refractory PTCL: analysis of patients from a phase IIb trial.
T follicular helper (TFH)-derived peripheral T-cell lymphomas (PTCLs) harbor frequent mutations in epigenetic regulators and are sensitive to epigenetic therapies. The histone deacetylase inhibitor tucidinostat demonstrated efficacy in relapsed/refractory PTCL, especially angioimmunoblastic T-cell lymphoma (AITL), in a phase IIb trial; however, the lack of TFH phenotyping has prevented assessment of the predictive value of this phenotype across a broader PTCL spectrum. Therefore, we retrospectively analyzed patients originally diagnosed with AITL or PTCL not otherwise specified (NOS) based on 2008 World Health Organization criteria who participated in the aforementioned trial. TFH phenotype was defined as the expression of ≥ 2 TFH markers. Among the 23 evaluable patients, the TFH group (n = 17) included six with AITL and 11 with PTCL-NOS exhibiting TFH features, and the non-TFH group included six patients with PTCL-NOS. The objective response rate was numerically higher in the TFH group (12/17, 70.6%) than in the non-TFH group (2/6, 33.3%; P = 0.162). Three patients with the TFH phenotype maintained a progression-free survival exceeding 3 years. These findings highlight the potential long-term benefit of tucidinostat in patients with TFH-derived PTCL, supporting the distinct susceptibility of this subtype to epigenetic modulation.
proteins
2026-05-27 | Immune Correlates of Denileukin Diftitox Treatment in TFH-Type Lymphoma.
Background/Objectives: Follicular helper T-cell (TFH)-type lymphomas, including angioimmunoblastic T-cell lymphoma (AITL) and TFH lymphoma, not otherwise specified (TFH-NOS), are characterized by marked immune dysregulation in the tumor microenvironment. We investigated whether TFH-type lymphomas are enriched in immunosuppressive cells and explored immunologic changes associated with denileukin diftitox (DD) treatment. Methods: FOXP3-positive mononuclear cells were quantified by immunohistochemistry in lymph node specimens from 10 patients with TFH-type lymphoma and six with non-TFH-type T-cell lymphoma. Paired skin biopsy specimens obtained before and after DD treatment from two patients with AITL were evaluated for CD4, CD8, CD68, CD163, and FOXP3 expression. Longitudinal flow cytometric T-cell receptor Vβ repertoire analysis of CD8-positive T-cell subsets was performed in three patients with AITL treated with DD. Clinical responses were retrospectively assessed in seven patients with relapsed or refractory TFH-type lymphoma treated with DD. Results: TFH-type lymphomas showed significantly higher intra-tumoral FOXP3-positive cell densities than non-TFH-type lymphomas (p = 0.0024). In paired skin biopsies, DD treatment was associated with reductions in CD68- and CD163-positive macrophage-rich infiltrates and a suggested decrease in FOXP3-positive cells. Among seven patients treated with DD, the overall response rate was 86%, including one complete response and five partial responses. Responders showed selective Vβ over-representation patterns in effector and/or memory CD8-positive T-cell subsets, whereas such findings were not convincing in the non-responder. Conclusions: TFH-type lymphomas were associated with higher FOXP3-positive cell density than selected non-TFH-type comparators. DD treatment may be associated with changes in tissue immune infiltrates and peripheral CD8/TCR Vβ skewing in responding cases, although these findings remain exploratory and do not establish causality.
2026-04-16 | Phage Display Driven Identification and Computational Mapping of Macrocyclic Peptides Targeting RhoA G17V.
Mutant RhoA G17V is a clinically significant yet historically undruggable oncogenic GTPase that drives angioimmunoblastic T-cell lymphoma through a neomorphic interaction with the guanine nucleotide exchange factor Vav1. Its rigid GTPase fold, absence of deep binding pockets, and transient protein-protein interfaces have hindered conventional small-molecule approaches, creating a critical need for alternative therapeutic modalities. Here, we report a systematic strategy to target RhoA G17V using macrocyclic peptides. Two complementary phage-displayed cyclic peptide libraries, an AcrK-mediated 10-mer cyclic library and a CAmCBT-cyclized 12-mer library, were subjected to high-stringency biopanning against recombinant RhoA G17V. While the 10-mer library yielded moderate-affinity binders, the 12-mer library enabled the discovery of Z1, a macrocyclic peptide with submicromolar affinity (KD = 136 nM), representing the highest-affinity peptide reported for RhoA G17V to date. Computational docking combined with long-timescale molecular dynamics simulations revealed a stable peptide-protein interaction governed by cooperative hydrophobic and electrostatic interactions. Systematic alanine scanning mutagenesis experimentally validated the predicted binding determinants, confirming the key residues within the macrocycle. Collectively, this work establishes macrocyclic phage display as a powerful and generalizable platform for discovering high-affinity ligands against challenging mutant GTPases and lays a foundation for the development of precision peptide-based therapeutics.
2025-06-13 | Integrative Genomic and Transcriptomic Analysis Reveals Targetable Vulnerabilities in Angioimmunoblastic T-Cell Lymphoma.
Nodal follicular helper T-cell (T FH) lymphoma of the angioimmunoblastic (AITL) subtype has a dismal prognosis. Using whole-exome sequencing (n = 124), transcriptomic (n = 78), and methylation (n = 40) analysis, we identified recurrent mutations in known epigenetic drivers (TET2, DNMT3A, IDH2 R172 ) and novel ones (TET3, KMT2D). TET2, IDH2 R172 , DNMT3A co-mutated AITLs had poor prognosis (p < 0.0001). Genes regulating T-cell receptor (TCR) signaling (CD28, PLCG1, VAV1, FYN) or activation (RHOA G17V ) or regulators of the PI3K-pathway (PIK(3)C members, PTEN, PHLPP1, PHLPP2) were mutated. CD28 mutation/fusion was associated with poor prognosis (p = 0.02). WES of purified, neoplastic T-cell (CD3+PD1+) demonstrated high concordance with whole tumor biopsies and validated the presence of TET2 and DNMT3A in tumor and non-lymphoid cells, but other mutations (CD28, RHOA G17V , IDH2 R172 , PLCG1) in neoplastic cells. Integrated DNA-methylation and mRNA expression analysis revealed epigenetic alterations in genes regulating TCR, cytokines, PI3K-signaling, and apoptosis. RNA-seq analysis identified fusion transcripts regulating TCR-activation (8%), revealed a restricted TCR-repertoire (α = 87%, β = 72%), and showed the presence of Epstein-Barr virus transcriptome (73%). GEP demonstrated the association of B-cells or dendritic cells in the tumor milieu with prognosis (p < 0.01). RNA-seq and WES analysis of 12 AITL-patient-derived-xenografts (PDX) showed that bi-allelic TET2 and DNMT3A mutations or sub-clonal mutations (PLCG1, PHLPP2) propagated in sequential passages, and gene signatures related to T FH and T CM (central-memory) were well-maintained through passages. Gene expression signatures associated with late PDX passages (3rd-5th) were enriched with proliferation and metabolic reprogramming-related genes and predicted prognosis in an independent AITL series. Low PHLPP2 mRNA expression predicted poor prognosis (p = 0.05) and engineered PHLPP2 or TET2 loss in CD4+ T-cells showed enhanced PI(3)K activation, thus uncovering a therapeutic target for clinical trials.
2023-08-25 | Correlation of low numbers of intratumoral FOXP3+ cells with worse progression-free survival in angioimmunoblastic T cell lymphoma.
Angioimmunoblastic T cell lymphoma (AITL) is a T cell lymphoma with aberrant immune activity. It is characterised by inflammatory and immune reactions. However, the impact of regulatory T (Treg) cells on AITL remains unclear. We retrospectively collected 46 AITL cases and performed immunohistochemical analysis of forkhead box P3 (FOXP3) expression. The number of immunostained FOXP3 cells was determined using a digital pathology system with whole-slide imaging. The average number of FOXP3+ cells per high-power field (HPF) was determined by randomly counting 20 HPFs. AITL cases were categorised into high-expression and low-expression groups based on the median count of FOXP3+ cells in all analysed samples. The relationship between FOXP3 expression and clinicopathological features was assessed. Among the studied patients, 14 (30.4%) were females and 32 (69.6%) were males, and the median age at diagnosis was 64.1 years. The median expression of FOXP3 was 84.9 positive cells/HPF. FOXP3 expression negatively correlated with Epstein-Barr virus-encoded small RNA positivity in tumour (p=0.041). The patients with low FOXP3 expression presented with aggressive clinical behaviour, including advance-staged diseases (p=0.043), splenomegaly (p=0.008), B symptoms (p=0.019) and extranodal involvement (p=0.019). The neutrophil-to-lymphocyte ratio was higher in the patients with low FOXP3 expression, compared with those with high FOXP3 expression. Low FOXP3 expression had an adverse effect on progression-free survival (PFS, p=0.033), and increased the risk of recurrence 2.320-fold (HR 2.320 (95% CI 1.109 to 4.856); p=0.025). Patients with AITL with low FOXP3 expression tend to have aggressive clinical presentation and shortened PFS. These findings may help with risk stratification and determination of new treatment strategy.
2022-05-01 | Mitochondria-specific peptide amphiphiles induce mitochondrial dysfunction and peripheral T-cell lymphomas (PTCL) damage
Peripheral T-cell lymphomas (PTCL) are aggressive lymphomas with poor prognosis, and therefore, there is a pressing need to explore new targets or compounds. Mitochondria may serve as a potential therapeutic target for PTCL. A designed positively-charged segment (pKV) is anchored to the specific 15 amino acid sequence (MIASHLLAYFFTELN) to yield a cell-penetrating peptide (pHK-pKV) and a lipid chain (Pal) is conjugated to the N-terminus of pHK-pKV (Pal-pHK-pKV) are bioactive amphiphilic peptide assemblies targeting the interaction between mitochondrial voltage dependent anion channel 1 (VDAC1) and hexokinase II (HKII).PTCL cell line H9 was treated with Pal-pHK-pKV and pHK-pKV, respectively. Cell proliferation in each group was measured by detecting cell viability and the corresponding marker Ki-67. Apoptosis was detected by immunofluorescence, flow cytometry and western blot. We also measured mitochondrial membrane potential, adenosine triphosphate (ATP) production, the cytochrome c distribution and the expression levels of B cell lymphoma 2 (BCL-2) and BCL-2 associated X protein (BAX). Western blot was used to detect the activation of the extracellular regulated protein kinases (ERK) signaling pathway.Pal-pHK-pKV and pHK-pKV with 20 µM blocked the interaction between VDAC1 and HKII, and detached HKII from mitochondria, which depolarized the mitochondrial membrane potential, induced mitochondria dysfunction, and decreased ATP production. The decreased ATP subsequently inhibited the activation of the ERK/BCL-2 pathway and increased the BAX/BCL-2 ratio. Cytochrome c was then released from the mitochondria and induced capase-3 activation and subsequently apoptosis. Additionally, decreased ATP induced the expression of FAS and then apoptosis.Mitochondria specific peptide amphiphiles induce mitochondrial dysfunction and provide a new approach for the treatment of PTCL.
cell therapies
2026-08-08 | Angioimmunoblastic T-cell lymphoma associated with myeloid neoplasms: a case report and literature review supporting a shared clonal origin
血管免疫母细胞性 T 细胞淋巴瘤 (AITL) 常携带 TET2、 DNMT3A、 IDH2等表观调控基因突变, 此类突变在克隆性造血 (CH) 和髓系肿瘤中同样高频存在, 提示淋巴、 髓系恶性肿瘤可能具备共同细胞起源。 既往 AITL 合并骨髓增生异常肿瘤 (MDS) 和急性髓系白血病 (AML) 病例大多为异时发病, 二者克隆同源的直接分子证据较为匮乏。 本文报道 1 例同步确诊 AITL 伴原始细胞增多的骨髓增生异常肿瘤-2 (MDS-IB2) 的87岁男性患者。 患者以全身瘙痒红斑皮损和全血细胞减少为首发表现, 皮肤活检确诊 AITL, 骨髓穿刺结合流式细胞学确诊 MDS-IB2, PET-CT 提示全身骨髓和淋巴结同步出现肿瘤浸润。 对皮肤淋巴瘤组织与配对骨髓样本进行靶向二代测序, 两份标本均检出 IDH2 p.R140Q 和 ASXL1 p.R1415X 共有致病突变; 淋巴病灶独有 TP53、 CIITA、 NOTCH1 突变, 骨髓髓系病灶特有 SRSF2、 STAG2、 BCOR 突变。 分子检测证实两类肿瘤起源于携带早期克隆造血突变的同一造血干祖细胞, 后续各自获得谱系特异性突变, 发生分支克隆演化。 本文汇总既往相关病例, 多数患者在 AITL 发病数月至数年后继发髓系肿瘤, 部分病例经分子检测证实两类肿瘤共享克隆造血相关突变。 本例同步发病病例, 为 AITL 与髓系肿瘤存在共同克隆起源提供了关键直接分子证据。
2026-07-28 | Angioimmunoblastic T-cell lymphoma following Castleman’s disease: diagnostic challenges and literature review
Castleman disease (CD) represents a heterogeneous group of hematologic disorders characterized by distinct histopathological features. While CD is regarded as a pre-lymphomatous condition, its reactive or neoplastic nature is still a matter of controversy. Although rare, lymphoma has been reported in patients with CD, most commonly B-cell lymphomas. Here, we present a case of a 69-year-old man initially diagnosed with CD who subsequently developed angioimmunoblastic T-cell lymphoma (AITL) during treatment. To elucidate the potential biological relationship between these two disease entities, we performed whole-exome sequencing to compare genomic alterations between the two disease states. Additionally, we provide a concise review of published cases documenting lymphoma occurring after or coexisting with CD, summarizing patients’ characteristics and the various treatment strategies employed thus far.
2026-07-23 | Autologous Stem Cell Transplant Consolidation Is Associated With Improved Overall Survival in Angioimmunoblastic T-Cell Lymphoma: A Real-World National Cancer Database Study.
Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive peripheral T-cell lymphoma with poor outcomes, and the role of autologous stem cell transplantation (ASCT) as consolidation after frontline therapy remains controversial. We conducted a retrospective cohort study using the National Cancer Database, including adults diagnosed with AITL between 2004 and 2020 who received frontline systemic therapy. Patients were categorized as chemotherapy alone (Chemo) or chemotherapy followed by ASCT (Chemo + ASCT). To mitigate immortal time bias, prespecified landmark analyses were performed, with a 6-month landmark analysis as the primary approach and a 9-month landmark analysis as a sensitivity analysis. Multivariable Cox regression and propensity score weighting using inverse probability of treatment weighting for the average treatment effect were used to address measured confounding. Among 3996 patients receiving systemic therapy, 686 (17.2%) underwent ASCT. In the 6-month landmark analysis, ASCT was associated with improved overall survival (HR, 0.53; 95% CI, 0.45-0.62; p < 0.001). Findings were consistent in the 9-month landmark analysis (HR, 0.58; 95% CI, 0.49-0.69; p < 0.001) and IPTW-adjusted model (HR, 0.51; 95% CI, 0.44-0.60; p < 0.001). In this large real-world cohort, ASCT consolidation was consistently associated with improved survival in patients with AITL. Although treatment-response data were unavailable and residual confounding cannot be excluded, these findings provide supportive real-world evidence and warrant prospective studies with treatment-timing and response data to better define patient selection.
2026-04-01 | Efficacy of modified dendritic cell–cytokine-induced killer cells loaded with tumour stem cell membrane microparticle therapy in the treatment of relapsed or refractory T- and NK-cell lymphoid proliferations and lymphomas: a report of three cases
The prognosis of relapsed or refractory T-cell and NK-cell lymphoid proliferations and lymphomas (R/R T/NK-LPD/LYM) remains poor. Modified dendritic cell–cytokine-induced killer (DC–CIK) cells loaded with tumour stem cell (TSC) membrane microparticles (MMPs) can improve the targeted killing activity against tumours. However, the use of this treatment has not been reported for R/R T/NK-LPD/LYM. Herein, we report 3 cases. Case 1 involved an 8-year-old male who presented with bilateral cervical painless lymphadenopathy and a left elbow mass. Case 2 involved a 44-year-old man with recurrent nasal congestion and a runny nose. Case 3 involved a 49-year-old man whose bilateral cervical, axillary, and inguinal lymph nodes were enlarged. The biopsy results revealed T-lymphoblastic leukaemia/lymphoma, not otherwise specified (NOS); extranodal NK/T-cell lymphoma, nasal type; and nodal T follicular helper (TFH) cell lymphoma, angioimmunoblastic type (nTFHL-AI) for Patients 1, 2, and 3, respectively. All three patients ultimately underwent modified dendritic cell–cytokine-induced killer cell therapy loaded with tumour stem cell membrane microparticles following disease progression, relapse, and chemotherapy-associated complications after first-line therapy and multiple lines of salvage therapy. Following treatment with modified dendritic cell–cytokine-induced killer cells loaded with tumour stem cell membrane microparticles, two of these three patients achieved complete and durable remission, whereas the third patient achieved a partial response, with no treatment-related adverse events reported. At the most recent follow-up, two patients maintained stable disease (SD) with preserved quality of life, while one patient experienced progressive disease (PD) and died because of multiple organ dysfunction syndrome secondary to transplantation-associated colitis. To our knowledge, this is the first report of the use of modified dendritic cell–cytokine-induced killer cells loaded with tumour stem cell membrane microparticles for the treatment of R/R T/NK-LPD/LYM. Our findings warrant further evaluation of this novel targeted immunotherapy in future prospective clinical trials.
2026-02-20 | Therapeutic plasma exchange as a rescue and bridging therapy for life-threatening autoimmune hemolytic anemia associated with angioimmunoblastic T-cell lymphoma.
Autoimmune hemolytic anemia (AIHA) is a potentially life-threatening complication of lymphoid malignancies, and transfusion management can be particularly challenging in refractory cases. We report a case of angioimmunoblastic T-cell lymphoma complicated by severe, transfusion-refractory warm AIHA, in which red blood cell transfusion was paradoxically associated with a hyperhemolysis-like process and overt disseminated intravascular coagulation. Despite corticosteroid therapy and rituximab, repeated transfusions failed to produce sustained hemoglobin increments and were followed by worsening hemolysis and coagulopathy. Detailed immunohematologic evaluation demonstrated panreactive IgG autoantibodies with persistently positive direct antiglobulin testing and elevated polyethylene glycol-enhanced indirect antiglobulin test reactivity. Therapeutic plasma exchange was initiated as a rescue intervention, resulting in a progressive reduction in circulating autoantibody reactivity, restoration of transfusion efficiency, and stabilization of hemoglobin levels, despite persistent direct antiglobulin test positivity. Following effective lymphoma-directed chemotherapy, hemolysis resolved completely, and transfusion independence was achieved. This case highlights post-transfusion deterioration resembling hyperhemolysis in lymphoma-associated AIHA and underscores the potential role of therapeutic plasma exchange as a rescue and bridging therapy in life-threatening, transfusion-refractory disease.
antibodies
2026-05-23 | Single-cell transcriptomic mapping of immune heterogeneity across angioimmunoblastic T-cell lymphoma subtypes.
Relapse and treatment resistance remain critical obstacles in the clinical management of angioimmunoblastic T-cell lymphoma (AITL), limiting the success of current therapeutic strategies. Therefore, a comprehensive characterization of the tumor microenvironment (TME) in AITL is essential to enhance treatment efficacy. This study analyzed samples from 68 patients with AITL, stratified into three molecular subtypes based on immunoglobulin (IG) gene rearrangement and flow cytometry results. Utilizing single-cell RNA sequencing, the TME was profiled across subtypes A, B, and C, sampling multiple disease sites including the bone marrow, lymph nodes, and peripheral blood. Our findings revealed subtype-specific variations in cellular composition and transcriptional programs within the TME. Unlike other subtypes, subtype C was associated with a pronounced immunosuppressive environment at diagnosis and relapse. Additionally, it exhibited an enhanced response to Epstein-Barr virus infection, consistent with upregulated CD70 expression at relapse. Through the analysis of cellular communication networks, CD70, programmed cell death 1 (PDCD1), and inducible T cell costimulator (ICOS) were identified as promising immunotherapeutic targets in AITL. Finally, we delineated distinct cellular proportions and gene expression signatures characteristic of each subtype, providing a foundation for the development of tailored therapeutic interventions for patients with AITL.
2026-02-19 | Xenium-based spatial transcriptomic analyses uncover prognosis-associated heterogeneity in the tumor microenvironment (TME) of angioimmunoblastic T-cell lymphoma (AITL).
Angioimmunoblastic T-cell lymphoma (AITL) exemplifies a neoplasm characterized by prominent inflammatory infiltration and robust immune responses in the tumor microenvironment (TME). The pathophysiology of refractory/recurrent (RR) AITL remains poorly understood due to profound intratumoral heterogeneity and complex TME features, contributing to limited therapeutic efficacy. Using Xenium-based spatial transcriptomics on 10 clinical samples, we compared RR AITL with treatment-responsive [non-refractory/recurrent event in 3 years (NR)] cases to map the TME architecture. We identified a novel cluster of NEIL3+ (Nei Like DNA Glycosylase 3) T-follicular helper (Tfh) cells, which exhibited stem-like characteristics at the transcriptional level, featuring self-renewal and multilineage differentiation capacity, and were highly enriched in RR tumors. Furthermore, we found major differences in immune cell organization between NR and RR microenvironments: RR cases were dominated by B cells primed for adaptive immunity and myeloid cells driving angiogenesis, whereas NR cases exhibited a chemokine-mediated regulatory landscape. These findings provide comprehensive characterization of the TME ecosystem in AITL and reveal potential therapeutic targets for high-risk RR AITL patients. © 2026 The Pathological Society of Great Britain and Ireland.
2026-01-28 | Phase I Study of Mogamulizumab in Combination with Pembrolizumab in Patients with Relapsed or Refractory Non-Hodgkin Lymphoma-A National Cancer Institute Experimental Therapeutics Clinical Trials Network (NCI-ETCTN) Trial.
Introduction: Immune evasion through inhibition of effector T cells is a key survival mechanism of lymphoma cells. We hypothesized that reinstating effector T cell activity through concurrent inhibition of the PD1/PD-L1 axis and of Treg activity will result in a synergistic anti-tumor effect with an acceptable toxicity profile. Methods: Phase I multi-institutional NCI-ETCTN trial aimed to evaluate the safety and tolerability of the combination of mogamulizumab and pembrolizumab in relapsed or refractory non-Hodgkin lymphoma. The study used a 3 + 3 design. Treatment consisted of mogamulizumab 1 mg/kg on days 1, 8, and 15 of cycle 1, followed by 1.5 mg/kg on day 1 of each subsequent 21-day cycle in combination with pembrolizumab 200 mg on day 1 of each cycle. A de-escalation level was defined as a 50% reduction in the dose of mogamulizumab (registered in clinicaltrials.gov NCT03309878). Results: The study was discontinued early, after treating seven patients (two angioimmunoblastic T cell lymphoma, four transformed follicular lymphoma, and one diffuse large B cell lymphoma of germinal center subtype) for concerns of futility and non-tolerability. Only two patients completed the first two cycles of treatment. Three patients presented with an early progression and three withdrew consent in the setting of general deterioration with clinically suspected progression. All six patients expired shortly after withdrawal from the study. The remaining patient experienced stress cardiomyopathy during the third cycle and was taken off the study. Discussion: In striking difference to the observation in solid malignancies, the combination of mogamulizumab with pembrolizumab was associated with low tolerability and suspected hyper-progression in patients with lymphoma.
2026-01-16 | Normalized NanoString nCounter expression data from AITL patients
his dataset contains normalized NanoString nCounter gene expression datafrom angioimmunoblastic T-cell lymphoma (AITL) samples.Raw RCC files are not available.No directly identifiable personal information is included.
2026-01-15 | Unraveling the many faces of angioimmunoblastic T-cell lymphoma: clinical, pathological, and molecular heterogeneity.
Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of peripheral T-cell lymphoma originating from follicular helper T cells and characterized by profound clinical, pathological, and molecular heterogeneity. Despite advances in classification and diagnosis, therapeutic outcomes remain suboptimal, particularly in relapsed or refractory settings. In recent years, the evolution of risk stratification models and a deeper understanding of AITL’s molecular pathogenesis, including its unique pattern of clonal evolution, have paved the way for precision medicine. Notably, targeted treatment approaches, such as immunomodulatory agents, epigenetic therapies, kinase inhibitors, and immune checkpoint blockade, are demonstrating promising clinical efficacy, especially in patients harboring specific molecular aberrations. This review comprehensively summarizes the multilayered heterogeneity of AITL, emphasizes the role of immune and molecular profiling in informing therapeutic decisions, and outlines future directions for personalized, multi-agent treatment strategies aimed at overcoming resistance and improving survival.
other
2025-01-29 | Angioimmunoblastic T-cell lymphoma: Characterization of clonal T and B cells and a patient-derived xenograft study of coexisting T- and B-cell proliferation.
Angioimmunoblastic T-cell lymphoma (AITL) is a rare and aggressive lymphoma with a poor prognosis. AITL is associated with Epstein-Barr virus (EBV)-positive B cells in most cases, suggesting a possible role for the virus in the pathobiology of AITL. Cell lines from AITL patients do not exist and models of human AITL are needed. We aim to establish such a model and use it for preclinical therapeutic evaluation. Primary lymph node tissue from an AITL patient was used for tumor cell isolation and injection to NSG mice. The established patient-derived xenograft (PDX) model was characterized by immunophenotyping, whole-exome sequencing (WES), and T/B-cell receptor gene rearrangement studies. In vivo AITL PDX trials were performed with elotuzumab, romidepsin, and rituximab. An AITL PDX mouse model that includes a coexisting EBV+ B-cell proliferation was established. We confirmed clonal identity of the engrafted T cells with the primary T-lymphoma cells. WES on DNA from xenografted sorted T and B cells identified eight and three mutations previously reported in the COSMIC database, respectively. Primary tumor cells could be passaged serially in NSG mice with an increasing percentage of monoclonal B cells that mimic the human condition in which the clonal B-cell component in some cases may mask an underling T-cell lymphoma. In this PDX mouse study, single agent elotuzumab or rituximab significantly improved mice survival. Survival was further improved when elotuzumab or romidepsin was combined with rituximab. To our knowledge, this is the first molecular characterization of AITL model coexisting with associated EBV+ B cells, and use of such a PDX model for therapeutic evaluation of agents targeting both malignant T cells and B cells simultaneously.
2023-03-31 | Data from Genome-Wide miRNA Expression Profiling of Molecular Subgroups of Peripheral T-cell Lymphoma
<div>AbstractPurpose:<p>Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non–Hodgkin lymphomas with aggressive clinical behavior. We performed comprehensive miRNA profiling in PTCLs and corresponding normal CD4<sup>+</sup> Th1/2 and TFH-like polarized subsets to elucidate the role of miRNAs in T-cell lymphomagenesis.</p>Experimental Design:<p>We used nCounter (NanoString Inc) for miRNA profiling and validated using Taqman qRT-PCR (Applied Biosystems, Inc). Normal CD4<sup>+</sup> T cells were polarized into effector Th subsets using signature cytokines, and miRNA significance was revealed using functional experiments.</p>Results:<p>Effector Th subsets showed distinct miRNA expression with corresponding transcription factor expression (e.g., BCL6/miR-19b, -106, -30d, -26b, in IL21-polarized; GATA3/miR-155, miR-337 in Th2-polarized; and TBX21/miR-181a, -331-3p in Th1-polarized cells). Integration of miRNA signatures suggested activation of TCR and PI3K signaling in IL21-polarized cells, ERK signaling in Th1-polarized cells, and AKT–mTOR signaling in Th2-polarized cells, validated at protein level. In neoplastic counterparts, distinctive miRNAs were identified and confirmed in an independent cohort. Integrative miRNA–mRNA analysis identified a decrease in target transcript abundance leading to deregulation of sphingolipid and Wnt signaling and epigenetic dysregulation in angioimmunoblastic T-cell lymphoma (AITL), while ERK, MAPK, and cell cycle were identified in PTCL subsets, and decreased target transcript abundance was validated in an independent cohort. Elevated expression of miRNAs (miR-126-3p, miR-145-5p) in AITL was associated with poor clinical outcome. <i>In silico</i> and experimental validation suggest two targets (miR-126→ SIPR2 and miR-145 → ROCK1) resulting in reduced RhoA-GTPase activity and T–B-cell interaction.</p>Conclusions:<p>Unique miRNAs and deregulated oncogenic pathways are associated with PTCL subtypes. Upregulated miRNA-126-3p and miR-145-5p expression regulate RhoA-GTPase and inhibit T-cell migration, crucial for AITL pathobiology.</p></div>
2023-02-17 | Cardiac Tamponade as a Recurrence of Angioimmunoblastic T-Cell Lymphoma with the Detection of a p.Gly17Val RHOA Mutation in the Pericardial Effusion.
Angioimmunoblastic T-cell lymphoma (AITL) is an intractable type of T-cell lymphoma. We and others have identified that the p.Gly17Val RHOA mutation is specifically identified in AITL. We herein report a patient whose condition deteriorated, resulting from massive pericardial effusion one month after undergoing autologous transplantation for AITL. He was diagnosed with cardiac tamponade caused by AITL recurrence in the presence of the p.Gly17Val RHOA mutation as well as T-lineage cells with an aberrant immune-phenotype in the pericardial effusion. This case suggests that a precision medicine approach by detecting the presence of a p.Gly17Val RHOA mutation is useful for the management of AITL.
2022-03-31 | Genome-Wide miRNA Expression Profiling of Molecular Subgroups of Peripheral T-cell Lymphoma.
Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas with aggressive clinical behavior. We performed comprehensive miRNA profiling in PTCLs and corresponding normal CD4+ Th1/2 and TFH-like polarized subsets to elucidate the role of miRNAs in T-cell lymphomagenesis. We used nCounter (NanoString Inc) for miRNA profiling and validated using Taqman qRT-PCR (Applied Biosystems, Inc). Normal CD4+ T cells were polarized into effector Th subsets using signature cytokines, and miRNA significance was revealed using functional experiments. Effector Th subsets showed distinct miRNA expression with corresponding transcription factor expression (e.g., BCL6/miR-19b, -106, -30d, -26b, in IL21-polarized; GATA3/miR-155, miR-337 in Th2-polarized; and TBX21/miR-181a, -331-3p in Th1-polarized cells). Integration of miRNA signatures suggested activation of TCR and PI3K signaling in IL21-polarized cells, ERK signaling in Th1-polarized cells, and AKT-mTOR signaling in Th2-polarized cells, validated at protein level. In neoplastic counterparts, distinctive miRNAs were identified and confirmed in an independent cohort. Integrative miRNA-mRNA analysis identified a decrease in target transcript abundance leading to deregulation of sphingolipid and Wnt signaling and epigenetic dysregulation in angioimmunoblastic T-cell lymphoma (AITL), while ERK, MAPK, and cell cycle were identified in PTCL subsets, and decreased target transcript abundance was validated in an independent cohort. Elevated expression of miRNAs (miR-126-3p, miR-145-5p) in AITL was associated with poor clinical outcome. In silico and experimental validation suggest two targets (miR-126→ SIPR2 and miR-145 → ROCK1) resulting in reduced RhoA-GTPase activity and T-B-cell interaction. Unique miRNAs and deregulated oncogenic pathways are associated with PTCL subtypes. Upregulated miRNA-126-3p and miR-145-5p expression regulate RhoA-GTPase and inhibit T-cell migration, crucial for AITL pathobiology.
2022-01-31 | Mice transgenic for human CTLA4-CD28 fusion gene show proliferation and transformation of ATLL-like and AITL-like T cells.
CTLA4-CD28 gene fusion has been reported to occur in diverse types of T cell lymphoma. The fusion event is expected to convert inhibitory signals to activating signals and promote proliferation and potentially transformation of T cells. To test the function of the CTLA4-CD28 fusion gene in vivo, we generated a murine model that expresses the gene in a T cell-specific manner. The transgenic mice have shorter life spans and display inflammatory responses including lymphadenopathy and splenomegaly. T cells in turn show higher levels of activation and infiltrate various organs including the lung and skin. T cells, in particular CD4+ helper T cells, were also readily transplantable to immunocompromised mice. Transcriptomic profiling revealed that the gene expression pattern in CD4 + T cells closely resembles that of adult T cell leukemia/lymphoma (ATLL) and that of angioimmunoblastic T cell lymphoma (AITL) tissues. Consistently, we detected supernumerary FOXP3+ cells and PD-1+ cells in transgenic and transplanted mice. This is the first report demonstrating the transforming activity of the CTLA4-CD28 fusion gene in vivo, and this murine model should be useful in dissecting the molecular events downstream to this mutation.
small molecules
2026-08-21 | Long-Lasting and Well-Tolerated Response after Belinostat Treatment as Part of a Maintenance-Like Approach in a Case of Relapsed AITL
Among Peripheral T-cell lymphomas (PTCLs), T-follicular helper (TFH)-PTCLs are characterized by a common genetic profile and immunophenotype in their malignant cells. Notably, TFH-PTCLs harbor variants in genes involved in epigenetic regulation, suggesting that these entities may be sensitive to Histone Deacetylase Inhibitors (HDACis). This report presents the case of a 79-year-old woman diagnosed with TFH-PTCL of Angioimmunoblastic-Type (AITL). The diagnosis was based solely on histopathological findings from a cervical lymph node biopsy. The expression of three TFH markers (PD-1, BCL6 and CXCL13), together with the typical morphological hallmarks of AITL, was identified in the patient’s biopsy. After receiving six cycles of a combination of 5-Azacitidine (5-AZA) and CHOP, the patient achieved a Complete Metabolic Response (CMR), which was not sustained. Treatment with belinostat, a pan-HDACi, assecond-line therapy resulted in a long-lasting and well-tolerated response. Interestingly, administering belinostat for 22 months after the patient reached a CMR proved successful as a maintenance-like strategy.
2026-08-11 | Multi-omics analysis identifies GAA as an independent poor prognostic biomarker and candidate therapeutic target in angioimmunoblastic T-cell lymphoma
Background Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive subtype of peripheral T-cell lymphoma with poor clinical outcomes and limited therapeutic options. The contribution of metabolic reprogramming and immune microenvironmental alterations to AITL progression remains insufficiently defined. Methods We conducted integrative transcriptomic and proteomic analyses of AITL samples compared with reactive lymphoid hyperplasia to identify molecules associated with treatment response and prognosis. Immune infiltration and pathway enrichment analyses were performed, and findings were validated in independent GEO cohorts (GSE19069 and GSE58445). Key protein expression was confirmed by immunohistochemistry and multiplex immunofluorescence. Results Differential expression analyses revealed that lysosomal alpha-glucosidase (GAA), a key enzyme involved in glycogen metabolism, was significantly upregulated at both the RNA and protein levels in patients who failed to respond to standard chemotherapy. Elevated GAA expression was associated with inferior overall survival in multivariate analysis. Immunohistochemistry staining and multiplex immunofluorescence further confirmed the spatial expression pattern of GAA in AITL tissues. Immune deconvolution and pathway enrichment analyses suggested that GAA-high tumors exhibited increased CD8 + T-cell infiltration accompanied by transcriptional features of T-cell exhaustion, as well as transcriptionally inferred metabolic alterations characterized by enhanced glycolysis-related signatures and reduced oxidative phosphorylation-related signatures. These findings were further validated in an independent AITL cohort from the GEO database. Conclusions Our study identifies GAA as a candidate biomarker associated with adverse clinical outcomes, immune microenvironmental features, and metabolic pathway alterations in AITL, highlighting glycogen metabolism as a previously underexplored biological axis and a potential therapeutic vulnerability warranting further functional investigation.
2026-07-18 | Chidamide‑augmented BEAM conditioning and maintenance in first-remission T‑cell lymphoma: a single‑arm phase 2 experience
T‑cell lymphoma (TCL) is a rare subset of non‑Hodgkin lymphoma (NHL), accounting for 5–10% of cases in Western countries and 15–20% in Asia [ 1 ]. TCL encompasses multiple pathological subtypes, including nodal T‑follicular helper cell lymphoma, angioimmunoblastic‑type (nTFHL‑AI), peripheral T‑cell lymphoma‑not otherwise specified (PTCL‑NOS), and anaplastic large‑cell lymphoma (ALCL) [ 2 ]. First‑line CHOP‑based regimens yield unsatisfactory outcomes [ 2 ]. Autologous stem cell transplantation (ASCT) is a standard consolidation strategy for TCL in first remission, yet the 2‑year progression‑free survival (PFS) with BEAM conditioning is only 52.9% [ 3 ]. Chidamide, an oral HDAC1/2/3/10 inhibitor, has demonstrated efficacy in relapsed/refractory TCL [ 4 ]. Preclinical studies suggest synergistic effects with chemotherapeutic agents such as cytarabine and etoposide [ 5 ]. However, no study has systematically integrated chidamide into the BEAM (carmustine, etoposide, cytarabine, and melphalan) backbone to improve transplant outcomes.
2026-06-29 | Multiple subcutaneous nodules as the primary presentation of angioimmunoblastic T-cell lymphoma: a case report and literature review.
Angioimmunoblastic T-cell lymphoma (AITL) frequently involves the skin, typically presenting as rash or pruritus. However, AITL presenting primarily with multiple subcutaneous nodules is exceedingly rare and poses significant diagnostic challenges, often leading to misdiagnosis. We reported a 53-year-old man who presented with widespread subcutaneous nodules. He had a 1-month history of multiple painless subcutaneous nodules on the trunk and upper limbs. Physical examination revealed multiple firm nodules measuring 0.5-2 cm, accompanied by dark red plaques. Laboratory investigations showed mild anemia, elevated inflammatory markers, decreased IgA levels, and increased IgE levels. Imaging findings demonstrated generalized lymphadenopathy. Histopathological examination revealed effacement of the lymph node architecture with atypical lymphoid cells; immunohistochemistry was positive for CD3, CD4, PD-1, and EBER. A diagnosis of AITL of stage III was established. The patient achieved complete remission (CR) after 6 cycles of chidamide plus CHOP chemotherapy, with no evidence of recurrence at 6 months. This case broadens the recognized cutaneous spectrum of AITL and underscores the importance of considering lymphoma in the differential diagnosis of unexplained subcutaneous nodules.
2026-06-09 | TFH phenotype and response to tucidinostat in relapsed/refractory PTCL: analysis of patients from a phase IIb trial.
T follicular helper (TFH)-derived peripheral T-cell lymphomas (PTCLs) harbor frequent mutations in epigenetic regulators and are sensitive to epigenetic therapies. The histone deacetylase inhibitor tucidinostat demonstrated efficacy in relapsed/refractory PTCL, especially angioimmunoblastic T-cell lymphoma (AITL), in a phase IIb trial; however, the lack of TFH phenotyping has prevented assessment of the predictive value of this phenotype across a broader PTCL spectrum. Therefore, we retrospectively analyzed patients originally diagnosed with AITL or PTCL not otherwise specified (NOS) based on 2008 World Health Organization criteria who participated in the aforementioned trial. TFH phenotype was defined as the expression of ≥ 2 TFH markers. Among the 23 evaluable patients, the TFH group (n = 17) included six with AITL and 11 with PTCL-NOS exhibiting TFH features, and the non-TFH group included six patients with PTCL-NOS. The objective response rate was numerically higher in the TFH group (12/17, 70.6%) than in the non-TFH group (2/6, 33.3%; P = 0.162). Three patients with the TFH phenotype maintained a progression-free survival exceeding 3 years. These findings highlight the potential long-term benefit of tucidinostat in patients with TFH-derived PTCL, supporting the distinct susceptibility of this subtype to epigenetic modulation.
proteins
2026-05-27 | Immune Correlates of Denileukin Diftitox Treatment in TFH-Type Lymphoma.
Background/Objectives: Follicular helper T-cell (TFH)-type lymphomas, including angioimmunoblastic T-cell lymphoma (AITL) and TFH lymphoma, not otherwise specified (TFH-NOS), are characterized by marked immune dysregulation in the tumor microenvironment. We investigated whether TFH-type lymphomas are enriched in immunosuppressive cells and explored immunologic changes associated with denileukin diftitox (DD) treatment. Methods: FOXP3-positive mononuclear cells were quantified by immunohistochemistry in lymph node specimens from 10 patients with TFH-type lymphoma and six with non-TFH-type T-cell lymphoma. Paired skin biopsy specimens obtained before and after DD treatment from two patients with AITL were evaluated for CD4, CD8, CD68, CD163, and FOXP3 expression. Longitudinal flow cytometric T-cell receptor Vβ repertoire analysis of CD8-positive T-cell subsets was performed in three patients with AITL treated with DD. Clinical responses were retrospectively assessed in seven patients with relapsed or refractory TFH-type lymphoma treated with DD. Results: TFH-type lymphomas showed significantly higher intra-tumoral FOXP3-positive cell densities than non-TFH-type lymphomas (p = 0.0024). In paired skin biopsies, DD treatment was associated with reductions in CD68- and CD163-positive macrophage-rich infiltrates and a suggested decrease in FOXP3-positive cells. Among seven patients treated with DD, the overall response rate was 86%, including one complete response and five partial responses. Responders showed selective Vβ over-representation patterns in effector and/or memory CD8-positive T-cell subsets, whereas such findings were not convincing in the non-responder. Conclusions: TFH-type lymphomas were associated with higher FOXP3-positive cell density than selected non-TFH-type comparators. DD treatment may be associated with changes in tissue immune infiltrates and peripheral CD8/TCR Vβ skewing in responding cases, although these findings remain exploratory and do not establish causality.
2026-04-16 | Phage Display Driven Identification and Computational Mapping of Macrocyclic Peptides Targeting RhoA G17V.
Mutant RhoA G17V is a clinically significant yet historically undruggable oncogenic GTPase that drives angioimmunoblastic T-cell lymphoma through a neomorphic interaction with the guanine nucleotide exchange factor Vav1. Its rigid GTPase fold, absence of deep binding pockets, and transient protein-protein interfaces have hindered conventional small-molecule approaches, creating a critical need for alternative therapeutic modalities. Here, we report a systematic strategy to target RhoA G17V using macrocyclic peptides. Two complementary phage-displayed cyclic peptide libraries, an AcrK-mediated 10-mer cyclic library and a CAmCBT-cyclized 12-mer library, were subjected to high-stringency biopanning against recombinant RhoA G17V. While the 10-mer library yielded moderate-affinity binders, the 12-mer library enabled the discovery of Z1, a macrocyclic peptide with submicromolar affinity (KD = 136 nM), representing the highest-affinity peptide reported for RhoA G17V to date. Computational docking combined with long-timescale molecular dynamics simulations revealed a stable peptide-protein interaction governed by cooperative hydrophobic and electrostatic interactions. Systematic alanine scanning mutagenesis experimentally validated the predicted binding determinants, confirming the key residues within the macrocycle. Collectively, this work establishes macrocyclic phage display as a powerful and generalizable platform for discovering high-affinity ligands against challenging mutant GTPases and lays a foundation for the development of precision peptide-based therapeutics.
2025-06-13 | Integrative Genomic and Transcriptomic Analysis Reveals Targetable Vulnerabilities in Angioimmunoblastic T-Cell Lymphoma.
Nodal follicular helper T-cell (T FH) lymphoma of the angioimmunoblastic (AITL) subtype has a dismal prognosis. Using whole-exome sequencing (n = 124), transcriptomic (n = 78), and methylation (n = 40) analysis, we identified recurrent mutations in known epigenetic drivers (TET2, DNMT3A, IDH2 R172 ) and novel ones (TET3, KMT2D). TET2, IDH2 R172 , DNMT3A co-mutated AITLs had poor prognosis (p < 0.0001). Genes regulating T-cell receptor (TCR) signaling (CD28, PLCG1, VAV1, FYN) or activation (RHOA G17V ) or regulators of the PI3K-pathway (PIK(3)C members, PTEN, PHLPP1, PHLPP2) were mutated. CD28 mutation/fusion was associated with poor prognosis (p = 0.02). WES of purified, neoplastic T-cell (CD3+PD1+) demonstrated high concordance with whole tumor biopsies and validated the presence of TET2 and DNMT3A in tumor and non-lymphoid cells, but other mutations (CD28, RHOA G17V , IDH2 R172 , PLCG1) in neoplastic cells. Integrated DNA-methylation and mRNA expression analysis revealed epigenetic alterations in genes regulating TCR, cytokines, PI3K-signaling, and apoptosis. RNA-seq analysis identified fusion transcripts regulating TCR-activation (8%), revealed a restricted TCR-repertoire (α = 87%, β = 72%), and showed the presence of Epstein-Barr virus transcriptome (73%). GEP demonstrated the association of B-cells or dendritic cells in the tumor milieu with prognosis (p < 0.01). RNA-seq and WES analysis of 12 AITL-patient-derived-xenografts (PDX) showed that bi-allelic TET2 and DNMT3A mutations or sub-clonal mutations (PLCG1, PHLPP2) propagated in sequential passages, and gene signatures related to T FH and T CM (central-memory) were well-maintained through passages. Gene expression signatures associated with late PDX passages (3rd-5th) were enriched with proliferation and metabolic reprogramming-related genes and predicted prognosis in an independent AITL series. Low PHLPP2 mRNA expression predicted poor prognosis (p = 0.05) and engineered PHLPP2 or TET2 loss in CD4+ T-cells showed enhanced PI(3)K activation, thus uncovering a therapeutic target for clinical trials.
2023-08-25 | Correlation of low numbers of intratumoral FOXP3+ cells with worse progression-free survival in angioimmunoblastic T cell lymphoma.
Angioimmunoblastic T cell lymphoma (AITL) is a T cell lymphoma with aberrant immune activity. It is characterised by inflammatory and immune reactions. However, the impact of regulatory T (Treg) cells on AITL remains unclear. We retrospectively collected 46 AITL cases and performed immunohistochemical analysis of forkhead box P3 (FOXP3) expression. The number of immunostained FOXP3 cells was determined using a digital pathology system with whole-slide imaging. The average number of FOXP3+ cells per high-power field (HPF) was determined by randomly counting 20 HPFs. AITL cases were categorised into high-expression and low-expression groups based on the median count of FOXP3+ cells in all analysed samples. The relationship between FOXP3 expression and clinicopathological features was assessed. Among the studied patients, 14 (30.4%) were females and 32 (69.6%) were males, and the median age at diagnosis was 64.1 years. The median expression of FOXP3 was 84.9 positive cells/HPF. FOXP3 expression negatively correlated with Epstein-Barr virus-encoded small RNA positivity in tumour (p=0.041). The patients with low FOXP3 expression presented with aggressive clinical behaviour, including advance-staged diseases (p=0.043), splenomegaly (p=0.008), B symptoms (p=0.019) and extranodal involvement (p=0.019). The neutrophil-to-lymphocyte ratio was higher in the patients with low FOXP3 expression, compared with those with high FOXP3 expression. Low FOXP3 expression had an adverse effect on progression-free survival (PFS, p=0.033), and increased the risk of recurrence 2.320-fold (HR 2.320 (95% CI 1.109 to 4.856); p=0.025). Patients with AITL with low FOXP3 expression tend to have aggressive clinical presentation and shortened PFS. These findings may help with risk stratification and determination of new treatment strategy.
2022-05-01 | Mitochondria-specific peptide amphiphiles induce mitochondrial dysfunction and peripheral T-cell lymphomas (PTCL) damage
Peripheral T-cell lymphomas (PTCL) are aggressive lymphomas with poor prognosis, and therefore, there is a pressing need to explore new targets or compounds. Mitochondria may serve as a potential therapeutic target for PTCL. A designed positively-charged segment (pKV) is anchored to the specific 15 amino acid sequence (MIASHLLAYFFTELN) to yield a cell-penetrating peptide (pHK-pKV) and a lipid chain (Pal) is conjugated to the N-terminus of pHK-pKV (Pal-pHK-pKV) are bioactive amphiphilic peptide assemblies targeting the interaction between mitochondrial voltage dependent anion channel 1 (VDAC1) and hexokinase II (HKII).PTCL cell line H9 was treated with Pal-pHK-pKV and pHK-pKV, respectively. Cell proliferation in each group was measured by detecting cell viability and the corresponding marker Ki-67. Apoptosis was detected by immunofluorescence, flow cytometry and western blot. We also measured mitochondrial membrane potential, adenosine triphosphate (ATP) production, the cytochrome c distribution and the expression levels of B cell lymphoma 2 (BCL-2) and BCL-2 associated X protein (BAX). Western blot was used to detect the activation of the extracellular regulated protein kinases (ERK) signaling pathway.Pal-pHK-pKV and pHK-pKV with 20 µM blocked the interaction between VDAC1 and HKII, and detached HKII from mitochondria, which depolarized the mitochondrial membrane potential, induced mitochondria dysfunction, and decreased ATP production. The decreased ATP subsequently inhibited the activation of the ERK/BCL-2 pathway and increased the BAX/BCL-2 ratio. Cytochrome c was then released from the mitochondria and induced capase-3 activation and subsequently apoptosis. Additionally, decreased ATP induced the expression of FAS and then apoptosis.Mitochondria specific peptide amphiphiles induce mitochondrial dysfunction and provide a new approach for the treatment of PTCL.
cell therapies
2026-08-08 | Angioimmunoblastic T-cell lymphoma associated with myeloid neoplasms: a case report and literature review supporting a shared clonal origin
血管免疫母细胞性 T 细胞淋巴瘤 (AITL) 常携带 TET2、 DNMT3A、 IDH2等表观调控基因突变, 此类突变在克隆性造血 (CH) 和髓系肿瘤中同样高频存在, 提示淋巴、 髓系恶性肿瘤可能具备共同细胞起源。 既往 AITL 合并骨髓增生异常肿瘤 (MDS) 和急性髓系白血病 (AML) 病例大多为异时发病, 二者克隆同源的直接分子证据较为匮乏。 本文报道 1 例同步确诊 AITL 伴原始细胞增多的骨髓增生异常肿瘤-2 (MDS-IB2) 的87岁男性患者。 患者以全身瘙痒红斑皮损和全血细胞减少为首发表现, 皮肤活检确诊 AITL, 骨髓穿刺结合流式细胞学确诊 MDS-IB2, PET-CT 提示全身骨髓和淋巴结同步出现肿瘤浸润。 对皮肤淋巴瘤组织与配对骨髓样本进行靶向二代测序, 两份标本均检出 IDH2 p.R140Q 和 ASXL1 p.R1415X 共有致病突变; 淋巴病灶独有 TP53、 CIITA、 NOTCH1 突变, 骨髓髓系病灶特有 SRSF2、 STAG2、 BCOR 突变。 分子检测证实两类肿瘤起源于携带早期克隆造血突变的同一造血干祖细胞, 后续各自获得谱系特异性突变, 发生分支克隆演化。 本文汇总既往相关病例, 多数患者在 AITL 发病数月至数年后继发髓系肿瘤, 部分病例经分子检测证实两类肿瘤共享克隆造血相关突变。 本例同步发病病例, 为 AITL 与髓系肿瘤存在共同克隆起源提供了关键直接分子证据。
2026-07-28 | Angioimmunoblastic T-cell lymphoma following Castleman’s disease: diagnostic challenges and literature review
Castleman disease (CD) represents a heterogeneous group of hematologic disorders characterized by distinct histopathological features. While CD is regarded as a pre-lymphomatous condition, its reactive or neoplastic nature is still a matter of controversy. Although rare, lymphoma has been reported in patients with CD, most commonly B-cell lymphomas. Here, we present a case of a 69-year-old man initially diagnosed with CD who subsequently developed angioimmunoblastic T-cell lymphoma (AITL) during treatment. To elucidate the potential biological relationship between these two disease entities, we performed whole-exome sequencing to compare genomic alterations between the two disease states. Additionally, we provide a concise review of published cases documenting lymphoma occurring after or coexisting with CD, summarizing patients’ characteristics and the various treatment strategies employed thus far.
2026-07-23 | Autologous Stem Cell Transplant Consolidation Is Associated With Improved Overall Survival in Angioimmunoblastic T-Cell Lymphoma: A Real-World National Cancer Database Study.
Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive peripheral T-cell lymphoma with poor outcomes, and the role of autologous stem cell transplantation (ASCT) as consolidation after frontline therapy remains controversial. We conducted a retrospective cohort study using the National Cancer Database, including adults diagnosed with AITL between 2004 and 2020 who received frontline systemic therapy. Patients were categorized as chemotherapy alone (Chemo) or chemotherapy followed by ASCT (Chemo + ASCT). To mitigate immortal time bias, prespecified landmark analyses were performed, with a 6-month landmark analysis as the primary approach and a 9-month landmark analysis as a sensitivity analysis. Multivariable Cox regression and propensity score weighting using inverse probability of treatment weighting for the average treatment effect were used to address measured confounding. Among 3996 patients receiving systemic therapy, 686 (17.2%) underwent ASCT. In the 6-month landmark analysis, ASCT was associated with improved overall survival (HR, 0.53; 95% CI, 0.45-0.62; p < 0.001). Findings were consistent in the 9-month landmark analysis (HR, 0.58; 95% CI, 0.49-0.69; p < 0.001) and IPTW-adjusted model (HR, 0.51; 95% CI, 0.44-0.60; p < 0.001). In this large real-world cohort, ASCT consolidation was consistently associated with improved survival in patients with AITL. Although treatment-response data were unavailable and residual confounding cannot be excluded, these findings provide supportive real-world evidence and warrant prospective studies with treatment-timing and response data to better define patient selection.
2026-04-01 | Efficacy of modified dendritic cell–cytokine-induced killer cells loaded with tumour stem cell membrane microparticle therapy in the treatment of relapsed or refractory T- and NK-cell lymphoid proliferations and lymphomas: a report of three cases
The prognosis of relapsed or refractory T-cell and NK-cell lymphoid proliferations and lymphomas (R/R T/NK-LPD/LYM) remains poor. Modified dendritic cell–cytokine-induced killer (DC–CIK) cells loaded with tumour stem cell (TSC) membrane microparticles (MMPs) can improve the targeted killing activity against tumours. However, the use of this treatment has not been reported for R/R T/NK-LPD/LYM. Herein, we report 3 cases. Case 1 involved an 8-year-old male who presented with bilateral cervical painless lymphadenopathy and a left elbow mass. Case 2 involved a 44-year-old man with recurrent nasal congestion and a runny nose. Case 3 involved a 49-year-old man whose bilateral cervical, axillary, and inguinal lymph nodes were enlarged. The biopsy results revealed T-lymphoblastic leukaemia/lymphoma, not otherwise specified (NOS); extranodal NK/T-cell lymphoma, nasal type; and nodal T follicular helper (TFH) cell lymphoma, angioimmunoblastic type (nTFHL-AI) for Patients 1, 2, and 3, respectively. All three patients ultimately underwent modified dendritic cell–cytokine-induced killer cell therapy loaded with tumour stem cell membrane microparticles following disease progression, relapse, and chemotherapy-associated complications after first-line therapy and multiple lines of salvage therapy. Following treatment with modified dendritic cell–cytokine-induced killer cells loaded with tumour stem cell membrane microparticles, two of these three patients achieved complete and durable remission, whereas the third patient achieved a partial response, with no treatment-related adverse events reported. At the most recent follow-up, two patients maintained stable disease (SD) with preserved quality of life, while one patient experienced progressive disease (PD) and died because of multiple organ dysfunction syndrome secondary to transplantation-associated colitis. To our knowledge, this is the first report of the use of modified dendritic cell–cytokine-induced killer cells loaded with tumour stem cell membrane microparticles for the treatment of R/R T/NK-LPD/LYM. Our findings warrant further evaluation of this novel targeted immunotherapy in future prospective clinical trials.
2026-02-20 | Therapeutic plasma exchange as a rescue and bridging therapy for life-threatening autoimmune hemolytic anemia associated with angioimmunoblastic T-cell lymphoma.
Autoimmune hemolytic anemia (AIHA) is a potentially life-threatening complication of lymphoid malignancies, and transfusion management can be particularly challenging in refractory cases. We report a case of angioimmunoblastic T-cell lymphoma complicated by severe, transfusion-refractory warm AIHA, in which red blood cell transfusion was paradoxically associated with a hyperhemolysis-like process and overt disseminated intravascular coagulation. Despite corticosteroid therapy and rituximab, repeated transfusions failed to produce sustained hemoglobin increments and were followed by worsening hemolysis and coagulopathy. Detailed immunohematologic evaluation demonstrated panreactive IgG autoantibodies with persistently positive direct antiglobulin testing and elevated polyethylene glycol-enhanced indirect antiglobulin test reactivity. Therapeutic plasma exchange was initiated as a rescue intervention, resulting in a progressive reduction in circulating autoantibody reactivity, restoration of transfusion efficiency, and stabilization of hemoglobin levels, despite persistent direct antiglobulin test positivity. Following effective lymphoma-directed chemotherapy, hemolysis resolved completely, and transfusion independence was achieved. This case highlights post-transfusion deterioration resembling hyperhemolysis in lymphoma-associated AIHA and underscores the potential role of therapeutic plasma exchange as a rescue and bridging therapy in life-threatening, transfusion-refractory disease.
antibodies
2026-05-23 | Single-cell transcriptomic mapping of immune heterogeneity across angioimmunoblastic T-cell lymphoma subtypes.
Relapse and treatment resistance remain critical obstacles in the clinical management of angioimmunoblastic T-cell lymphoma (AITL), limiting the success of current therapeutic strategies. Therefore, a comprehensive characterization of the tumor microenvironment (TME) in AITL is essential to enhance treatment efficacy. This study analyzed samples from 68 patients with AITL, stratified into three molecular subtypes based on immunoglobulin (IG) gene rearrangement and flow cytometry results. Utilizing single-cell RNA sequencing, the TME was profiled across subtypes A, B, and C, sampling multiple disease sites including the bone marrow, lymph nodes, and peripheral blood. Our findings revealed subtype-specific variations in cellular composition and transcriptional programs within the TME. Unlike other subtypes, subtype C was associated with a pronounced immunosuppressive environment at diagnosis and relapse. Additionally, it exhibited an enhanced response to Epstein-Barr virus infection, consistent with upregulated CD70 expression at relapse. Through the analysis of cellular communication networks, CD70, programmed cell death 1 (PDCD1), and inducible T cell costimulator (ICOS) were identified as promising immunotherapeutic targets in AITL. Finally, we delineated distinct cellular proportions and gene expression signatures characteristic of each subtype, providing a foundation for the development of tailored therapeutic interventions for patients with AITL.
2026-02-19 | Xenium-based spatial transcriptomic analyses uncover prognosis-associated heterogeneity in the tumor microenvironment (TME) of angioimmunoblastic T-cell lymphoma (AITL).
Angioimmunoblastic T-cell lymphoma (AITL) exemplifies a neoplasm characterized by prominent inflammatory infiltration and robust immune responses in the tumor microenvironment (TME). The pathophysiology of refractory/recurrent (RR) AITL remains poorly understood due to profound intratumoral heterogeneity and complex TME features, contributing to limited therapeutic efficacy. Using Xenium-based spatial transcriptomics on 10 clinical samples, we compared RR AITL with treatment-responsive [non-refractory/recurrent event in 3 years (NR)] cases to map the TME architecture. We identified a novel cluster of NEIL3+ (Nei Like DNA Glycosylase 3) T-follicular helper (Tfh) cells, which exhibited stem-like characteristics at the transcriptional level, featuring self-renewal and multilineage differentiation capacity, and were highly enriched in RR tumors. Furthermore, we found major differences in immune cell organization between NR and RR microenvironments: RR cases were dominated by B cells primed for adaptive immunity and myeloid cells driving angiogenesis, whereas NR cases exhibited a chemokine-mediated regulatory landscape. These findings provide comprehensive characterization of the TME ecosystem in AITL and reveal potential therapeutic targets for high-risk RR AITL patients. © 2026 The Pathological Society of Great Britain and Ireland.
2026-01-28 | Phase I Study of Mogamulizumab in Combination with Pembrolizumab in Patients with Relapsed or Refractory Non-Hodgkin Lymphoma-A National Cancer Institute Experimental Therapeutics Clinical Trials Network (NCI-ETCTN) Trial.
Introduction: Immune evasion through inhibition of effector T cells is a key survival mechanism of lymphoma cells. We hypothesized that reinstating effector T cell activity through concurrent inhibition of the PD1/PD-L1 axis and of Treg activity will result in a synergistic anti-tumor effect with an acceptable toxicity profile. Methods: Phase I multi-institutional NCI-ETCTN trial aimed to evaluate the safety and tolerability of the combination of mogamulizumab and pembrolizumab in relapsed or refractory non-Hodgkin lymphoma. The study used a 3 + 3 design. Treatment consisted of mogamulizumab 1 mg/kg on days 1, 8, and 15 of cycle 1, followed by 1.5 mg/kg on day 1 of each subsequent 21-day cycle in combination with pembrolizumab 200 mg on day 1 of each cycle. A de-escalation level was defined as a 50% reduction in the dose of mogamulizumab (registered in clinicaltrials.gov NCT03309878). Results: The study was discontinued early, after treating seven patients (two angioimmunoblastic T cell lymphoma, four transformed follicular lymphoma, and one diffuse large B cell lymphoma of germinal center subtype) for concerns of futility and non-tolerability. Only two patients completed the first two cycles of treatment. Three patients presented with an early progression and three withdrew consent in the setting of general deterioration with clinically suspected progression. All six patients expired shortly after withdrawal from the study. The remaining patient experienced stress cardiomyopathy during the third cycle and was taken off the study. Discussion: In striking difference to the observation in solid malignancies, the combination of mogamulizumab with pembrolizumab was associated with low tolerability and suspected hyper-progression in patients with lymphoma.
2026-01-16 | Normalized NanoString nCounter expression data from AITL patients
his dataset contains normalized NanoString nCounter gene expression datafrom angioimmunoblastic T-cell lymphoma (AITL) samples.Raw RCC files are not available.No directly identifiable personal information is included.
2026-01-15 | Unraveling the many faces of angioimmunoblastic T-cell lymphoma: clinical, pathological, and molecular heterogeneity.
Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of peripheral T-cell lymphoma originating from follicular helper T cells and characterized by profound clinical, pathological, and molecular heterogeneity. Despite advances in classification and diagnosis, therapeutic outcomes remain suboptimal, particularly in relapsed or refractory settings. In recent years, the evolution of risk stratification models and a deeper understanding of AITL’s molecular pathogenesis, including its unique pattern of clonal evolution, have paved the way for precision medicine. Notably, targeted treatment approaches, such as immunomodulatory agents, epigenetic therapies, kinase inhibitors, and immune checkpoint blockade, are demonstrating promising clinical efficacy, especially in patients harboring specific molecular aberrations. This review comprehensively summarizes the multilayered heterogeneity of AITL, emphasizes the role of immune and molecular profiling in informing therapeutic decisions, and outlines future directions for personalized, multi-agent treatment strategies aimed at overcoming resistance and improving survival.
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2025-01-29 | Angioimmunoblastic T-cell lymphoma: Characterization of clonal T and B cells and a patient-derived xenograft study of coexisting T- and B-cell proliferation.
Angioimmunoblastic T-cell lymphoma (AITL) is a rare and aggressive lymphoma with a poor prognosis. AITL is associated with Epstein-Barr virus (EBV)-positive B cells in most cases, suggesting a possible role for the virus in the pathobiology of AITL. Cell lines from AITL patients do not exist and models of human AITL are needed. We aim to establish such a model and use it for preclinical therapeutic evaluation. Primary lymph node tissue from an AITL patient was used for tumor cell isolation and injection to NSG mice. The established patient-derived xenograft (PDX) model was characterized by immunophenotyping, whole-exome sequencing (WES), and T/B-cell receptor gene rearrangement studies. In vivo AITL PDX trials were performed with elotuzumab, romidepsin, and rituximab. An AITL PDX mouse model that includes a coexisting EBV+ B-cell proliferation was established. We confirmed clonal identity of the engrafted T cells with the primary T-lymphoma cells. WES on DNA from xenografted sorted T and B cells identified eight and three mutations previously reported in the COSMIC database, respectively. Primary tumor cells could be passaged serially in NSG mice with an increasing percentage of monoclonal B cells that mimic the human condition in which the clonal B-cell component in some cases may mask an underling T-cell lymphoma. In this PDX mouse study, single agent elotuzumab or rituximab significantly improved mice survival. Survival was further improved when elotuzumab or romidepsin was combined with rituximab. To our knowledge, this is the first molecular characterization of AITL model coexisting with associated EBV+ B cells, and use of such a PDX model for therapeutic evaluation of agents targeting both malignant T cells and B cells simultaneously.
2023-03-31 | Data from Genome-Wide miRNA Expression Profiling of Molecular Subgroups of Peripheral T-cell Lymphoma
<div>AbstractPurpose:<p>Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non–Hodgkin lymphomas with aggressive clinical behavior. We performed comprehensive miRNA profiling in PTCLs and corresponding normal CD4<sup>+</sup> Th1/2 and TFH-like polarized subsets to elucidate the role of miRNAs in T-cell lymphomagenesis.</p>Experimental Design:<p>We used nCounter (NanoString Inc) for miRNA profiling and validated using Taqman qRT-PCR (Applied Biosystems, Inc). Normal CD4<sup>+</sup> T cells were polarized into effector Th subsets using signature cytokines, and miRNA significance was revealed using functional experiments.</p>Results:<p>Effector Th subsets showed distinct miRNA expression with corresponding transcription factor expression (e.g., BCL6/miR-19b, -106, -30d, -26b, in IL21-polarized; GATA3/miR-155, miR-337 in Th2-polarized; and TBX21/miR-181a, -331-3p in Th1-polarized cells). Integration of miRNA signatures suggested activation of TCR and PI3K signaling in IL21-polarized cells, ERK signaling in Th1-polarized cells, and AKT–mTOR signaling in Th2-polarized cells, validated at protein level. In neoplastic counterparts, distinctive miRNAs were identified and confirmed in an independent cohort. Integrative miRNA–mRNA analysis identified a decrease in target transcript abundance leading to deregulation of sphingolipid and Wnt signaling and epigenetic dysregulation in angioimmunoblastic T-cell lymphoma (AITL), while ERK, MAPK, and cell cycle were identified in PTCL subsets, and decreased target transcript abundance was validated in an independent cohort. Elevated expression of miRNAs (miR-126-3p, miR-145-5p) in AITL was associated with poor clinical outcome. <i>In silico</i> and experimental validation suggest two targets (miR-126→ SIPR2 and miR-145 → ROCK1) resulting in reduced RhoA-GTPase activity and T–B-cell interaction.</p>Conclusions:<p>Unique miRNAs and deregulated oncogenic pathways are associated with PTCL subtypes. Upregulated miRNA-126-3p and miR-145-5p expression regulate RhoA-GTPase and inhibit T-cell migration, crucial for AITL pathobiology.</p></div>
2023-02-17 | Cardiac Tamponade as a Recurrence of Angioimmunoblastic T-Cell Lymphoma with the Detection of a p.Gly17Val RHOA Mutation in the Pericardial Effusion.
Angioimmunoblastic T-cell lymphoma (AITL) is an intractable type of T-cell lymphoma. We and others have identified that the p.Gly17Val RHOA mutation is specifically identified in AITL. We herein report a patient whose condition deteriorated, resulting from massive pericardial effusion one month after undergoing autologous transplantation for AITL. He was diagnosed with cardiac tamponade caused by AITL recurrence in the presence of the p.Gly17Val RHOA mutation as well as T-lineage cells with an aberrant immune-phenotype in the pericardial effusion. This case suggests that a precision medicine approach by detecting the presence of a p.Gly17Val RHOA mutation is useful for the management of AITL.
2022-03-31 | Genome-Wide miRNA Expression Profiling of Molecular Subgroups of Peripheral T-cell Lymphoma.
Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas with aggressive clinical behavior. We performed comprehensive miRNA profiling in PTCLs and corresponding normal CD4+ Th1/2 and TFH-like polarized subsets to elucidate the role of miRNAs in T-cell lymphomagenesis. We used nCounter (NanoString Inc) for miRNA profiling and validated using Taqman qRT-PCR (Applied Biosystems, Inc). Normal CD4+ T cells were polarized into effector Th subsets using signature cytokines, and miRNA significance was revealed using functional experiments. Effector Th subsets showed distinct miRNA expression with corresponding transcription factor expression (e.g., BCL6/miR-19b, -106, -30d, -26b, in IL21-polarized; GATA3/miR-155, miR-337 in Th2-polarized; and TBX21/miR-181a, -331-3p in Th1-polarized cells). Integration of miRNA signatures suggested activation of TCR and PI3K signaling in IL21-polarized cells, ERK signaling in Th1-polarized cells, and AKT-mTOR signaling in Th2-polarized cells, validated at protein level. In neoplastic counterparts, distinctive miRNAs were identified and confirmed in an independent cohort. Integrative miRNA-mRNA analysis identified a decrease in target transcript abundance leading to deregulation of sphingolipid and Wnt signaling and epigenetic dysregulation in angioimmunoblastic T-cell lymphoma (AITL), while ERK, MAPK, and cell cycle were identified in PTCL subsets, and decreased target transcript abundance was validated in an independent cohort. Elevated expression of miRNAs (miR-126-3p, miR-145-5p) in AITL was associated with poor clinical outcome. In silico and experimental validation suggest two targets (miR-126→ SIPR2 and miR-145 → ROCK1) resulting in reduced RhoA-GTPase activity and T-B-cell interaction. Unique miRNAs and deregulated oncogenic pathways are associated with PTCL subtypes. Upregulated miRNA-126-3p and miR-145-5p expression regulate RhoA-GTPase and inhibit T-cell migration, crucial for AITL pathobiology.
2022-01-31 | Mice transgenic for human CTLA4-CD28 fusion gene show proliferation and transformation of ATLL-like and AITL-like T cells.
CTLA4-CD28 gene fusion has been reported to occur in diverse types of T cell lymphoma. The fusion event is expected to convert inhibitory signals to activating signals and promote proliferation and potentially transformation of T cells. To test the function of the CTLA4-CD28 fusion gene in vivo, we generated a murine model that expresses the gene in a T cell-specific manner. The transgenic mice have shorter life spans and display inflammatory responses including lymphadenopathy and splenomegaly. T cells in turn show higher levels of activation and infiltrate various organs including the lung and skin. T cells, in particular CD4+ helper T cells, were also readily transplantable to immunocompromised mice. Transcriptomic profiling revealed that the gene expression pattern in CD4 + T cells closely resembles that of adult T cell leukemia/lymphoma (ATLL) and that of angioimmunoblastic T cell lymphoma (AITL) tissues. Consistently, we detected supernumerary FOXP3+ cells and PD-1+ cells in transgenic and transplanted mice. This is the first report demonstrating the transforming activity of the CTLA4-CD28 fusion gene in vivo, and this murine model should be useful in dissecting the molecular events downstream to this mutation.
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Drug Discovery Landscape
5 orphan drug designations for Angioimmunoblastic T-cell lymphoma.
5 orphan drug designations for Angioimmunoblastic T-cell lymphoma.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
allogeneic chimeric antigen receptor (CAR) T-cell therapy targeting CD70 | cell therapies | FDA | Nanjing Miracle Biotechnology Co., Ltd. | |
imiquimod-ferulic acid | small molecules | FDA | — | Celista Pharmaceuticals LLC |
4-[[(1S)-1-(4, 8-dichloro-1-oxo-2-phenyl-3-isoquinolyl) ethyl] amino]-8H-pyrido[2,3-d] pyrimidin-5-one] | small molecules | FDA | — | Boryung Co., Ltd. |
nanatinostat and valganciclovir | small molecules | FDA | Viracta Therapeutics, Inc. | |
brentuximab vedotin | antibodies | FDA | Seattle Genetics, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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