RARE DISEASE
Primary cutaneous lymphoma
Primary cutaneous lymphoma
Primary cutaneous lymphoma
Drug discovery
1
drug
With orphan designation
Overview
Primary cutaneous lymphoma (PCL) encompasses rare, heterogeneous non-Hodgkin lymphomas arising in the skin without extracutaneous involvement at diagnosis. Major subtypes include cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary syndrome) and cutaneous B-cell lymphoma (CBCL) (e.g., primary cutaneous follicle center, marginal zone, and diffuse large B-cell lymphoma, leg type). Prognosis varies widely, with indolent forms demonstrating high survival rates (e.g., 10-year survival >90% for some CBCL subtypes) and aggressive subtypes (e.g., diffuse large B-cell lymphoma, leg type) showing 5-year survival rates of ~50% [1][4][7][11].
Population
Incidence: CTCL accounts for 71% of cases (7.7/million person-years), CBCL 29% (3.1/million) [2][14].
Demographics: Higher incidence in males (male-female ratio 1.7:1) [2], non-Hispanic Blacks (CTCL: 10.0/million) and non-Hispanic whites (CBCL: 3.5/million) [2][5][14]. Median age at diagnosis: 50–70 years [5][9].
Burden
Mortality: 5-year survival exceeds 95% for indolent subtypes but drops to 50–60% for aggressive forms [1][4][11]. Sézary syndrome carries a median survival of ≤4 years [9].
Relapse: Common in CBCL (56% relapse post-R-CHOP) [7] and CTCL, necessitating lifelong monitoring [4][11].
Quality of life: Chronic pruritus, disfigurement, and treatment-related complications (e.g., skin infections, therapy resistance) contribute to morbidity [1][5][12].
Therapies
Skin-directed therapies: First-line for localized disease—topical corticosteroids, phototherapy (UVB/PUVA), radiation (total skin electron beam for extensive CTCL) [3][7][11].
Systemic therapies: Retinoids, monoclonal antibodies (e.g., rituximab for CBCL), interferon-α, and combination regimens (e.g., R-CHOP for aggressive CBCL) [4][7][11].
Novel agents: Emerging use of checkpoint inhibitors, Bruton tyrosine kinase inhibitors, and CAR T-cell therapy for refractory cases [7][8].
Categories: rare hematological diseases, rare neoplastic diseases, rare skin diseases, rare transplant-related disorders
Research Papers
1,014 drug discovery papers about Primary cutaneous lymphoma, with 3 first-in-class and 11 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,014 drug discovery papers about Primary cutaneous lymphoma, with 3 first-in-class and 11 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
antibodies
2026-09-15 | Immune Dysregulation, Compartment-Specific Biology, and Therapeutic Biomarkers in Mycosis Fungoides and Sézary Syndrome.
Cutaneous T-cell lymphoma (CTCL), including mycosis fungoides (MF) and Sézary syndrome (SS), is defined by malignant CD4+ T-cell clones that evolve within and remodel the skin and systemic immune compartments. For disease biology and immune remodeling, we prioritize evidence from human primary samples; for therapeutic implications, we integrate clinical-trial and translational biomarker studies. We organize evidence by compartment (skin vs. blood) and, within skin, by stage (patch/plaque vs. tumor). Early patch/plaque MF often shows features consistent with constrained inflammation: skin-resident memory T-cell (TRM)-like malignant clones are in a Th1-leaning microenvironment with relatively preserved cytotoxic surveillance. Progression to tumor-stage MF (and/or large-cell transformation) is frequently associated with clonal dominance, Th2 cytokine polarization, upregulation of checkpoint pathways, and remodeling of myeloid/fibroblast populations. SS is typically associated with leukemic clonal dominance, systemic Th2 skewing, and broad impairment of cytotoxic immune control. These trajectories support an interpretive framework that aligns immune-directed therapies with compartment- and stage-associated biology; these include strategies that (i) deplete malignant clones (e.g., CCR4, CD30, KIR3DL2 targeting), (ii) re-engage exhausted effectors (PD-1/PD-L1 axis), (iii) reprogram cytokine balance (IFN-γ, IL-12, extracorporeal photopheresis), or (iv) suppress malignant signaling programs with secondary immune effects (JAK/STAT inhibition). We highlight potential candidate predictive biomarkers at varying levels of maturity, most of which require prospective validation, including antigen density, compartmental tumor burden, tumor cell fraction, effector-cell substrate, and interferon/cytokine signatures.
2026-09-09 | Recurrent Primary Cutaneous Anaplastic Large Cell Lymphoma With T-Cell Receptor-ϒδ Phenotype and DUSP22-IRF4 Unbalanced Rearrangement: A Rare and Diagnostically Challenging Presentation.
Primary cutaneous anaplastic large cell lymphoma (pcALCL) is an indolent CD30+ T-cell lymphoma, typically of T-cell receptor (TCR)-αβ origin with an excellent prognosis. Rare cases may exhibit a TCR-ϒδ phenotype or rearrangement of the DUSP22 and IRF4 genes on chromosome 6p25.3, but the concurrence of both features is exceedingly rare. We present herein a case of a 78-year-old man with a history of pcALCL who, 5 years after achieving complete remission with radiation therapy, experienced a recurrent neck nodule. Histopathological examination revealed a dense dermal infiltrate of medium to large atypical lymphoid cells. The lesion was strongly positive for CD30, TCR-δ, and LEF1 but negative for CD4, CD8, CD7, TCR-β, and ALK, and TIA-1. p-STAT3 was predominantly negative with labeling of few scattered cells. Fluorescence in situ hybridization studies confirmed a DUSP22-IRF4 abnormality. In view of immunohistochemical findings (LEF1+, TIA-1-, predominantly p-STAT3-), an unbalanced DUSP22-IRF4 rearrangement was favored. A diagnosis of pcALCL with TCR-ϒδ phenotype and DUSP22-IRF4 unbalanced rearrangement was rendered. This case adds to the small but growing number of reported cases of pcALCL with TCR-ϒδ phenotype and DUSP22-IRF4 alteration.
2026-08-11 | Coexistence of Mycosis Fungoides and Hodgkin Lymphoma in a Pediatric Patient: A Report of a Rare Case.
Mycosis fungoides (MF) is the most common primary cutaneous T‑cell lymphoma, usually affecting adults aged 50-60 years; pediatric presentation is rare. We report a 12‑year‑old patient whose course spanned five years; skin lesions began at age 8, were misdiagnosed and treated as inflammatory dermatosis with topical steroids for four years. At age 12, B‑symptoms, lymphadenopathy and organomegaly led to the diagnosis of MF Stage IA (T1bNxM0B0) and synchronous Hodgkin lymphoma (HL) Stage IVB, with an Epstein-Barr virus (EBV) viral load of 2.5 log₁₀ copies/mL. Treatment with three cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) + pembrolizumab due to drug availability, followed by six cycles of PC‑AVBE (prednisone, cyclophosphamide, doxorubicin, vincristine, bleomycin, and etoposide) and radiotherapy, achieving complete remission. This case highlights diagnostic challenges, immune dysregulation, and adapted treatment in resource‑limited settings.
2026-07-23 | Final results of UK NCRI phase II trial of pembrolizumab and radiotherapy in cutaneous T cell lymphoma.
The outlook for patients with advanced cutaneous T-cell lymphomas (CTCL); mycosis fungoides (MF) and Sézary syndrome (SS) remains poor and most systemic treatments provide short-lived remissions. Immunotherapy has provided a major cancer breakthrough, and the PORT trial was designed to investigate the efficacy of Pembrolizumab and whether the addition of Radiotherapy (RT) could further enhance systemic "abscopal" anti-tumour immune responses. Pembrolizumab followed by 12Gy in 3 fractions RT to a localized lesion was investigated in a single-arm, multicentre phase II trial for relapsed/refractory CTCL. Primary endpoint was overall response rate (ORR), secondary endpoints included duration of response (DOR), abscopal response, progression-free survival (PFS), overall survival (OS). 46 patients (41 MF, 5 SS) were registered, median age 63 (24-83), 24% stage IV. Median follow-up was 24.8 months. 24% of patients remained on treatment for >1 year whilst 57% received.
2026-06-11 | Case Report: Cutaneous niche-restricted malignant phenotypes in PTCL-NOS revealed by single-cell sequencing.
Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) presenting with disseminated cutaneous involvement represents an aggressive disease subset with poor response to conventional chemotherapy and dismal prognosis. The tissue-specific molecular mechanisms driving cutaneous aggression remain poorly characterized at single-cell resolution. Here we report a 67-year-old male PTCL-NOS patient with hypertension and coronary artery disease history, presenting with generalized cutaneous nodules and rapid progression despite multi-line chemotherapy. Single-cell RNA sequencing (scRNA-seq) performed on paired skin lesions and peripheral blood at diagnosis revealed striking microenvironmental dichotomy: skin-resident malignant T cells exhibited hyperproliferative phenotypes (high CDC20B, HIST1H3B, MKI67+), activation of NF-κB and IL-17 signaling, and extensive crosstalk with endothelial cells; conversely, blood-derived lymphoma cells displayed immune evasion signatures and metabolic stress markers. Copy number variation analysis confirmed clonal expansion across both compartments with distinct tissue-specific transcriptional programs. Despite CHOP, CHOEP, DA-EPOCH, and AC-CHOP (azacitidine plus chidamide) regimens, the patient experienced primary refractory disease and died 6 months from diagnosis following COVID-19 superinfection. To our knowledge, this is the first case reporting single-cell transcriptomic comparison of skin versus blood compartments in PTCL-NOS, revealing how cutaneous microenvironment sculpts aggressive malignant phenotypes and providing potential targets for compartment-specific therapy.
small molecules
2026-09-15 | WEE1 Inhibition as a Novel Therapeutic Strategy in Cutaneous T-Cell Lymphoma.
Background/Objectives: Cutaneous T-cell lymphomas (CTCL), most commonly mycosis fungoides and Sézary syndrome, are rare non-Hodgkin lymphomas. Advanced disease responds poorly to current treatments, highlighting the need for new molecularly targeted therapies. WEE1 is a central regulator of the G2/M checkpoint and S-phase progression and has emerged as a therapeutic target in several malignancies, yet it has not been systematically explored in CTCL. Methods: We screened a library of more than 2200 kinase inhibitors in CTCL cell lines and selected adavosertib for further study. Its effects were tested in four CTCL lines; primary keratinocytes and fibroblasts; patient-derived malignant CD4+ T cells and healthy donor CD4+ T cells; and a MyLa xenograft model, using viability, apoptosis, cell-cycle, Western blot, and phospho-protein array assays. Results: Adavosertib reduced viability at submicromolar IC50 values (0.26-0.56 µM) across all four CTCL lines while largely sparing primary skin cells and was more active in malignant than in healthy donor CD4+ T cells. It induced apoptosis and cell-line-specific S-phase and/or G2/M accumulation, lowered WEE1 and phospho-CDK1 (Tyr15), and increased phospho-H2A.X. A phospho-protein array showed activation of checkpoint and stress signalling. In a preliminary xenograft experiment, adavosertib slowed MyLa tumour growth. Conclusions: These preclinical data identify WEE1 as a therapeutic target in CTCL and support further preclinical and early-phase clinical evaluation of adavosertib in this disease.
2026-08-21 | Multifocal Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type, Presenting on Face and Chest: Complete Remission With R-CHOP.
Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT), is an aggressive subtype of primary cutaneous B-cell lymphoma that predominantly affects the lower extremities of elderly individuals. We report a rare case of a 79-year-old woman presenting with rapidly enlarging, erythematous-to-violaceous tumors and plaques on the face, chest, left upper arm, and upper back, an uncommon non-leg manifestation of PCDLBCL-LT, confirmed by histopathology and immunohistochemistry. The patient was successfully treated with six cycles of the rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy, achieving complete remission with no relapse during 1.5 years of follow-up. This case emphasizes that PCDLBCL-LT can present in locations outside the legs, highlighting the need for early recognition and systemic therapy in atypical locations.
2026-08-04 | Primary Cutaneous Gamma-Delta T-Cell Lymphoma Complicating Long-Standing Immunosuppressed Dermatomyositis.
Primary cutaneous gamma-delta T-cell lymphoma (PCGD-TCL) is a rare cytotoxic lymphoma with key oncogenic drivers in the JAK/STAT pathway. Also primarily involving the subcutaneous adipose tissue, subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is more frequently encountered in scenarios of autoimmune disorders. SPTCL shares clinicopathologic overlap with lupus panniculitis. However, the link between autoimmunity and PCGD-TCL is much less established, particularly in the setting of long-standing, immunosuppressed dermatomyositis (DM). We report two cases of PCGD-TCL arising in women with chronic anti-TIF1-γ DM following years of immunosuppressive therapy. Case 1 is a 47-year-old woman with a 19-year history of DM on azathioprine/prednisone who developed rapidly progressive, painful subcutaneous nodules. Incisional biopsy confirmed a TCR-delta+, CD8+ cytotoxic T-cell lymphoproliferative disorder (TCLPD) compatible with PCGD-TCL. She achieved complete remission following pralatrexate and subsequent allogeneic hematopoietic stem cell transplant. Case 2 is a 27-year-old woman with DM on mycophenolate/rituximab who developed subcutaneous nodules with an indolent course and some spontaneous regression. A biopsy revealed a similar panniculitic infiltrate with an atypical TCR-delta+, CD8+ phenotype. Notably, both cases were negative for high-risk JAK/STAT pathway mutations. These cases identify PCGD-TCLPD/TCL as a potential complication of chronic, immunosuppressed DM. The shared, atypical CD8+ immunophenotype and absence of canonical driver mutations suggest a distinct pathogenic mechanism possibly linked to long-term immune modulation. Unlike classic PCGD-TCL, which is characterized by an aggressive course and < 2-year median survival, the clinical courses in these two cases were variable, with one requiring transplant and the other showing indolent behavior and responsiveness to therapy.
2026-08-02 | Comparison of narrowband ultraviolet B with psoralen plus ultraviolet A phototherapy for patients with early-stage mycosis fungoides: a systematic review and meta-analysis.
The most prevalent cutaneous T-cell lymphoma is mycosis fungoides (MF), managed in early stages with psoralen plus ultraviolet A (PUVA) or narrowband ultraviolet B (NB-UVB) phototherapy. To evaluate the therapeutic effectiveness and side effect profiles of PUVA vs. NB-UVB in patients with early-stage MF. A systematic review was conducted, incorporating data from nine studies sourced from PubMed, Cochrane and Google Scholar. Eligible studies were those that simultaneously evaluated PUVA and NB-UVB, enrolling at least 10 adult participants per group with histologically confirmed early-stage (IA-IIA) MF and reported treatment outcomes. Exclusions were advanced disease, paediatric patients, noncomparative or nonrelevant treatments, small sample sizes or lack of outcome data. No language restrictions were applied. Key outcomes included any response, complete response, partial response, treatment failure, relapse-free interval and adverse effects. A total of 923 patients (age range 33-71 years; 52.5% men) were included: 556 treated with PUVA and 367 with NB-UVB. Any response was seen in 90.5% of those treated with PUVA vs. 88.3% of patients who received NB-UVB [odds ratio (OR) 1.18, 95% confidence interval (CI) 0.73-1.90; P = 0.50]. Complete response rates were 72% for those treated with PUVA and 61.8% for those treated with NB-UVB (OR 1.12, 95% CI 0.60-2.07; P = 0.73). Partial response was observed in 19.2% of patients who received PUVA and 28.0% of those who received NB-UVB (OR 0.87, 95% CI 0.45-1.69; P = 0.69). Treatment failure rates were lower with PUVA (9.7%) than with NB-UVB (12.6%) (OR 0.81, 95% CI 0.49-1.33; P = 0.41). Patients who received PUVA had a significantly longer median relapse-free interval (hazard ratio 1.94, 95% CI 1.07-3.51; P < 0.01). Adverse effects, including erythema, nausea, pruritus, burning, hyperpigmentation, pain, phototoxic reactions and polymorphic light eruption, showed no significant differences between groups. Both PUVA and NB-UVB are effective, but PUVA may be preferred when sustained remission is the primary therapeutic goal.
2026-07-28 | Cutaneous Malignancies Metastatic to the Female Genital Tract and Pelvic Lymph Nodes: Analysis of Metastatic Patterns and Pathogenesis.
Background/Objectives: Metastases from cutaneous malignancies to the female genital tract and pelvic lymph nodes are rare clinical entities that frequently masquerade as primary gynecologic tumors, leading to significant diagnostic challenges. The distinction between primary and metastatic disease is critical, yet complex, given the varying patterns of spread exhibited by different skin cancers. This study aims to provide a tumor-specific overview of these metastatic patterns to guide diagnosis and therapy. Methods: We conducted a narrative review informed by a systematic literature search of MEDLINE/PubMed, Embase, Scopus, and Web of Science for records regarding primary cutaneous melanoma, cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma (BCC), Merkel cell carcinoma (MCC), and cutaneous lymphomas metastasizing to the female genital tract (FGT) or pelvic lymph nodes. Data were synthesized qualitatively to identify organotropic patterns, diagnostic pitfalls, and management outcomes across these distinct malignancies. Results: The analysis reveals distinct metastatic niches: cutaneous melanoma shows a predilection for the ovary, often mimicking epithelial ovarian carcinoma, whereas cSCC and MCC typically involve pelvic lymph nodes via contiguous spread from inguinal basins. Histologic evaluation with broad immunohistochemical panels is mandatory to confirm the diagnosis, as imaging alone lacks specificity. Crucially, the introduction of immune checkpoint inhibitors and targeted therapies has significantly improved survival in advanced melanoma, cSCC, and MCC, altering the role of pelvic surgery. Conclusions: Management of cutaneous malignancies metastatic to the pelvis is shifting from a focus on radical surgery to a systemic-first approach. Pelvic metastasectomy should be reserved for selected oligometastatic cases or symptom control within a multidisciplinary framework. Clinicians must maintain a high index of suspicion in patients with a history of skin cancer to avoid overtreatment and optimize quality of life.
proteins
2026-01-21 | Localized palmar mycosis fungoides: A case report.
Mycosis fungoides (MF) is the most common primary cutaneous T-cell lymphoma, yet palmar MF is extremely rare and easily mistaken for chronic dermatoses such as psoriasis. Delayed recognition can lead to inappropriate treatment and worse outcomes. This case demonstrates how careful histopathology and immunohistochemistry can provide critical diagnostic clarity in atypical presentations. A 63-year-old woman presented with an 8-year history of erythema, dryness, scaling, and fissuring on both palms. The lesions had been misdiagnosed as psoriasis and showed no response to long-term topical calcipotriol. Histopathology of a palm biopsy revealed epidermotropism of atypical lymphocytes with cerebriform nuclei and Pautrier microabscesses. Immunohistochemistry demonstrated positivity for CD2, CD3, CD4, and CD45RO with immunophenotypic variation, confirming palmar MF. The patient was staged as early MF (IA-IB). Systemic therapy with intramuscular interferon α-2b, oral methylprednisolone, and acitretin was initiated due to chronicity, bilateral palm involvement, and resistance to topical therapy. Significant improvement was noted after 2 months. At the 1-year follow-up, her palms showed complete clearance of lesions with sustained remission. This case highlights the diagnostic pitfalls of palmar MF and underscores the necessity of early biopsy in patients with persistent, treatment-resistant palm dermatoses. Raising clinical awareness of this rare entity may prevent misdiagnosis, facilitate timely therapy, and ultimately improve patient prognosis.
2024-12-19 | Efficacy and Safety of Denileukin Diftitox-Cxdl, an Improved Purity Formulation of Denileukin Diftitox, in Patients With Relapsed or Refractory Cutaneous T-Cell Lymphoma.
Denileukin diftitox (DD)-cxdl is a fusion protein comprising diphtheria toxin fragments A and B and human interleukin-2. This phase III, multicenter, open-label, single-arm registrational trial evaluated the efficacy and safety of DD-cxdl in patients with relapsed/refractory (R/R) cutaneous T-cell lymphoma (CTCL). In the main study, which followed a dose-finding lead-in, DD-cxdl was administered intravenously daily (5 days; 9 µg/kg/d once daily) every 21 days for up to eight cycles. Patients in the primary efficacy analysis set (PEAS) were required to have stage IA-IIIB CTCL (mycosis fungoides and/or Sézary syndrome) and at least ≥one previous systemic therapy. The primary efficacy end point was objective response rate (ORR) using the Global Response Score. Secondary end points were duration of response (DOR), time to response (TTR), skin tumor burden, and safety and tolerability. The PEAS included 69 patients (median age, 64.0 years). The ORR was 36.2% (95% CI, 25.0 to 48.7), including 8.7% with complete response. The median DOR was 8.9 months (95% CI, 5.0 to not estimable), and the median (Q1-Q3) TTR was 1.4 (0.7-2.1) months. A total of 84.4% of patients showed decreased skin tumor burden, with 48.4% showing a ≥50% decrease. Treatment-emergent adverse events (TEAEs) of special interest, most of which were grade 1 or 2, included infusion reaction (73.9%), hypersensitivity (68.1%), hepatotoxicity (36.2%), and capillary leak syndrome (20.3% [grade ≥3, 5.8%]). Other common TEAEs were nausea (43.5%) and fatigue (31.9%). Efficacy and safety results show that DD-cxdl would potentially fulfill a serious, unmet medical need for patients with R/R CTCL.
2024-04-10 | Real-world study of pegylated interferon α-2a to treat mycosis fungoides/Sézary syndrome using time to next treatment as a measure of clinical benefit: an EORTC CLTG study.
Mycosis fungoides (MF) and Sézary syndrome (SS) are chronic malignant diseases that typically necessitate diverse strategies to achieve remission. Systemic interferon (IFN)-α (subtypes 2a and 2b) has been used to treat MF/SS since 1984; however, its production was recently stopped. The recombinant pegylated (PEG) form of IFN-α-2a remains the only alternative IFN treatment, although it has not been approved for use in MF/SS. To assess the effectiveness and safety of PEG-IFN-α-2a in monotherapy and in combination with other treatments using time to next treatment (TTNT) as a measure of clinical therapeutic benefit in a real-world setting. We conducted an international, multicentre retrospective study of patients with MF and SS (of any stage) treated with PEG-IFN-α-2a from July 2012 to February 2022. Patients were included across 11 centres in 10 countries. The primary endpoints were to determine the TTNT of PEG-IFN-α-2a and adverse events (AEs) in MF/SS. In total, 105 patients were included [mean (SD) age 61 (13.1) years]; 42 (40.0%) had stage IA-IIA and 63 (60.0%) had stage IIB-IVB disease. PEG-IFN-α-2a was combined with other therapies in 67 (63.8%) patients, most commonly with extracorporeal photopheresis (36%) and bexarotene (22%). Patients with stage I-IIA disease achieved an overall response rate (ORR) of 57%; the ORR in those with stage IIB-IVB disease was 51%. Combination treatment resulted in a median TTNT of 10.4 months (range 0.6-50.7) vs. 7.0 months (range 0.7-52.4) for those who received monotherapy (P < 0.01). Overall, the mean (SD) TTNT was 9.2 (10.6) months and the ORR was 53.3% (n = 56). A complete response was seen in 13% of patients and a partial response in 40%. AEs were described in 68.6% (n = 72) of patients. Flu-like symptoms (n = 28; 26.7%), lymphopenia (n = 24; 22.9%) and elevated liver function (n = 10; 9.5%) were the most frequently reported. Grade 3-4 AEs were reported in 23 (21.9%) patients, mostly related to myelosuppression. PEG-IFN-α-2a for MF/SS resulted in an ORR of 53.3% and a mean (SD) TTNT of 9.2 (10.6) months. Combination regimens were superior to monotherapy and doses of 180 µg PEG-IFN-α-2a weekly were related to a higher ORR.
2023-09-12 | Skin infiltrating NK cells in cutaneous T-cell lymphoma are increased in number and display phenotypic alterations partially driven by the tumor.
Cutaneous T-cell lymphomas (CTCL) are characterized by focal infiltration of malignant T cell clones in solitary skin lesions. Many CTCL patients experience an indolent disease, but some progress to advanced disease with high fatality. We hypothesized that natural killer (NK) cells participate in local control of tumor growth in CTCL skin. Immunohistochemistry and flow cytometry analysis of the density, localization, phenotype and function of NK cells in twenty-nine fresh or formalin-fixed skin biopsies from twenty-four CTCL patients and twenty-three biopsies from twenty healthy controls highlighted higher numbers of CD56+CD3- NK cells in CTCL skin. A reduced fraction of CTCL skin NK cells expressed the maturation marker CD57, the cytotoxic protein granzyme B and the activation marker CD69, indicating reduced tumor-killing abilities of the NK cells. Retained expression of immune checkpoint proteins or inhibitory proteins including PD1, TIM3, LAG3, CD73 and NKG2A and the activating receptors CD16 and NKp46 indicated maintained effector functions. Indeed, the capacity of NK cells to produce anti-tumor acting IFNγ upon PMA+ionomycin stimulation was similar in cells from CTCL and healthy skin. Co-cultures of primary human NK cells or the NK cell line NKL with CTCL cells resulted in reduced levels of granzyme B and CD69, indicating that close cellular interactions with CTCL cells induced the impaired functional NK cell phenotype. In conclusion, increased numbers of NK cells in CTCL skin exhibit a partially impaired phenotype in terms of activity. Enhancing NK cell activity with NK cell activating cytokines such as IL-15 or immune checkpoint blockade therefore represents a potential immunotherapeutic approach in CTCL.
2021-11-28 | Clinical Response to Anti-CD47 Immunotherapy Is Associated with Rapid Reduction of Exhausted Bystander CD4+ BTLA+ T Cells in Tumor Microenvironment of Mycosis Fungoides
Cancer progression in mycosis fungoides, the most common form of cutaneous T-cell lymphoma, occurs in a predictable, sequential pattern that starts from patches and that evolves to plaques and later to tumors. Therefore, unlocking the relationship between the microarchitecture of mycosis fungoides and the clinical counterparts of that microstructure represents important steps for the design of targeted therapies. Using multispectral fluorescent imaging, we show that the progression of mycosis fungoides from plaque to tumor parallels the cutaneous expansion of the malignant CD4+ T cells that express TOX. The density of exhausted BTLA+ CD4+ T cells around malignant CD4+TOX+ cells was higher in tumors than it was in plaques, suggesting that undesired safeguards are in place within the tumor microenvironment that prevent immune activation and subsequent cancer eradication. Overriding the CD47 checkpoint with an intralesional SIRPαFc fusion decoy receptor induced the resolution of mycosis fungoides in patients that paralleled an amplified expansion of NK and CD8+ T cells in addition to a reduction of the exhausted BTLA+ CD4+ T cells that were engaged in promiscuous intercellular interactions. These therapeutic benefits of the CD47 blockade were further unleashed by adjuvant interferon-α, which stimulates cytotoxic cells, underscoring the importance of an inflamed microenvironment in facilitating the response to immunotherapy. Collectively, these findings support CD47 as a therapeutic target in treating mycosis fungoides and demonstrate a synergistic role of interferon-α in exploiting these clinical benefits.
cell therapies
2026-09-29 | Graft-Versus-Tumour Effect Following Allogeneic Haematopoietic Stem Cell Transplantation in a Paediatric Patient With Mogamulizumab-Treated Primary Cutaneous Peripheral T-Cell Lymphoma.
Primary cutaneous peripheral T-cell lymphoma, not otherwise specified (pcPTCL-NOS), is exceptionally rare in children, and evidence guiding diagnosis and treatment is limited. A 10-year-old boy with pcPTCL-NOS refractory to chemotherapy received mogamulizumab prior to allogeneic haematopoietic stem cell transplantation (allo-HSCT). Despite a 60-day washout period, he developed prolonged steroid-refractory acute graft-versus-host disease requiring ruxolitinib and extracorporeal photopheresis. Concurrently, transient skin lesions developed at previous lymphoma sites and regressed spontaneously, with biopsy supporting the interpretation of visible graft-versus-lymphoma. This case underscores the need to optimise allo-HSCT timing after mogamulizumab and preserve graft-versus-lymphoma effect while limiting graft-versus-host disease. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.
2026-05-27 | Beyond Hematology-Current Insights into Chimeric Antigen Receptor (CAR) T-Cell Therapy for Skin and Connective Tissue Disorders.
Chimeric antigen receptor (CAR) T-cell therapy represents a major advance in modern immunotherapy. This narrative review summarizes evidence from the past five years, including case reports, case series, and clinical trials, on its application beyond hematologic malignancies, focusing on autoimmune diseases such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc), as well as solid tumors including melanoma and primary cutaneous lymphomas. CD19-directed CAR T-cells have demonstrated clinical benefits in SLE and SSc, with sustained immune reset, reduced autoreactive antibody levels, and clinical improvement. In melanoma, CAR T-cells targeting GD2, cMET, and CD20 have shown in vivo expansion and tumor infiltration; however, clinical efficacy remains limited, with transient stabilization or disease progression in most patients. In primary cutaneous lymphomas, early-phase studies with anti-CD70 and anti-CCR4.30 CAR T-cells indicate partial tumor regression and disease stabilization, often requiring additional therapy. Key challenges include limited durability of immune reset due to persistent plasma cells in autoimmune disorders, tumor heterogeneity, antigen loss or overlap, infiltration barriers, resistance mechanisms, and T-cell depletion in solid tumors, collectively reducing response durability and safety. The main toxicities include grade 1-2 cytokine release syndrome and rare hematologic complications, while immune effector cell-associated neurotoxicity syndrome is uncommon. Clinical translation remains limited and requires larger studies to improve efficacy and define safety profiles.
2026-02-15 | Primary Cutaneous Lymphomas in Children: A Case Series Review with Emphasis on Diagnostic Imaging and Multidisciplinary Management.
Primary Cutaneous Lymphomas (PCLs) are rare extranodal non-Hodgkin lymphomas that present in the skin without extracutaneous disease at diagnosis; they are exceptionally uncommon in children and frequently mimic benign dermatoses, delaying recognition. We report a case series of three pediatric patients managed at a national referral center. Case 1: A 16-year-old with erythrodermic mycosis fungoides (stage IIIA) refractory to multiple systemic and skin-directed therapies who achieved remission after haploidentical allogeneic hematopoietic stem-cell transplantation. Case 2: A 3-year-old with aggressive cytotoxic CD8-positive Tcell lymphoma with EBV-associated disease and severe infectious complications during CHOP-based therapy, culminating in death despite salvage treatments and EBRT. Case 3: A 10-year-old with CD30-positive primary cutaneous anaplastic large cell lymphoma with a relapsing course, treated with BFM-90 chemotherapy, gemcitabine, pegylated doxorubicin plus total skin electron beam therapy, and ongoing PUVA with good dermatologic control. Across cases, diagnosis relied on clinicopathologic correlation with immunohistochemistry and staging CT; serum IgE was elevated in all three children. Pediatric PCLs show heterogeneous behavior and therapeutic responses. Early biopsy of atypical or treatment-refractory eruptions, comprehensive histopathology and immunophenotyping, targeted EBV testing when suggested, and appropriate use of skin-directed radiotherapy (EBRT/TSEBT) and transplantation in selected refractory disease are essential. Multidisciplinary management and equitable access to specialized therapies are critical to optimize outcomes.
2026-01-30 | Primary Cutaneous Peripheral T-Cell Lymphoma With TFH Phenotype With Divergent Clonal B- and Plasma-Cell Populations and DNMT3A Mutation.
Primary cutaneous peripheral T-cell lymphoma with T-follicular helper phenotype (pcTFH-PTCL) is rare, and concurrent clonal B-lineage proliferations are uncommon. This lymphoma subtype presents unique diagnostic challenges due to its rarity and potential for misdiagnosis. We present a case of pcTFH-PTCL in an 88-year-old man with pruritic nodules on the shoulders, later developing multifocal cutaneous lesions including a prominent eyebrow nodule. Biopsies showed dense dermal infiltrates of CD4 positive T cells expressing TFH markers (PD-1, ICOS, and BCL6). Three lesions demonstrated an identical clonal T-cell receptor (TCR) gene rearrangement, confirming a clonal T-cell process. Remarkably, accompanying B-lineage components varied: lambda-restricted plasma cells and kappa-restricted B cells were identified in multiple lesions. Clonality studies revealed mostly distinct immunoglobulin heavy chain (IGH) rearrangements across separate sites, indicating independent B-cell clones. Whole exome sequencing revealed a pathogenic DNMT3A p.Arg882Cys mutation in two different biopsy sites. This case represents a rare pcTFH-PTCL with a persistent T-cell clone coexisting with divergent clonal B- and plasma cell populations. The findings emphasize the role of TFH-derived neoplasms in fostering B-cell expansions and highlight the diagnostic and therapeutic complexity posed by dual-lineage clonality in cutaneous lymphomas.
2026-01-08 | [Recent Research Advances in Classification and Treatment of Primary Cutaneous Lymphoma--Review].
Primary cutaneous lymphoma (PCL) is a group of heterogeneous diseases. Traditional chemotherapy methods often result in substantial toxic side effects due to their low tumor selectivity. Currently, individualized therapy based on the genetic characteristics and target molecules of tumors constitutes the main treatment strategy for managing PCL. In recent years, research on novel treatment options has developed rapidly. These innovative therapies, which primarily include monoclonal antibodies, immune checkpoint inhibitors, small-molecule inhibitors, and chimeric antigen receptor T-cell (CAR-T) therapies, not only expand the treatment options for patients but also significantly improve their survival outcomes. The objective of this article is to provide a comprehensive review of the latest classification system for PCL and the most recent research advancements in cutting-edge treatment strategies.
other
2025-11-10 | Design of chimera vaccine against cutavirus using vaccinomics and immunoinformatics approaches.
Cutavirus (CuV) is a newly discovered human parvovirus, which gained tremendous interest due to its association with cutaneous lymphoma T cells. CuV transmission primarily occur via fecal-oral route and identified as a causal agent of diarrhea. The current study based on prediction of novel multi-epitopic potential vaccine models against CuV by predicted by selecting highly antigenic proteins using reverse vaccinology approaches. A top-ranked T and B cell epitopes from lead vaccine candidate proteins were selected and linked via immunogenic adjuvant peptides and linker sequences to design model vaccine. The models were assessed in terms of physicochemical properties including antigenicity, non-allergenicity, and their binding affinities to TLR4 immune receptors. The in-silico restriction and cloning analysis were pursued to check the expression capacity of model vaccine. Several vaccine models were designed from lead epitopes of CuV vaccine candidates' proteins along with combination of immune-enhancer adjuvants and linkers. Physicochemical and immunoinformatics analyses prioritized a V2 model construct as top-ranked. The molecular docking and molecular dynamic simulation analyses ensured the V2 construct molecular stability and strong interaction with TLR4 immune receptor with binding affinity of - 41.27 kcal/mol. The normal mode analysis (NMA) predicted improved flexibility, proper molecular mobility, and decreased protein deformability of immune complex for the generation of powerful immune response. Molecular dynamics simulation confirmed the structural stability of the V2-TLR4 complex with minimal RMSD fluctuations and sustained hydrogen bonding. Principal component analysis (PCA) revealed limited conformational shifts, indicating a stable dynamic behavior of the vaccine-receptor complex. These results support the robust interaction and stability of the designed vaccine, reinforcing its potential for effective immune activation. Immune simulation predicted a strong primary and memory immune response with elevated levels of IgG, IFN-γ, and T-cell activity. Codon optimization yielded a CAI score of 0.98 and GC content of 53.1%, indicating efficient expression in E. coli. The multi-epitope vaccine construct prioritized in the current study is effectively bind with immune receptors and elicit potent immune response against CuV. The online version contains supplementary material available at 10.1007/s40203-025-00467-6.
2025-06-13 | IgM Immunohistochemical Expression is a Potential Risk Factor for Extracutaneous Dissemination in Patients With Primary Cutaneous Follicle Center Lymphoma.
Primary cutaneous follicle center lymphoma (PCFCL) is a type of cutaneous B-cell lymphoma with an indolent behavior and a 5-year disease-specific survival of 95%. Given the difficulty of identifying patients at risk for developing extracutaneous dissemination (ECD), this study aimed to identify predictors in the clinical presentation, histopathology, immune phenotype, and genetic profile of PCFCL patients by comparing those who developed ECD with those whose disease remained skin limited (SL) during follow-up. After review of clinical data and histopathology, a total of 13 ECD-PCFCL patients and 15 SL-PCFCL patients with varying treatments were included from the Dutch Cutaneous Lymphomas Registry. At diagnosis, all patients presented with classic PCFCL lesions on the trunk or head-and-neck region, and histology indicated a predominance of centrocytes admixed with centroblasts. IgM expression was significantly more frequent in ECD-PCFCL (54%) than in SL-PCFCL (7%; P =0.006). Targeted next-generation sequencing (NGS) with a 200 B-cell lymphoma-related gene panel demonstrated known PCFCL-like mutations in both groups. In addition, ECD-PCFCL demonstrated an enrichment of mutations associated with the activated B-cell genotype, including MYD88 (n=2), and some unique mutations, such as in ERBB4 (n=4). In conclusion, this study identified IgM expression at diagnosis as a potential biomarker for extracutaneous spread in PCFCL. In IgM-positive cases, genetic testing may be warranted. Patients with uncommon mutational profiles, such as those resembling the ABC-DLBCL genotype, may particularly benefit from closer follow-up and consideration of more aggressive treatment, including immuno-polychemotherapy. As these observations were made in a limited number of patients, our results require validation in an independent cohort.
2025-02-13 | Antibody-Drug Conjugates Targeting CD30 in T-Cell Lymphomas: Clinical Progression and Mechanism.
CD30 is overexpressed in many T-cell lymphoma (TCL) entities, including subsets of peripheral T-cell lymphomas (PTCL) and cutaneous T-cell lymphomas (CTCL). The antibody-drug conjugate brentuximab vedotin (BV), targeting CD30-positive cells, has been approved for the treatment of relapsed or refractory (R/R) systemic anaplastic large cell lymphoma (sALCL), and primary cutaneous anaplastic large cell lymphoma or mycosis fungoides in patients who have received previous systemic therapy. However, many patients still experience disease progression after BV monotherapy. Extensive efforts have been dedicated to investigating effective combinations of BV. A phase III clinical study demonstrated that the combination of BV with cyclophosphamide, doxorubicin, and prednisone (CHP) is superior to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for CD30-positive PTCL. This study led to the approval of BV with CHP as the first-line therapy for CD30-positive PTCL (sALCL in Europe). We summarize the encouraging combination applications of BV in this review. Ongoing studies on combination therapies of BV are also listed, highlighting potential directions for the future application of BV. We focus on dissecting the underlying mechanisms of BV, discussing its effects on both tumor cells and the tumor microenvironment. Exploring resistance mechanisms in TCL provide valuable insights for optimizing BV-based therapies in the future.
2025-01-29 | A Rare Head and Neck Tumor: Making Simple Things Complicated.
Primary cutaneous anaplastic large cell lymphoma (ALCL) is a very uncommon type of CD30-positive T-cell lymphoma, and it very rarely affects the forehead. We report the case of a 68-year-old male presenting with an ulcerative lesion on the right forehead, initially suspected as a benign condition. Fine needle aspiration suggested a lymphoproliferative disorder, with biopsy and immunohistochemistry confirming primary cutaneous ALCL (CD30-positive, anaplastic lymphoma kinase [ALK]-negative). The patient was treated with a standardized chemotherapy regimen and achieved a complete response. This case underscores the importance of considering primary cutaneous ALCL in the differential diagnosis of persistent ulcerative lesions in anatomically sensitive areas. Early diagnosis, multidisciplinary management, and advanced therapeutic strategies such as Brentuximab Vedotin + Cyclophosphamide, Hydroxyrubicin, and Prednisone (BV + CHP) are critical to optimizing outcomes in this rare presentation.
2024-09-11 | Non-coding RNAs in the spotlight of the pathogenesis, diagnosis, and therapy of cutaneous T cell lymphoma.
Cutaneous T-cell lymphoma (CTCL) is a group of primary and secondary cutaneous malignancies characterized by aberrant T-cells in the skin. Diagnosing CTCL in its early stage can be difficult because of CTCL's ability to mimic benign cutaneous inflammatory skin diseases. CTCL has multiple subtypes with different disease progression and diagnostic parameters despite similar clinical manifestations. The accurate diagnosis and prognosis of a varied range of diseases require the detection of molecular entities to capture the complete footprint of disease physiology. Non-coding RNAs (ncRNAs) have recently been discovered as major regulators of CTCL gene expression. They can affect tumor cell growth, migration, programmed cell death (PCD), and immunoregulation through interactions with the tumor microenvironment (TME), which in turn affect CTCL progression. This review summarizes recent advances in how ncRNAs regulate CTCL cell activity, especially their role in PCD. It also discusses the potential use of ncRNAs as diagnostic and prognostic biomarkers for different subtypes of CTCL. Furthermore, prospective targets and therapeutic approaches influenced by ncRNAs are presented. A better appreciation of the intricate epigenetic landscape of CTCL is expected to facilitate the creation of innovative targeted therapies for the condition.
antibodies
2026-09-15 | Immune Dysregulation, Compartment-Specific Biology, and Therapeutic Biomarkers in Mycosis Fungoides and Sézary Syndrome.
Cutaneous T-cell lymphoma (CTCL), including mycosis fungoides (MF) and Sézary syndrome (SS), is defined by malignant CD4+ T-cell clones that evolve within and remodel the skin and systemic immune compartments. For disease biology and immune remodeling, we prioritize evidence from human primary samples; for therapeutic implications, we integrate clinical-trial and translational biomarker studies. We organize evidence by compartment (skin vs. blood) and, within skin, by stage (patch/plaque vs. tumor). Early patch/plaque MF often shows features consistent with constrained inflammation: skin-resident memory T-cell (TRM)-like malignant clones are in a Th1-leaning microenvironment with relatively preserved cytotoxic surveillance. Progression to tumor-stage MF (and/or large-cell transformation) is frequently associated with clonal dominance, Th2 cytokine polarization, upregulation of checkpoint pathways, and remodeling of myeloid/fibroblast populations. SS is typically associated with leukemic clonal dominance, systemic Th2 skewing, and broad impairment of cytotoxic immune control. These trajectories support an interpretive framework that aligns immune-directed therapies with compartment- and stage-associated biology; these include strategies that (i) deplete malignant clones (e.g., CCR4, CD30, KIR3DL2 targeting), (ii) re-engage exhausted effectors (PD-1/PD-L1 axis), (iii) reprogram cytokine balance (IFN-γ, IL-12, extracorporeal photopheresis), or (iv) suppress malignant signaling programs with secondary immune effects (JAK/STAT inhibition). We highlight potential candidate predictive biomarkers at varying levels of maturity, most of which require prospective validation, including antigen density, compartmental tumor burden, tumor cell fraction, effector-cell substrate, and interferon/cytokine signatures.
2026-09-09 | Recurrent Primary Cutaneous Anaplastic Large Cell Lymphoma With T-Cell Receptor-ϒδ Phenotype and DUSP22-IRF4 Unbalanced Rearrangement: A Rare and Diagnostically Challenging Presentation.
Primary cutaneous anaplastic large cell lymphoma (pcALCL) is an indolent CD30+ T-cell lymphoma, typically of T-cell receptor (TCR)-αβ origin with an excellent prognosis. Rare cases may exhibit a TCR-ϒδ phenotype or rearrangement of the DUSP22 and IRF4 genes on chromosome 6p25.3, but the concurrence of both features is exceedingly rare. We present herein a case of a 78-year-old man with a history of pcALCL who, 5 years after achieving complete remission with radiation therapy, experienced a recurrent neck nodule. Histopathological examination revealed a dense dermal infiltrate of medium to large atypical lymphoid cells. The lesion was strongly positive for CD30, TCR-δ, and LEF1 but negative for CD4, CD8, CD7, TCR-β, and ALK, and TIA-1. p-STAT3 was predominantly negative with labeling of few scattered cells. Fluorescence in situ hybridization studies confirmed a DUSP22-IRF4 abnormality. In view of immunohistochemical findings (LEF1+, TIA-1-, predominantly p-STAT3-), an unbalanced DUSP22-IRF4 rearrangement was favored. A diagnosis of pcALCL with TCR-ϒδ phenotype and DUSP22-IRF4 unbalanced rearrangement was rendered. This case adds to the small but growing number of reported cases of pcALCL with TCR-ϒδ phenotype and DUSP22-IRF4 alteration.
2026-08-11 | Coexistence of Mycosis Fungoides and Hodgkin Lymphoma in a Pediatric Patient: A Report of a Rare Case.
Mycosis fungoides (MF) is the most common primary cutaneous T‑cell lymphoma, usually affecting adults aged 50-60 years; pediatric presentation is rare. We report a 12‑year‑old patient whose course spanned five years; skin lesions began at age 8, were misdiagnosed and treated as inflammatory dermatosis with topical steroids for four years. At age 12, B‑symptoms, lymphadenopathy and organomegaly led to the diagnosis of MF Stage IA (T1bNxM0B0) and synchronous Hodgkin lymphoma (HL) Stage IVB, with an Epstein-Barr virus (EBV) viral load of 2.5 log₁₀ copies/mL. Treatment with three cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) + pembrolizumab due to drug availability, followed by six cycles of PC‑AVBE (prednisone, cyclophosphamide, doxorubicin, vincristine, bleomycin, and etoposide) and radiotherapy, achieving complete remission. This case highlights diagnostic challenges, immune dysregulation, and adapted treatment in resource‑limited settings.
2026-07-23 | Final results of UK NCRI phase II trial of pembrolizumab and radiotherapy in cutaneous T cell lymphoma.
The outlook for patients with advanced cutaneous T-cell lymphomas (CTCL); mycosis fungoides (MF) and Sézary syndrome (SS) remains poor and most systemic treatments provide short-lived remissions. Immunotherapy has provided a major cancer breakthrough, and the PORT trial was designed to investigate the efficacy of Pembrolizumab and whether the addition of Radiotherapy (RT) could further enhance systemic "abscopal" anti-tumour immune responses. Pembrolizumab followed by 12Gy in 3 fractions RT to a localized lesion was investigated in a single-arm, multicentre phase II trial for relapsed/refractory CTCL. Primary endpoint was overall response rate (ORR), secondary endpoints included duration of response (DOR), abscopal response, progression-free survival (PFS), overall survival (OS). 46 patients (41 MF, 5 SS) were registered, median age 63 (24-83), 24% stage IV. Median follow-up was 24.8 months. 24% of patients remained on treatment for >1 year whilst 57% received.
2026-06-11 | Case Report: Cutaneous niche-restricted malignant phenotypes in PTCL-NOS revealed by single-cell sequencing.
Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) presenting with disseminated cutaneous involvement represents an aggressive disease subset with poor response to conventional chemotherapy and dismal prognosis. The tissue-specific molecular mechanisms driving cutaneous aggression remain poorly characterized at single-cell resolution. Here we report a 67-year-old male PTCL-NOS patient with hypertension and coronary artery disease history, presenting with generalized cutaneous nodules and rapid progression despite multi-line chemotherapy. Single-cell RNA sequencing (scRNA-seq) performed on paired skin lesions and peripheral blood at diagnosis revealed striking microenvironmental dichotomy: skin-resident malignant T cells exhibited hyperproliferative phenotypes (high CDC20B, HIST1H3B, MKI67+), activation of NF-κB and IL-17 signaling, and extensive crosstalk with endothelial cells; conversely, blood-derived lymphoma cells displayed immune evasion signatures and metabolic stress markers. Copy number variation analysis confirmed clonal expansion across both compartments with distinct tissue-specific transcriptional programs. Despite CHOP, CHOEP, DA-EPOCH, and AC-CHOP (azacitidine plus chidamide) regimens, the patient experienced primary refractory disease and died 6 months from diagnosis following COVID-19 superinfection. To our knowledge, this is the first case reporting single-cell transcriptomic comparison of skin versus blood compartments in PTCL-NOS, revealing how cutaneous microenvironment sculpts aggressive malignant phenotypes and providing potential targets for compartment-specific therapy.
small molecules
2026-09-15 | WEE1 Inhibition as a Novel Therapeutic Strategy in Cutaneous T-Cell Lymphoma.
Background/Objectives: Cutaneous T-cell lymphomas (CTCL), most commonly mycosis fungoides and Sézary syndrome, are rare non-Hodgkin lymphomas. Advanced disease responds poorly to current treatments, highlighting the need for new molecularly targeted therapies. WEE1 is a central regulator of the G2/M checkpoint and S-phase progression and has emerged as a therapeutic target in several malignancies, yet it has not been systematically explored in CTCL. Methods: We screened a library of more than 2200 kinase inhibitors in CTCL cell lines and selected adavosertib for further study. Its effects were tested in four CTCL lines; primary keratinocytes and fibroblasts; patient-derived malignant CD4+ T cells and healthy donor CD4+ T cells; and a MyLa xenograft model, using viability, apoptosis, cell-cycle, Western blot, and phospho-protein array assays. Results: Adavosertib reduced viability at submicromolar IC50 values (0.26-0.56 µM) across all four CTCL lines while largely sparing primary skin cells and was more active in malignant than in healthy donor CD4+ T cells. It induced apoptosis and cell-line-specific S-phase and/or G2/M accumulation, lowered WEE1 and phospho-CDK1 (Tyr15), and increased phospho-H2A.X. A phospho-protein array showed activation of checkpoint and stress signalling. In a preliminary xenograft experiment, adavosertib slowed MyLa tumour growth. Conclusions: These preclinical data identify WEE1 as a therapeutic target in CTCL and support further preclinical and early-phase clinical evaluation of adavosertib in this disease.
2026-08-21 | Multifocal Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type, Presenting on Face and Chest: Complete Remission With R-CHOP.
Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT), is an aggressive subtype of primary cutaneous B-cell lymphoma that predominantly affects the lower extremities of elderly individuals. We report a rare case of a 79-year-old woman presenting with rapidly enlarging, erythematous-to-violaceous tumors and plaques on the face, chest, left upper arm, and upper back, an uncommon non-leg manifestation of PCDLBCL-LT, confirmed by histopathology and immunohistochemistry. The patient was successfully treated with six cycles of the rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy, achieving complete remission with no relapse during 1.5 years of follow-up. This case emphasizes that PCDLBCL-LT can present in locations outside the legs, highlighting the need for early recognition and systemic therapy in atypical locations.
2026-08-04 | Primary Cutaneous Gamma-Delta T-Cell Lymphoma Complicating Long-Standing Immunosuppressed Dermatomyositis.
Primary cutaneous gamma-delta T-cell lymphoma (PCGD-TCL) is a rare cytotoxic lymphoma with key oncogenic drivers in the JAK/STAT pathway. Also primarily involving the subcutaneous adipose tissue, subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is more frequently encountered in scenarios of autoimmune disorders. SPTCL shares clinicopathologic overlap with lupus panniculitis. However, the link between autoimmunity and PCGD-TCL is much less established, particularly in the setting of long-standing, immunosuppressed dermatomyositis (DM). We report two cases of PCGD-TCL arising in women with chronic anti-TIF1-γ DM following years of immunosuppressive therapy. Case 1 is a 47-year-old woman with a 19-year history of DM on azathioprine/prednisone who developed rapidly progressive, painful subcutaneous nodules. Incisional biopsy confirmed a TCR-delta+, CD8+ cytotoxic T-cell lymphoproliferative disorder (TCLPD) compatible with PCGD-TCL. She achieved complete remission following pralatrexate and subsequent allogeneic hematopoietic stem cell transplant. Case 2 is a 27-year-old woman with DM on mycophenolate/rituximab who developed subcutaneous nodules with an indolent course and some spontaneous regression. A biopsy revealed a similar panniculitic infiltrate with an atypical TCR-delta+, CD8+ phenotype. Notably, both cases were negative for high-risk JAK/STAT pathway mutations. These cases identify PCGD-TCLPD/TCL as a potential complication of chronic, immunosuppressed DM. The shared, atypical CD8+ immunophenotype and absence of canonical driver mutations suggest a distinct pathogenic mechanism possibly linked to long-term immune modulation. Unlike classic PCGD-TCL, which is characterized by an aggressive course and < 2-year median survival, the clinical courses in these two cases were variable, with one requiring transplant and the other showing indolent behavior and responsiveness to therapy.
2026-08-02 | Comparison of narrowband ultraviolet B with psoralen plus ultraviolet A phototherapy for patients with early-stage mycosis fungoides: a systematic review and meta-analysis.
The most prevalent cutaneous T-cell lymphoma is mycosis fungoides (MF), managed in early stages with psoralen plus ultraviolet A (PUVA) or narrowband ultraviolet B (NB-UVB) phototherapy. To evaluate the therapeutic effectiveness and side effect profiles of PUVA vs. NB-UVB in patients with early-stage MF. A systematic review was conducted, incorporating data from nine studies sourced from PubMed, Cochrane and Google Scholar. Eligible studies were those that simultaneously evaluated PUVA and NB-UVB, enrolling at least 10 adult participants per group with histologically confirmed early-stage (IA-IIA) MF and reported treatment outcomes. Exclusions were advanced disease, paediatric patients, noncomparative or nonrelevant treatments, small sample sizes or lack of outcome data. No language restrictions were applied. Key outcomes included any response, complete response, partial response, treatment failure, relapse-free interval and adverse effects. A total of 923 patients (age range 33-71 years; 52.5% men) were included: 556 treated with PUVA and 367 with NB-UVB. Any response was seen in 90.5% of those treated with PUVA vs. 88.3% of patients who received NB-UVB [odds ratio (OR) 1.18, 95% confidence interval (CI) 0.73-1.90; P = 0.50]. Complete response rates were 72% for those treated with PUVA and 61.8% for those treated with NB-UVB (OR 1.12, 95% CI 0.60-2.07; P = 0.73). Partial response was observed in 19.2% of patients who received PUVA and 28.0% of those who received NB-UVB (OR 0.87, 95% CI 0.45-1.69; P = 0.69). Treatment failure rates were lower with PUVA (9.7%) than with NB-UVB (12.6%) (OR 0.81, 95% CI 0.49-1.33; P = 0.41). Patients who received PUVA had a significantly longer median relapse-free interval (hazard ratio 1.94, 95% CI 1.07-3.51; P < 0.01). Adverse effects, including erythema, nausea, pruritus, burning, hyperpigmentation, pain, phototoxic reactions and polymorphic light eruption, showed no significant differences between groups. Both PUVA and NB-UVB are effective, but PUVA may be preferred when sustained remission is the primary therapeutic goal.
2026-07-28 | Cutaneous Malignancies Metastatic to the Female Genital Tract and Pelvic Lymph Nodes: Analysis of Metastatic Patterns and Pathogenesis.
Background/Objectives: Metastases from cutaneous malignancies to the female genital tract and pelvic lymph nodes are rare clinical entities that frequently masquerade as primary gynecologic tumors, leading to significant diagnostic challenges. The distinction between primary and metastatic disease is critical, yet complex, given the varying patterns of spread exhibited by different skin cancers. This study aims to provide a tumor-specific overview of these metastatic patterns to guide diagnosis and therapy. Methods: We conducted a narrative review informed by a systematic literature search of MEDLINE/PubMed, Embase, Scopus, and Web of Science for records regarding primary cutaneous melanoma, cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma (BCC), Merkel cell carcinoma (MCC), and cutaneous lymphomas metastasizing to the female genital tract (FGT) or pelvic lymph nodes. Data were synthesized qualitatively to identify organotropic patterns, diagnostic pitfalls, and management outcomes across these distinct malignancies. Results: The analysis reveals distinct metastatic niches: cutaneous melanoma shows a predilection for the ovary, often mimicking epithelial ovarian carcinoma, whereas cSCC and MCC typically involve pelvic lymph nodes via contiguous spread from inguinal basins. Histologic evaluation with broad immunohistochemical panels is mandatory to confirm the diagnosis, as imaging alone lacks specificity. Crucially, the introduction of immune checkpoint inhibitors and targeted therapies has significantly improved survival in advanced melanoma, cSCC, and MCC, altering the role of pelvic surgery. Conclusions: Management of cutaneous malignancies metastatic to the pelvis is shifting from a focus on radical surgery to a systemic-first approach. Pelvic metastasectomy should be reserved for selected oligometastatic cases or symptom control within a multidisciplinary framework. Clinicians must maintain a high index of suspicion in patients with a history of skin cancer to avoid overtreatment and optimize quality of life.
proteins
2026-01-21 | Localized palmar mycosis fungoides: A case report.
Mycosis fungoides (MF) is the most common primary cutaneous T-cell lymphoma, yet palmar MF is extremely rare and easily mistaken for chronic dermatoses such as psoriasis. Delayed recognition can lead to inappropriate treatment and worse outcomes. This case demonstrates how careful histopathology and immunohistochemistry can provide critical diagnostic clarity in atypical presentations. A 63-year-old woman presented with an 8-year history of erythema, dryness, scaling, and fissuring on both palms. The lesions had been misdiagnosed as psoriasis and showed no response to long-term topical calcipotriol. Histopathology of a palm biopsy revealed epidermotropism of atypical lymphocytes with cerebriform nuclei and Pautrier microabscesses. Immunohistochemistry demonstrated positivity for CD2, CD3, CD4, and CD45RO with immunophenotypic variation, confirming palmar MF. The patient was staged as early MF (IA-IB). Systemic therapy with intramuscular interferon α-2b, oral methylprednisolone, and acitretin was initiated due to chronicity, bilateral palm involvement, and resistance to topical therapy. Significant improvement was noted after 2 months. At the 1-year follow-up, her palms showed complete clearance of lesions with sustained remission. This case highlights the diagnostic pitfalls of palmar MF and underscores the necessity of early biopsy in patients with persistent, treatment-resistant palm dermatoses. Raising clinical awareness of this rare entity may prevent misdiagnosis, facilitate timely therapy, and ultimately improve patient prognosis.
2024-12-19 | Efficacy and Safety of Denileukin Diftitox-Cxdl, an Improved Purity Formulation of Denileukin Diftitox, in Patients With Relapsed or Refractory Cutaneous T-Cell Lymphoma.
Denileukin diftitox (DD)-cxdl is a fusion protein comprising diphtheria toxin fragments A and B and human interleukin-2. This phase III, multicenter, open-label, single-arm registrational trial evaluated the efficacy and safety of DD-cxdl in patients with relapsed/refractory (R/R) cutaneous T-cell lymphoma (CTCL). In the main study, which followed a dose-finding lead-in, DD-cxdl was administered intravenously daily (5 days; 9 µg/kg/d once daily) every 21 days for up to eight cycles. Patients in the primary efficacy analysis set (PEAS) were required to have stage IA-IIIB CTCL (mycosis fungoides and/or Sézary syndrome) and at least ≥one previous systemic therapy. The primary efficacy end point was objective response rate (ORR) using the Global Response Score. Secondary end points were duration of response (DOR), time to response (TTR), skin tumor burden, and safety and tolerability. The PEAS included 69 patients (median age, 64.0 years). The ORR was 36.2% (95% CI, 25.0 to 48.7), including 8.7% with complete response. The median DOR was 8.9 months (95% CI, 5.0 to not estimable), and the median (Q1-Q3) TTR was 1.4 (0.7-2.1) months. A total of 84.4% of patients showed decreased skin tumor burden, with 48.4% showing a ≥50% decrease. Treatment-emergent adverse events (TEAEs) of special interest, most of which were grade 1 or 2, included infusion reaction (73.9%), hypersensitivity (68.1%), hepatotoxicity (36.2%), and capillary leak syndrome (20.3% [grade ≥3, 5.8%]). Other common TEAEs were nausea (43.5%) and fatigue (31.9%). Efficacy and safety results show that DD-cxdl would potentially fulfill a serious, unmet medical need for patients with R/R CTCL.
2024-04-10 | Real-world study of pegylated interferon α-2a to treat mycosis fungoides/Sézary syndrome using time to next treatment as a measure of clinical benefit: an EORTC CLTG study.
Mycosis fungoides (MF) and Sézary syndrome (SS) are chronic malignant diseases that typically necessitate diverse strategies to achieve remission. Systemic interferon (IFN)-α (subtypes 2a and 2b) has been used to treat MF/SS since 1984; however, its production was recently stopped. The recombinant pegylated (PEG) form of IFN-α-2a remains the only alternative IFN treatment, although it has not been approved for use in MF/SS. To assess the effectiveness and safety of PEG-IFN-α-2a in monotherapy and in combination with other treatments using time to next treatment (TTNT) as a measure of clinical therapeutic benefit in a real-world setting. We conducted an international, multicentre retrospective study of patients with MF and SS (of any stage) treated with PEG-IFN-α-2a from July 2012 to February 2022. Patients were included across 11 centres in 10 countries. The primary endpoints were to determine the TTNT of PEG-IFN-α-2a and adverse events (AEs) in MF/SS. In total, 105 patients were included [mean (SD) age 61 (13.1) years]; 42 (40.0%) had stage IA-IIA and 63 (60.0%) had stage IIB-IVB disease. PEG-IFN-α-2a was combined with other therapies in 67 (63.8%) patients, most commonly with extracorporeal photopheresis (36%) and bexarotene (22%). Patients with stage I-IIA disease achieved an overall response rate (ORR) of 57%; the ORR in those with stage IIB-IVB disease was 51%. Combination treatment resulted in a median TTNT of 10.4 months (range 0.6-50.7) vs. 7.0 months (range 0.7-52.4) for those who received monotherapy (P < 0.01). Overall, the mean (SD) TTNT was 9.2 (10.6) months and the ORR was 53.3% (n = 56). A complete response was seen in 13% of patients and a partial response in 40%. AEs were described in 68.6% (n = 72) of patients. Flu-like symptoms (n = 28; 26.7%), lymphopenia (n = 24; 22.9%) and elevated liver function (n = 10; 9.5%) were the most frequently reported. Grade 3-4 AEs were reported in 23 (21.9%) patients, mostly related to myelosuppression. PEG-IFN-α-2a for MF/SS resulted in an ORR of 53.3% and a mean (SD) TTNT of 9.2 (10.6) months. Combination regimens were superior to monotherapy and doses of 180 µg PEG-IFN-α-2a weekly were related to a higher ORR.
2023-09-12 | Skin infiltrating NK cells in cutaneous T-cell lymphoma are increased in number and display phenotypic alterations partially driven by the tumor.
Cutaneous T-cell lymphomas (CTCL) are characterized by focal infiltration of malignant T cell clones in solitary skin lesions. Many CTCL patients experience an indolent disease, but some progress to advanced disease with high fatality. We hypothesized that natural killer (NK) cells participate in local control of tumor growth in CTCL skin. Immunohistochemistry and flow cytometry analysis of the density, localization, phenotype and function of NK cells in twenty-nine fresh or formalin-fixed skin biopsies from twenty-four CTCL patients and twenty-three biopsies from twenty healthy controls highlighted higher numbers of CD56+CD3- NK cells in CTCL skin. A reduced fraction of CTCL skin NK cells expressed the maturation marker CD57, the cytotoxic protein granzyme B and the activation marker CD69, indicating reduced tumor-killing abilities of the NK cells. Retained expression of immune checkpoint proteins or inhibitory proteins including PD1, TIM3, LAG3, CD73 and NKG2A and the activating receptors CD16 and NKp46 indicated maintained effector functions. Indeed, the capacity of NK cells to produce anti-tumor acting IFNγ upon PMA+ionomycin stimulation was similar in cells from CTCL and healthy skin. Co-cultures of primary human NK cells or the NK cell line NKL with CTCL cells resulted in reduced levels of granzyme B and CD69, indicating that close cellular interactions with CTCL cells induced the impaired functional NK cell phenotype. In conclusion, increased numbers of NK cells in CTCL skin exhibit a partially impaired phenotype in terms of activity. Enhancing NK cell activity with NK cell activating cytokines such as IL-15 or immune checkpoint blockade therefore represents a potential immunotherapeutic approach in CTCL.
2021-11-28 | Clinical Response to Anti-CD47 Immunotherapy Is Associated with Rapid Reduction of Exhausted Bystander CD4+ BTLA+ T Cells in Tumor Microenvironment of Mycosis Fungoides
Cancer progression in mycosis fungoides, the most common form of cutaneous T-cell lymphoma, occurs in a predictable, sequential pattern that starts from patches and that evolves to plaques and later to tumors. Therefore, unlocking the relationship between the microarchitecture of mycosis fungoides and the clinical counterparts of that microstructure represents important steps for the design of targeted therapies. Using multispectral fluorescent imaging, we show that the progression of mycosis fungoides from plaque to tumor parallels the cutaneous expansion of the malignant CD4+ T cells that express TOX. The density of exhausted BTLA+ CD4+ T cells around malignant CD4+TOX+ cells was higher in tumors than it was in plaques, suggesting that undesired safeguards are in place within the tumor microenvironment that prevent immune activation and subsequent cancer eradication. Overriding the CD47 checkpoint with an intralesional SIRPαFc fusion decoy receptor induced the resolution of mycosis fungoides in patients that paralleled an amplified expansion of NK and CD8+ T cells in addition to a reduction of the exhausted BTLA+ CD4+ T cells that were engaged in promiscuous intercellular interactions. These therapeutic benefits of the CD47 blockade were further unleashed by adjuvant interferon-α, which stimulates cytotoxic cells, underscoring the importance of an inflamed microenvironment in facilitating the response to immunotherapy. Collectively, these findings support CD47 as a therapeutic target in treating mycosis fungoides and demonstrate a synergistic role of interferon-α in exploiting these clinical benefits.
cell therapies
2026-09-29 | Graft-Versus-Tumour Effect Following Allogeneic Haematopoietic Stem Cell Transplantation in a Paediatric Patient With Mogamulizumab-Treated Primary Cutaneous Peripheral T-Cell Lymphoma.
Primary cutaneous peripheral T-cell lymphoma, not otherwise specified (pcPTCL-NOS), is exceptionally rare in children, and evidence guiding diagnosis and treatment is limited. A 10-year-old boy with pcPTCL-NOS refractory to chemotherapy received mogamulizumab prior to allogeneic haematopoietic stem cell transplantation (allo-HSCT). Despite a 60-day washout period, he developed prolonged steroid-refractory acute graft-versus-host disease requiring ruxolitinib and extracorporeal photopheresis. Concurrently, transient skin lesions developed at previous lymphoma sites and regressed spontaneously, with biopsy supporting the interpretation of visible graft-versus-lymphoma. This case underscores the need to optimise allo-HSCT timing after mogamulizumab and preserve graft-versus-lymphoma effect while limiting graft-versus-host disease. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.
2026-05-27 | Beyond Hematology-Current Insights into Chimeric Antigen Receptor (CAR) T-Cell Therapy for Skin and Connective Tissue Disorders.
Chimeric antigen receptor (CAR) T-cell therapy represents a major advance in modern immunotherapy. This narrative review summarizes evidence from the past five years, including case reports, case series, and clinical trials, on its application beyond hematologic malignancies, focusing on autoimmune diseases such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc), as well as solid tumors including melanoma and primary cutaneous lymphomas. CD19-directed CAR T-cells have demonstrated clinical benefits in SLE and SSc, with sustained immune reset, reduced autoreactive antibody levels, and clinical improvement. In melanoma, CAR T-cells targeting GD2, cMET, and CD20 have shown in vivo expansion and tumor infiltration; however, clinical efficacy remains limited, with transient stabilization or disease progression in most patients. In primary cutaneous lymphomas, early-phase studies with anti-CD70 and anti-CCR4.30 CAR T-cells indicate partial tumor regression and disease stabilization, often requiring additional therapy. Key challenges include limited durability of immune reset due to persistent plasma cells in autoimmune disorders, tumor heterogeneity, antigen loss or overlap, infiltration barriers, resistance mechanisms, and T-cell depletion in solid tumors, collectively reducing response durability and safety. The main toxicities include grade 1-2 cytokine release syndrome and rare hematologic complications, while immune effector cell-associated neurotoxicity syndrome is uncommon. Clinical translation remains limited and requires larger studies to improve efficacy and define safety profiles.
2026-02-15 | Primary Cutaneous Lymphomas in Children: A Case Series Review with Emphasis on Diagnostic Imaging and Multidisciplinary Management.
Primary Cutaneous Lymphomas (PCLs) are rare extranodal non-Hodgkin lymphomas that present in the skin without extracutaneous disease at diagnosis; they are exceptionally uncommon in children and frequently mimic benign dermatoses, delaying recognition. We report a case series of three pediatric patients managed at a national referral center. Case 1: A 16-year-old with erythrodermic mycosis fungoides (stage IIIA) refractory to multiple systemic and skin-directed therapies who achieved remission after haploidentical allogeneic hematopoietic stem-cell transplantation. Case 2: A 3-year-old with aggressive cytotoxic CD8-positive Tcell lymphoma with EBV-associated disease and severe infectious complications during CHOP-based therapy, culminating in death despite salvage treatments and EBRT. Case 3: A 10-year-old with CD30-positive primary cutaneous anaplastic large cell lymphoma with a relapsing course, treated with BFM-90 chemotherapy, gemcitabine, pegylated doxorubicin plus total skin electron beam therapy, and ongoing PUVA with good dermatologic control. Across cases, diagnosis relied on clinicopathologic correlation with immunohistochemistry and staging CT; serum IgE was elevated in all three children. Pediatric PCLs show heterogeneous behavior and therapeutic responses. Early biopsy of atypical or treatment-refractory eruptions, comprehensive histopathology and immunophenotyping, targeted EBV testing when suggested, and appropriate use of skin-directed radiotherapy (EBRT/TSEBT) and transplantation in selected refractory disease are essential. Multidisciplinary management and equitable access to specialized therapies are critical to optimize outcomes.
2026-01-30 | Primary Cutaneous Peripheral T-Cell Lymphoma With TFH Phenotype With Divergent Clonal B- and Plasma-Cell Populations and DNMT3A Mutation.
Primary cutaneous peripheral T-cell lymphoma with T-follicular helper phenotype (pcTFH-PTCL) is rare, and concurrent clonal B-lineage proliferations are uncommon. This lymphoma subtype presents unique diagnostic challenges due to its rarity and potential for misdiagnosis. We present a case of pcTFH-PTCL in an 88-year-old man with pruritic nodules on the shoulders, later developing multifocal cutaneous lesions including a prominent eyebrow nodule. Biopsies showed dense dermal infiltrates of CD4 positive T cells expressing TFH markers (PD-1, ICOS, and BCL6). Three lesions demonstrated an identical clonal T-cell receptor (TCR) gene rearrangement, confirming a clonal T-cell process. Remarkably, accompanying B-lineage components varied: lambda-restricted plasma cells and kappa-restricted B cells were identified in multiple lesions. Clonality studies revealed mostly distinct immunoglobulin heavy chain (IGH) rearrangements across separate sites, indicating independent B-cell clones. Whole exome sequencing revealed a pathogenic DNMT3A p.Arg882Cys mutation in two different biopsy sites. This case represents a rare pcTFH-PTCL with a persistent T-cell clone coexisting with divergent clonal B- and plasma cell populations. The findings emphasize the role of TFH-derived neoplasms in fostering B-cell expansions and highlight the diagnostic and therapeutic complexity posed by dual-lineage clonality in cutaneous lymphomas.
2026-01-08 | [Recent Research Advances in Classification and Treatment of Primary Cutaneous Lymphoma--Review].
Primary cutaneous lymphoma (PCL) is a group of heterogeneous diseases. Traditional chemotherapy methods often result in substantial toxic side effects due to their low tumor selectivity. Currently, individualized therapy based on the genetic characteristics and target molecules of tumors constitutes the main treatment strategy for managing PCL. In recent years, research on novel treatment options has developed rapidly. These innovative therapies, which primarily include monoclonal antibodies, immune checkpoint inhibitors, small-molecule inhibitors, and chimeric antigen receptor T-cell (CAR-T) therapies, not only expand the treatment options for patients but also significantly improve their survival outcomes. The objective of this article is to provide a comprehensive review of the latest classification system for PCL and the most recent research advancements in cutting-edge treatment strategies.
other
2025-11-10 | Design of chimera vaccine against cutavirus using vaccinomics and immunoinformatics approaches.
Cutavirus (CuV) is a newly discovered human parvovirus, which gained tremendous interest due to its association with cutaneous lymphoma T cells. CuV transmission primarily occur via fecal-oral route and identified as a causal agent of diarrhea. The current study based on prediction of novel multi-epitopic potential vaccine models against CuV by predicted by selecting highly antigenic proteins using reverse vaccinology approaches. A top-ranked T and B cell epitopes from lead vaccine candidate proteins were selected and linked via immunogenic adjuvant peptides and linker sequences to design model vaccine. The models were assessed in terms of physicochemical properties including antigenicity, non-allergenicity, and their binding affinities to TLR4 immune receptors. The in-silico restriction and cloning analysis were pursued to check the expression capacity of model vaccine. Several vaccine models were designed from lead epitopes of CuV vaccine candidates' proteins along with combination of immune-enhancer adjuvants and linkers. Physicochemical and immunoinformatics analyses prioritized a V2 model construct as top-ranked. The molecular docking and molecular dynamic simulation analyses ensured the V2 construct molecular stability and strong interaction with TLR4 immune receptor with binding affinity of - 41.27 kcal/mol. The normal mode analysis (NMA) predicted improved flexibility, proper molecular mobility, and decreased protein deformability of immune complex for the generation of powerful immune response. Molecular dynamics simulation confirmed the structural stability of the V2-TLR4 complex with minimal RMSD fluctuations and sustained hydrogen bonding. Principal component analysis (PCA) revealed limited conformational shifts, indicating a stable dynamic behavior of the vaccine-receptor complex. These results support the robust interaction and stability of the designed vaccine, reinforcing its potential for effective immune activation. Immune simulation predicted a strong primary and memory immune response with elevated levels of IgG, IFN-γ, and T-cell activity. Codon optimization yielded a CAI score of 0.98 and GC content of 53.1%, indicating efficient expression in E. coli. The multi-epitope vaccine construct prioritized in the current study is effectively bind with immune receptors and elicit potent immune response against CuV. The online version contains supplementary material available at 10.1007/s40203-025-00467-6.
2025-06-13 | IgM Immunohistochemical Expression is a Potential Risk Factor for Extracutaneous Dissemination in Patients With Primary Cutaneous Follicle Center Lymphoma.
Primary cutaneous follicle center lymphoma (PCFCL) is a type of cutaneous B-cell lymphoma with an indolent behavior and a 5-year disease-specific survival of 95%. Given the difficulty of identifying patients at risk for developing extracutaneous dissemination (ECD), this study aimed to identify predictors in the clinical presentation, histopathology, immune phenotype, and genetic profile of PCFCL patients by comparing those who developed ECD with those whose disease remained skin limited (SL) during follow-up. After review of clinical data and histopathology, a total of 13 ECD-PCFCL patients and 15 SL-PCFCL patients with varying treatments were included from the Dutch Cutaneous Lymphomas Registry. At diagnosis, all patients presented with classic PCFCL lesions on the trunk or head-and-neck region, and histology indicated a predominance of centrocytes admixed with centroblasts. IgM expression was significantly more frequent in ECD-PCFCL (54%) than in SL-PCFCL (7%; P =0.006). Targeted next-generation sequencing (NGS) with a 200 B-cell lymphoma-related gene panel demonstrated known PCFCL-like mutations in both groups. In addition, ECD-PCFCL demonstrated an enrichment of mutations associated with the activated B-cell genotype, including MYD88 (n=2), and some unique mutations, such as in ERBB4 (n=4). In conclusion, this study identified IgM expression at diagnosis as a potential biomarker for extracutaneous spread in PCFCL. In IgM-positive cases, genetic testing may be warranted. Patients with uncommon mutational profiles, such as those resembling the ABC-DLBCL genotype, may particularly benefit from closer follow-up and consideration of more aggressive treatment, including immuno-polychemotherapy. As these observations were made in a limited number of patients, our results require validation in an independent cohort.
2025-02-13 | Antibody-Drug Conjugates Targeting CD30 in T-Cell Lymphomas: Clinical Progression and Mechanism.
CD30 is overexpressed in many T-cell lymphoma (TCL) entities, including subsets of peripheral T-cell lymphomas (PTCL) and cutaneous T-cell lymphomas (CTCL). The antibody-drug conjugate brentuximab vedotin (BV), targeting CD30-positive cells, has been approved for the treatment of relapsed or refractory (R/R) systemic anaplastic large cell lymphoma (sALCL), and primary cutaneous anaplastic large cell lymphoma or mycosis fungoides in patients who have received previous systemic therapy. However, many patients still experience disease progression after BV monotherapy. Extensive efforts have been dedicated to investigating effective combinations of BV. A phase III clinical study demonstrated that the combination of BV with cyclophosphamide, doxorubicin, and prednisone (CHP) is superior to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for CD30-positive PTCL. This study led to the approval of BV with CHP as the first-line therapy for CD30-positive PTCL (sALCL in Europe). We summarize the encouraging combination applications of BV in this review. Ongoing studies on combination therapies of BV are also listed, highlighting potential directions for the future application of BV. We focus on dissecting the underlying mechanisms of BV, discussing its effects on both tumor cells and the tumor microenvironment. Exploring resistance mechanisms in TCL provide valuable insights for optimizing BV-based therapies in the future.
2025-01-29 | A Rare Head and Neck Tumor: Making Simple Things Complicated.
Primary cutaneous anaplastic large cell lymphoma (ALCL) is a very uncommon type of CD30-positive T-cell lymphoma, and it very rarely affects the forehead. We report the case of a 68-year-old male presenting with an ulcerative lesion on the right forehead, initially suspected as a benign condition. Fine needle aspiration suggested a lymphoproliferative disorder, with biopsy and immunohistochemistry confirming primary cutaneous ALCL (CD30-positive, anaplastic lymphoma kinase [ALK]-negative). The patient was treated with a standardized chemotherapy regimen and achieved a complete response. This case underscores the importance of considering primary cutaneous ALCL in the differential diagnosis of persistent ulcerative lesions in anatomically sensitive areas. Early diagnosis, multidisciplinary management, and advanced therapeutic strategies such as Brentuximab Vedotin + Cyclophosphamide, Hydroxyrubicin, and Prednisone (BV + CHP) are critical to optimizing outcomes in this rare presentation.
2024-09-11 | Non-coding RNAs in the spotlight of the pathogenesis, diagnosis, and therapy of cutaneous T cell lymphoma.
Cutaneous T-cell lymphoma (CTCL) is a group of primary and secondary cutaneous malignancies characterized by aberrant T-cells in the skin. Diagnosing CTCL in its early stage can be difficult because of CTCL's ability to mimic benign cutaneous inflammatory skin diseases. CTCL has multiple subtypes with different disease progression and diagnostic parameters despite similar clinical manifestations. The accurate diagnosis and prognosis of a varied range of diseases require the detection of molecular entities to capture the complete footprint of disease physiology. Non-coding RNAs (ncRNAs) have recently been discovered as major regulators of CTCL gene expression. They can affect tumor cell growth, migration, programmed cell death (PCD), and immunoregulation through interactions with the tumor microenvironment (TME), which in turn affect CTCL progression. This review summarizes recent advances in how ncRNAs regulate CTCL cell activity, especially their role in PCD. It also discusses the potential use of ncRNAs as diagnostic and prognostic biomarkers for different subtypes of CTCL. Furthermore, prospective targets and therapeutic approaches influenced by ncRNAs are presented. A better appreciation of the intricate epigenetic landscape of CTCL is expected to facilitate the creation of innovative targeted therapies for the condition.
Access all drug discovery papers and probability of success in trials forecasts:
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Drug Discovery Landscape
1 orphan drug designation for Primary cutaneous lymphoma.
1 orphan drug designation for Primary cutaneous lymphoma.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
miltefosine | small molecules | FDA | — | ExperGen Drug Development GmbH |
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