RARE DISEASE
Classic mycosis fungoides
Classic mycosis fungoides
Classic mycosis fungoides
Synonyms: Mycosis fungoides, Alibert-Bazin type
Synonyms: Mycosis fungoides, Alibert-Bazin type
Synonyms: Mycosis fungoides, Alibert-Bazin type
Drug discovery
7
drugs
With orphan designations
Overview
Classic mycosis fungoides (MF), the most common cutaneous T-cell lymphoma, presents as progressive skin lesions (patches → plaques → tumors) with epidermotropic CD4+ T-cell infiltration [1][6]. It follows an indolent course, often diagnosed in early stages, with a median survival of 18 years in stage IA disease [4][9]. While typically skin-limited, advanced stages may involve lymph nodes or viscera [1][6]. Diagnosis requires clinicopathological correlation due to frequent mimicry of inflammatory dermatoses [2][16].
Therapies
Early stages (IA-IIA): Skin-directed therapies (topical steroids, PUVA/UVB phototherapy, localized radiotherapy) [3][8][13]
Advanced disease (IIB-IV): Systemic agents (interferon-α, retinoids) and targeted therapies (brentuximab vedotin for CD30+ disease) [3][8][11]
Palliative focus: 80-90% achieve remission with phototherapy; only stem cell transplantation modifies disease progression [1][8][13]
Categories: rare hematological diseases, rare neoplastic diseases, rare skin diseases, rare transplant-related disorders
Research Papers
167 drug discovery papers about Classic mycosis fungoides, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
167 drug discovery papers about Classic mycosis fungoides, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-28 | Single-Cell Analysis Reclassifies Eczematous Mycosis Fungoides as Severe Atopic Dermatitis 2259810
Abstract Introduction Mycosis fungoides (MF), the prevalent subtype of cutaneous T-cell lymphoma (CTCL), primarily affects the skin and progresses systemically over time. Early-stage MF diagnosis relies on immunohistochemistry, T cell receptor (TCR) gene rearrangement testing, and clinical evaluation. However, in the clinic settings, we observe eczematous MF (eMF) patients who meet early-stage MF diagnostic criteria but exhibit phenotypes resembling atopic dermatitis (AD), and refractory to dupilumab. This study investigates the molecular characteristics of eMF in comparison to AD and classic MF, providing insights into its distinct pathophysiology and potential therapeutic implications. Methods Skin biopsies were collected from seven AD patients and eleven eMF patients. Paired single-cell RNA sequencing (scRNA-seq) and single-cell TCR sequencing (scTCR-seq) were conducted to evaluate transcriptional profiles and T-cell clonality. Publicly available MF and AD scRNA-seq data were used for comparative analysis. In addition, spatial transcriptomic profiling was performed to validate. Results Comparative transcriptomic analysis showed that the molecular profiles of T cells in eMF resembled those in AD rather than in conventional MF. Furthermore, in eMF, we observed oligoclonal T-cell expansions, which were not found in conventional MF both in scRNA-seq and spatial transcriptomic data. These expanded cells were predominantly Th22 cells, identified as the primary producers of IL-13, a key cytokine in AD pathophysiology. Conclusion eMF diagnostic phenotype resembles conventional MF, and AD primarily due to the hyperproliferation of Th22 cells and their expression of IL-13. In this context, this mechanism underscores the superior efficacy of Upadacitinib, which could target Th22 differentiation, over Dupilumab. As a result, our findings indicate that eMF is not cancer, but a Th22-mediated AD endotype. Funding Source n/a Topic Categories Immune Mechanisms of Human Disease (HUM)
2026-05-21 | Primary cutaneous lymphomas in children: a single-center retrospective analysis and narrative review of the literature.
Primary cutaneous lymphomas (PCLs) are uncommon in children, with mycosis fungoides (MF), lymphomatoid papulosis (LyP), and primary cutaneous small/medium CD4+ T-cell lymphoproliferative disorder (PCSM-TCLPD) representing the most frequent entities. Due to their rarity, available data derive mainly from case reports and small series, and diagnostic delays are frequent. This study aimed to describe the clinical, histopathological, and therapeutic features of pediatric PCLs in a single Italian referral centre and compare them with the literature evidence. We conducted a single-center, retrospective observational study including patients aged ≤16 years with a histologically confirmed diagnosis of PCLs, followed for at least six months at the Dermatology Unit of the University Hospital of Bologna between 2002 and 2024. Clinical, histological, therapeutic, and follow-up data were collected and analyzed. Among 354 PCL patients, 10 pediatric cases were identified: six MF, three LyP, and one PCSM-TCLPD. The mean age at diagnosis was 9.1 years. MF cases were mostly early-stage (IA, 5/6), with folliculotropic (67%), hypopigmented (50%), and classic (50%) variants; all were treated with topical corticosteroids and/or PUVA, with good long-term outcomes (67% complete remission). LyP patients presented at younger ages (mean 5.7 years) with type A (N.=2) and D (N.=1) subtypes; all achieved complete remission despite recurrences, one requiring methotrexate. The single PCSM-TCLPD case was cured with surgical excision. After a mean follow-up of 8.2 years, all patients were alive, most disease-free. Pediatric PCLs are rare but generally indolent, with an excellent prognosis. However, their clinical heterogeneity and diagnostic delay highlight the importance of early biopsy, integrated clinicopathological assessment, and long-term follow-up. Multicenter studies are needed to establish tailored treatment algorithms for children.
2025-12-24 | Central Nervous System Progression in Folliculotropic Mycosis Fungoides.
Central nervous system (CNS) involvement by cutaneous T-cell lymphomas (CTCL) is exceptionally rare and is associated with a poor prognosis. Folliculotropic mycosis fungoides (FMF) is a rare subtype of CTCL and often has more aggressive clinical behavior compared to classic MF. The risk factors for CNS progression in patients with primary CTCL are not well understood. We present the case of a 75-year-old male with a history of Stage IA FMF, who developed progressive neurologic and functional decline over six months. Workup revealed marked eosinophilia, and CSF analysis showed monoclonal T-cell population with positive T-cell receptor (TCR) gene rearrangement. Flow cytometry further showed an atypical CD4+ T-cell population with loss of CD7, consistent with the immunophenotype of patient's cutaneous MF, supporting secondary CNS involvement. An MRI of the brain showed T2 hyperintensity in the pons and right middle cerebellar peduncle, with low signal intensity throughout the bone marrow of the skull, concerning for CNS progression of FMF. The patient was started on high-dose steroids, which led to improvement in eosinophilia. Due to transaminitis, high-dose methotrexate therapy was deferred, and the patient was initiated on intrathecal (IT) chemotherapy with methotrexate and cytarabine. Following five cycles of IT chemotherapy, the patient's neurologic status significantly improved, and CSF analysis showed resolution of the atypical T-cell population. This case highlights the rare occurrence of CNS progression of FMF, even in the absence of lymphatic involvement and with well-controlled skin manifestations, and underscores the role of IT chemotherapy in managing this complication.
2025-09-26 | PAI-1 in Skin Malignancies: a Central Regulator of Tumor Progression and Therapeutic Resistance.
Plasminogen activator inhibitor-1 (PAI-1) plays a multifaceted and central role in the tumor biology of various skin malignancies. Beyond its classical function in fibrinolysis, PAI-1 contributes to tumor progression by promoting immunosuppression, angiogenesis, cellular senescence, and tissue remodeling. Its expression is particularly elevated in aggressive disease stages across cutaneous melanoma, cutaneous squamous cell carcinoma (cSCC), cutaneous angiosarcoma (CAS), and mycosis fungoides (MF), and is associated with poor clinical outcomes. The ability of PAI-1 to induce senescence-associated secretory phenotype (SASP), modulate PD-L1 expression, and recruit tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) suggests a key role in shaping the immunosuppressive tumor microenvironment (TME). This positions PAI-1 as both a potential biomarker for disease progression and a therapeutic target for restoring immune responsiveness, especially in tumors resistant to immune checkpoint inhibitors (ICIs). The PAI-1 inhibitor TM5614 has demonstrated promising activity in early clinical studies, particularly in anti-PD-1-refractory melanoma, and is currently under evaluation in multiple Phase II and III trials. Future strategies should focus on patient stratification using biomarkers such as SASP factors and PAI-1 levels, as well as rational combination therapies targeting interconnected pathways like IL-17/IL-23, AhR, and senescence signaling. Overall, PAI-1 inhibition offers a novel and mechanistically grounded approach to improve outcomes in skin cancers characterized by therapy resistance and an immunosuppressive microenvironment.
2025-06-16 | Classical and biological treatments in mycosis fungoides/Sézary syndrome. New horizons in oncodermatology.
In the strategic management of mycosis fungoides (MF)/Sézary syndrome (SS), an interdisciplinary framework is essential. The regimen typically encompasses dermatological-specific interventions, biologic response modulators, and, in advanced scenarios, systemic chemotherapeutic entities. This might integrate biologic response agents like bexarotene, histone deacetylase inhibitors such as romidepsin, and specialized monoclonal antibodies or conjugates, notably mogamulizumab and brentuximab vedotin. Decisions in therapeutic avenues are intricately individualized, considering determinants like patient age, functional health metrics, disease scope, evolutionary trajectory and previous therapeutic exposures. The high-frequency ultrasound seems to be a useful tool for monitoring infiltration of the skin. Moreover, ongoing studies are investigating novel therapeutic agents that may demonstrate efficacy in MF/SS.
oligonucleotides
2023-03-30 | Data from Inhibition of Constitutively Activated Nuclear Factor-κB Induces Reactive Oxygen Species- and Iron-Dependent Cell Death in Cutaneous T-Cell Lymphoma
<div>Abstract<p>Aberrant signaling of the nuclear facotr (NF-κB) pathway has been identified as a mediator of survival and apoptosis resistance in leukemias and lymphomas. Here, we report that cell death of cutaneous T-cell lymphoma cell lines induced by inhibition of the NF-κB pathway is independent of caspases or classic death receptors. We found that free intracellular iron and reactive oxygen species (ROS) are the main mediators of this cell death. Antioxidants such as <i>N</i>-Acetyl-l-cysteine and glutathione or the iron chelator desferrioxamine effectively block cell death in cutaneous T-cell lymphoma cell lines or primary T cells from Sézary patients. We show that inhibition of constitutively active NF-κB causes down-regulation of ferritin heavy chain (FHC) that leads to an increase of free intracellular iron, which, in turn, induces massive generation of ROS. Furthermore, direct down-regulation of FHC by siRNA caused a ROS-dependent cell death. Finally, high concentrations of ROS induce cell death of malignant T cells. In contrast, T cells isolated from healthy donors do not display down-regulation of FHC and, therefore, do not show an increase in iron and cell death upon NF-κB inhibition. In addition, in a murine T-cell lymphoma model, we show that inhibition of NF-κB and subsequent down-regulation of FHC significantly delays tumor growth <i>in vivo</i>. Thus, our results promote FHC as a potential target for effective therapy in lymphomas with aberrant NF-κB signaling. [Cancer Res 2009;69(6):2365–74]</p></div>
2019-01-22 | miRNA‑135a regulates Hut78 cell proliferation via the GATA‑3/TOX signaling pathway
The present study investigated the role of microRNA‑135a (miR‑135a) in cutaneous T‑cell lymphoma (CTCL) proliferation. Compared with the normal T lymphocyte control cell line, the mRNA and protein levels of GATA binding protein 3 (GATA‑3) were markedly increased in the Hut78 cell line and miR‑135a was markedly decreased (P<0.05). Based on bioinformatics, the target gene of miR‑135a was identified as GATA‑3. Dual luciferase and pre‑miR‑135a assays showed that miR‑135a regulated the translation of GATA‑3. In addition, the overexpression of miR‑135a mimics decreased the protein levels of GATA‑3 and thymocyte selection‑associated high mobility group box (TOX). The substantially increased mRNA and protein levels of GATA‑3 may be associated with the downregulation of miR‑135a, leading to T‑cell deregulation and proliferation through GATA‑3/TOX regulation and subsequently causing CTCL.
2012-01-03 | miR-122 Regulates p53/Akt Signalling and the Chemotherapy-Induced Apoptosis in Cutaneous T-Cell Lymphoma
Advanced cutaneous T-cell lymphoma (CTCL) is resistant to chemotherapy and presents a major area of medical need. In view of the known role of microRNAs (miRNAs) in the regulation of cellular signalling, we aimed to identify the functionally important miRNA species, which regulate apoptosis in CTCL. Using a recently established model in which apoptosis of CTCL cell lines is induced by Notch-1 inhibition by γ-secretase inhibitors (GSIs), we found that miR-122 was significantly increased in the apoptotic cells. miR-122 up-regulation was not specific for GSI-1 but was also seen during apoptosis induced by chemotherapies including doxorubicin and proteasome blockers (bortezomib, MG132). miR-122 was not expressed in quiescent T-cells, but was detectable in CTCL: in lesional skin in mycosis fungoides and in Sézary cells purified from peripheral blood. In situ hybridization results showed that miR-122 was expressed in the malignant T-cell infiltrate and increased in the advanced stage mycosis fungoides. Surprisingly, miR-122 overexpression decreased the sensitivity to the chemotherapy-induced apoptosis via a signaling circuit involving the activation of Akt and inhibition of p53. We have also shown that induction of miR-122 occurred via p53 and that p53 post-transcriptionally up-regulated miR-122. miR-122 is thus an amplifier of the antiapoptotic Akt/p53 circuit and it is conceivable that a pharmacological intervention in this pathway may provide basis for novel therapies for CTCL.
antibodies
2026-02-06 | A historical review of mycosis fungoides: from Alibert to mogamulizumab.
In 1806, French physician Baron Jean-Louis Alibert saw a man with a desquamating rash and skin tumours. Alibert considered this to be a variant of yaws. In 1829 Alibert named the condition mycosis fungoides (MF), meaning 'mushroom-like fungal disease'. Over 100 years later, French dermatologist Albert Sézary published papers from 1938 to 1949 detailing a mysterious disease containing 'cellules monstrueuses', describing cutaneous 'monster cells'. In 1961, these clinical findings were collated together into 'Sézary syndrome'. In the 1870s English dermatologist William Tilbury Fox published a dermatology atlas detailing cases similar to what we know now as MF, with the name 'fibroma fungoides'. The atlas described MF as a type of fungus, before giving a description of yaws and painting a clinical picture that differed from that of a lymphoma. Over the twentieth century, our understandings of the origins of MF were changing and by 1975 the classification system and term we now recognize as cutaneous T-cell lymphoma (CTCL) was developed. Neoplastic cells have been thought to arise from chronic activation of T cells via antigen-presenting cells due to inappropriate cytokines and C-C chemokine receptors. In 2018, the World Health Organization and European Organisation for Research and Treatment of Cancer officially recognized four variants of MF. These are the classic Alibert-Bazin variant and its three variants: folliculotropic MF, pagetoid reticulosis and granulomatous slack skin. Developments in immunohistochemistry for the T-cell receptor gene in the 1990s improved the diagnosis of CTCL; however, diagnosis is still challenging. Advanced MF therapies have evolved from cytotoxic chemotherapy to novel monoclonal antibodies such as mogamulizumab, targeting proteins on T-cell lymphoma cells.
2024-08-02 | Urticarial mycosis fungoides: A distinctive presentation with blood involvement and a peculiar immunophenotype.
Mycosis fungoides (MF) has been widely reported to mimick a considerable number of different dermatoses, including scarring alopecia, bullous dermatoses or cysts, and comedones. In atypical presentations, histopathology is essential for the diagnosis. We present two cases of MF with clinical urticarial lesions and a striking blood involvement that responded to mogamulizumab treatment. Histopathologically, both cases had classic MF features and shared a peculiar immunophenotype, with positivity for CD25 and FOXP3. Differential diagnoses included urticarial lymphomatoid drug reactions and other lymphomas, like T-cell prolymphocytic leukemia, atypical Sézary syndrome, or adult T-cell lymphocytic leukemia. A low suspicion threshold is necessary for the diagnosis of atypical presentations of MF.
2024-06-28 | P068 A history of mycosis fungoides: from Alibert to mogamulizumab
Abstract In 1806, French physician Baron Jean-Louis Alibert treated a 56-year-old man with a desquamating rash and skin tumours. Alibert considered this to be a variant of yaws. In 1829 Alibert named the condition mycosis fungoides (MF), meaning ‘mushroom-like fungal disease’. Over 100 years later, French dermatologist Albert Sézary published papers from 1938 to 1949 detailing a mysterious disease that caused erythroderma and ‘cellules monstrueuses’, describing cutaneous ‘monster cells’. In 1961, these clinical findings were collated together into ‘Sézary syndrome’. There was widespread confusion between these conditions, i.e. fungal infections and yaws. In the 1870s English dermatologist William Tilbury Fox published a dermatology atlas detailing cases similar to what we know now as MF, with the name ‘fibroma fungoides’. The atlas described MF as a type of fungus, before giving a description of yaws and painting a clinical picture that differed from that of a lymphoma. In 1975, Pierre-Antoine-Ernest Bazin and associates suggested the classification system and term we now recognize as cutaneous T-cell lymphoma (CTCL). Neoplastic cells have been thought to arise from chronic activation of T cells via antigen-presenting cells, yet the antigen to trigger this response remains unknown. Several potential bacterial, viral, fungal and iatrogenic causes have been studied, but no reliable triggers have been discovered. In 2018, the World Health Organization and European Organisation for Research and Treatment of Cancer officially recognized four types of MF. These are the classic Alibert–Bazin type (representing 88.6% of cases) and its three subtypes; folliculotropic MF (11.4%), Pagetoid reticulosis, and granulomatous slack skin (both with a combined 1% prevalence). CTCL has an incidence of approximately 0.2–0.6 per 100 000 person-years, with MF being the most common subtype. MF is twice as common in male as in female patients. It is twice as common in those of Black ethnic background than in White and Asian ethnicities. Development of immunohistochemistry and polymerase chain reaction for the T-cell receptor gene in the 1980s improved the diagnosis of CTCL. However, diagnosis of MF remains challenging due to its heterogeneous presentation, often mimicking inflammatory dermatoses. Advanced diseases therapies have evolved from cytotoxic chemotherapy in the 1970s to novel monoclonal antibodies such as mogamulizumab, targeting proteins on T-cell lymphoma cells (CCR4). Reflection on the past two centuries from Alibert to mogamulizumab offers insight into the challenges that accompany the aetiology, diagnosis, classification and management of MF.
2024-06-28 | H03 (P068) A history of mycosis fungoides: from Alibert to mogamulizumab
Abstract In 1806, French physician Baron Jean-Louis Alibert treated a 56-year-old man with a desquamating rash and skin tumours. Alibert considered this to be a variant of yaws. In 1829 Alibert named the condition mycosis fungoides (MF), meaning ‘mushroom-like fungal disease’. Over 100 years later, French dermatologist Albert Sézary published papers from 1938 to 1949 detailing a mysterious disease that caused erythroderma and ‘cellules monstrueuses’, describing cutaneous ‘monster cells’. In 1961, these clinical findings were collated together into ‘Sézary syndrome’. Over this time there was widespread confusion between these conditions, fungal infections and yaws. In the 1870s English dermatologist William Tilbury Fox published a dermatology atlas detailing cases similar to what we know now as MF, with the name ‘fibroma fungoides’. The atlas described MF as a type of fungus, before giving a description of yaws and painting a clinical picture that differed from that of a lymphoma. In 1975, Pierre-Antoine-Ernest Bazin and associates in suggested the classification system and term we now recognize as cutaneous T-cell lymphoma (CTCL). Neoplastic cells have been thought to arise from chronic activation of T cells via antigen-presenting cells, yet the antigen to trigger this response remains unknown. Several potential bacterial, viral, fungal and iatrogenic causes have been studied, but no reliable triggers have been discovered. In 2018, the World Health Organization and European Organisation for Research and Treatment of Cancer officially recognized four types of MF. These are the classic Alibert–Bazin type (representing 88.6% of cases) and its three subtypes; folliculotropic MF (11.4%), Pagetoid reticulosis, and granulomatous slack skin (both with a combined 1% prevalence). CTCL has an incidence of approximately 0.2–0.6 per 100 000 person-years, with MF being the most common subtype. MF is twice as common in male as in female patients. It is twice as common in those of Black ethnic background than in White and Asian ethnicities. Development of immunohistochemistry and polymerase chain reaction for the T-cell receptor gene in the 1980s improved the diagnosis of CTCL. However, diagnosis of MF remains challenging due to its heterogeneous presentation, often mimicking inflammatory dermatoses. Advanced disease therapies have evolved from cytotoxic chemotherapy in the 1970s to novel monoclonal antibodies such as mogamulizumab, targeting proteins on T-cell lymphoma cells (CCR4). Reflection on the past two centuries from Alibert to mogamulizumab offers insight into the challenges that accompany the aetiology, diagnosis, classification and management of MF.
2024-02-12 | Clinical and Real-World Effectiveness of Mogamulizumab: A Narrative Review
Mogamulizumab (MOG) is an antibody targeting the CCR4 receptor, authorized for relapsed or refractory peripheral T-cell (PTCL) and cutaneous T-cell lymphomas (CTCL). Its adoption in guidelines and endorsement by FDA and EMA established it as a systemic treatment, especially for advanced disease stages due to its comparatively lower toxicity. Clinical trials and real-world evidence have underscored its efficacy in advanced CTCLs, including mycosis fungoides and Sézary syndrome; PTCLs; and adult T-cell leukemia/lymphoma (ATLL), showcasing positive outcomes. Notably, the drug has demonstrated significant response rates, disease stability, and extended periods of progression-free survival, suggesting its applicability in cases with multiple treatment lines. Its safety profile is generally manageable, with adverse events (AEs) primarily related to the skin, infusion-related reactions, drug eruptions, autoimmune diseases, and skin disorders. The latter seem to appear as CCR4 can promote the skin-specific homing of lymphocytes, and MOG is directed against this receptor. While combination with immunostimulatory agents like interferon alpha and interleukin 12 has shown promising results, caution is urged when combining with PD1 inhibitors due to the heightened risk of immune-mediated AEs. The introduction of MOG as a systemic treatment implies a significant advancement in managing these diseases, supported by its favorable safety profile and complementary mechanisms.
proteins
2023-10-30 | Use of Pegylated Interferon Alpha-2a in Cutaneous T-cell Lymphoma: A Retrospective Case Collection
Mycosis fungoides and Sézary syndrome are rare and largely incurable types of cutaneous T-cell lymphoma with limited therapeutic options. In 1984 Bunn et al. reported that interferon alpha is an efficient monotherapy in cutaneous T-cell lymphoma and 14 years later it was shown in a prospective, randomized trial that a combination of interferon alpha and psoralen plus ultraviolet A therapy (PUVA) is most efficient in the treatment of cutaneous T-cell lymphoma. Since then interferon alpha as single agent or, most often, in combination with phototherapy and/or retinoids has been integrated as standard of care in cutaneous T-cell lymphoma guidelines worldwide. However, production of interferon alpha was discontinued recently worldwide and pegylated interferon alpha-2a (PEG-IFNα) has been used as an alternative therapy. In contrast to numerous interferon alpha studies, only a few studies focusing on PEG-IFNα are available. Therefore, the aim of this study was to conduct a retrospective data collection to report on the efficacy, adverse events and therapy regimens of PEG-IFNα in cutaneous T-cell lymphoma. In 28 patients with cutaneous T-cell lymphoma treated in Germany and in the Netherlands, 36% of patients achieved complete remission, 36% partial remission and 29% stable disease. Eighteen percent of patients developed adverse events during therapy, which led to the discontinuation of PEG-IFNα therapy in 2 patients. The most common concomittant therapies were oral PUVA phototherapy and local radiotherapy. In conclusion, PEG-IFNα, especially in combination with skin-directed therapies, is an effective treatment option for cutaneous T-cell lymphoma in clinical practice.
2023-10-24 | What Is New in Cutaneous T Cell Lymphoma?
This review focuses on updates in prognosis, pathogenesis, and treatment of cutaneous T cell lymphoma (CTCL).Cohort studies indicate imaging may be necessary in early-stage CTCL. Risk factors for progression of CTCL have been identified. Interactions between malignant cells and the tumor microenvironment (TME) and the skin microbiome advance the understanding of pathogenesis and tumor cell dissemination. Studies support a hypothesis of circulating malignant tumor cells. MicroRNA (miR) influence tumor progression and prognosis; the IL22-STAT3-CCL20 cascade may be a novel target. IL-4, IL-5, and IL-31 cytokines are relevant for pruritus and could be targets for therapeutic interventions. Systemic therapies, such as JAK inhibitors, targeted antibodies, and checkpoint inhibitors, show promise in advanced stages. Allogenic hematopoietic stem cell transplantation provides a potential curative option for patients. Further investigations of prognosis and translational research are necessary to improve stratification of patients for treatment.
2022-07-01 | CD47/SIRPα axis: bridging innate and adaptive immunity
Myeloid immune cells are frequently present in the tumor environment, and although they can positively contribute to tumor control they often negatively impact anticancer immune responses. One way of inhibiting the positive contributions of myeloid cells is by signaling through the cluster of differentiation 47 (CD47)/signal regulatory protein alpha (SIRPα) axis. The SIRPα receptor is expressed on myeloid cells and is an inhibitory immune receptor that, upon binding to CD47 protein, delivers a ‘don’t eat me’ signal. As CD47 is often overexpressed on cancer cells, treatments targeting CD47/SIRPα have been under active investigation and are currently being tested in clinical settings. Interestingly, the CD47/SIRPα axis is also involved in T cell-mediated antitumor responses. In this perspective we provide an overview of recent studies showing how therapeutic blockade of the CD47/SIRPα axis improves the adaptive immune response. Furthermore, we discuss the interconnection between the myeloid CD47/SIRPα axis and adaptive T cell responses as well as the potential therapeutic role of the CD47/SIRPα axis in tumors with acquired resistance to the classic immunotherapy through major histocompatibility complex downregulation. Altogether this review provides a profound insight for the optimal exploitation of CD47/SIRPα immune checkpoint therapy.
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.
small molecules
2026-07-28 | Single-Cell Analysis Reclassifies Eczematous Mycosis Fungoides as Severe Atopic Dermatitis 2259810
Abstract Introduction Mycosis fungoides (MF), the prevalent subtype of cutaneous T-cell lymphoma (CTCL), primarily affects the skin and progresses systemically over time. Early-stage MF diagnosis relies on immunohistochemistry, T cell receptor (TCR) gene rearrangement testing, and clinical evaluation. However, in the clinic settings, we observe eczematous MF (eMF) patients who meet early-stage MF diagnostic criteria but exhibit phenotypes resembling atopic dermatitis (AD), and refractory to dupilumab. This study investigates the molecular characteristics of eMF in comparison to AD and classic MF, providing insights into its distinct pathophysiology and potential therapeutic implications. Methods Skin biopsies were collected from seven AD patients and eleven eMF patients. Paired single-cell RNA sequencing (scRNA-seq) and single-cell TCR sequencing (scTCR-seq) were conducted to evaluate transcriptional profiles and T-cell clonality. Publicly available MF and AD scRNA-seq data were used for comparative analysis. In addition, spatial transcriptomic profiling was performed to validate. Results Comparative transcriptomic analysis showed that the molecular profiles of T cells in eMF resembled those in AD rather than in conventional MF. Furthermore, in eMF, we observed oligoclonal T-cell expansions, which were not found in conventional MF both in scRNA-seq and spatial transcriptomic data. These expanded cells were predominantly Th22 cells, identified as the primary producers of IL-13, a key cytokine in AD pathophysiology. Conclusion eMF diagnostic phenotype resembles conventional MF, and AD primarily due to the hyperproliferation of Th22 cells and their expression of IL-13. In this context, this mechanism underscores the superior efficacy of Upadacitinib, which could target Th22 differentiation, over Dupilumab. As a result, our findings indicate that eMF is not cancer, but a Th22-mediated AD endotype. Funding Source n/a Topic Categories Immune Mechanisms of Human Disease (HUM)
2026-05-21 | Primary cutaneous lymphomas in children: a single-center retrospective analysis and narrative review of the literature.
Primary cutaneous lymphomas (PCLs) are uncommon in children, with mycosis fungoides (MF), lymphomatoid papulosis (LyP), and primary cutaneous small/medium CD4+ T-cell lymphoproliferative disorder (PCSM-TCLPD) representing the most frequent entities. Due to their rarity, available data derive mainly from case reports and small series, and diagnostic delays are frequent. This study aimed to describe the clinical, histopathological, and therapeutic features of pediatric PCLs in a single Italian referral centre and compare them with the literature evidence. We conducted a single-center, retrospective observational study including patients aged ≤16 years with a histologically confirmed diagnosis of PCLs, followed for at least six months at the Dermatology Unit of the University Hospital of Bologna between 2002 and 2024. Clinical, histological, therapeutic, and follow-up data were collected and analyzed. Among 354 PCL patients, 10 pediatric cases were identified: six MF, three LyP, and one PCSM-TCLPD. The mean age at diagnosis was 9.1 years. MF cases were mostly early-stage (IA, 5/6), with folliculotropic (67%), hypopigmented (50%), and classic (50%) variants; all were treated with topical corticosteroids and/or PUVA, with good long-term outcomes (67% complete remission). LyP patients presented at younger ages (mean 5.7 years) with type A (N.=2) and D (N.=1) subtypes; all achieved complete remission despite recurrences, one requiring methotrexate. The single PCSM-TCLPD case was cured with surgical excision. After a mean follow-up of 8.2 years, all patients were alive, most disease-free. Pediatric PCLs are rare but generally indolent, with an excellent prognosis. However, their clinical heterogeneity and diagnostic delay highlight the importance of early biopsy, integrated clinicopathological assessment, and long-term follow-up. Multicenter studies are needed to establish tailored treatment algorithms for children.
2025-12-24 | Central Nervous System Progression in Folliculotropic Mycosis Fungoides.
Central nervous system (CNS) involvement by cutaneous T-cell lymphomas (CTCL) is exceptionally rare and is associated with a poor prognosis. Folliculotropic mycosis fungoides (FMF) is a rare subtype of CTCL and often has more aggressive clinical behavior compared to classic MF. The risk factors for CNS progression in patients with primary CTCL are not well understood. We present the case of a 75-year-old male with a history of Stage IA FMF, who developed progressive neurologic and functional decline over six months. Workup revealed marked eosinophilia, and CSF analysis showed monoclonal T-cell population with positive T-cell receptor (TCR) gene rearrangement. Flow cytometry further showed an atypical CD4+ T-cell population with loss of CD7, consistent with the immunophenotype of patient's cutaneous MF, supporting secondary CNS involvement. An MRI of the brain showed T2 hyperintensity in the pons and right middle cerebellar peduncle, with low signal intensity throughout the bone marrow of the skull, concerning for CNS progression of FMF. The patient was started on high-dose steroids, which led to improvement in eosinophilia. Due to transaminitis, high-dose methotrexate therapy was deferred, and the patient was initiated on intrathecal (IT) chemotherapy with methotrexate and cytarabine. Following five cycles of IT chemotherapy, the patient's neurologic status significantly improved, and CSF analysis showed resolution of the atypical T-cell population. This case highlights the rare occurrence of CNS progression of FMF, even in the absence of lymphatic involvement and with well-controlled skin manifestations, and underscores the role of IT chemotherapy in managing this complication.
2025-09-26 | PAI-1 in Skin Malignancies: a Central Regulator of Tumor Progression and Therapeutic Resistance.
Plasminogen activator inhibitor-1 (PAI-1) plays a multifaceted and central role in the tumor biology of various skin malignancies. Beyond its classical function in fibrinolysis, PAI-1 contributes to tumor progression by promoting immunosuppression, angiogenesis, cellular senescence, and tissue remodeling. Its expression is particularly elevated in aggressive disease stages across cutaneous melanoma, cutaneous squamous cell carcinoma (cSCC), cutaneous angiosarcoma (CAS), and mycosis fungoides (MF), and is associated with poor clinical outcomes. The ability of PAI-1 to induce senescence-associated secretory phenotype (SASP), modulate PD-L1 expression, and recruit tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) suggests a key role in shaping the immunosuppressive tumor microenvironment (TME). This positions PAI-1 as both a potential biomarker for disease progression and a therapeutic target for restoring immune responsiveness, especially in tumors resistant to immune checkpoint inhibitors (ICIs). The PAI-1 inhibitor TM5614 has demonstrated promising activity in early clinical studies, particularly in anti-PD-1-refractory melanoma, and is currently under evaluation in multiple Phase II and III trials. Future strategies should focus on patient stratification using biomarkers such as SASP factors and PAI-1 levels, as well as rational combination therapies targeting interconnected pathways like IL-17/IL-23, AhR, and senescence signaling. Overall, PAI-1 inhibition offers a novel and mechanistically grounded approach to improve outcomes in skin cancers characterized by therapy resistance and an immunosuppressive microenvironment.
2025-06-16 | Classical and biological treatments in mycosis fungoides/Sézary syndrome. New horizons in oncodermatology.
In the strategic management of mycosis fungoides (MF)/Sézary syndrome (SS), an interdisciplinary framework is essential. The regimen typically encompasses dermatological-specific interventions, biologic response modulators, and, in advanced scenarios, systemic chemotherapeutic entities. This might integrate biologic response agents like bexarotene, histone deacetylase inhibitors such as romidepsin, and specialized monoclonal antibodies or conjugates, notably mogamulizumab and brentuximab vedotin. Decisions in therapeutic avenues are intricately individualized, considering determinants like patient age, functional health metrics, disease scope, evolutionary trajectory and previous therapeutic exposures. The high-frequency ultrasound seems to be a useful tool for monitoring infiltration of the skin. Moreover, ongoing studies are investigating novel therapeutic agents that may demonstrate efficacy in MF/SS.
oligonucleotides
2023-03-30 | Data from Inhibition of Constitutively Activated Nuclear Factor-κB Induces Reactive Oxygen Species- and Iron-Dependent Cell Death in Cutaneous T-Cell Lymphoma
<div>Abstract<p>Aberrant signaling of the nuclear facotr (NF-κB) pathway has been identified as a mediator of survival and apoptosis resistance in leukemias and lymphomas. Here, we report that cell death of cutaneous T-cell lymphoma cell lines induced by inhibition of the NF-κB pathway is independent of caspases or classic death receptors. We found that free intracellular iron and reactive oxygen species (ROS) are the main mediators of this cell death. Antioxidants such as <i>N</i>-Acetyl-l-cysteine and glutathione or the iron chelator desferrioxamine effectively block cell death in cutaneous T-cell lymphoma cell lines or primary T cells from Sézary patients. We show that inhibition of constitutively active NF-κB causes down-regulation of ferritin heavy chain (FHC) that leads to an increase of free intracellular iron, which, in turn, induces massive generation of ROS. Furthermore, direct down-regulation of FHC by siRNA caused a ROS-dependent cell death. Finally, high concentrations of ROS induce cell death of malignant T cells. In contrast, T cells isolated from healthy donors do not display down-regulation of FHC and, therefore, do not show an increase in iron and cell death upon NF-κB inhibition. In addition, in a murine T-cell lymphoma model, we show that inhibition of NF-κB and subsequent down-regulation of FHC significantly delays tumor growth <i>in vivo</i>. Thus, our results promote FHC as a potential target for effective therapy in lymphomas with aberrant NF-κB signaling. [Cancer Res 2009;69(6):2365–74]</p></div>
2019-01-22 | miRNA‑135a regulates Hut78 cell proliferation via the GATA‑3/TOX signaling pathway
The present study investigated the role of microRNA‑135a (miR‑135a) in cutaneous T‑cell lymphoma (CTCL) proliferation. Compared with the normal T lymphocyte control cell line, the mRNA and protein levels of GATA binding protein 3 (GATA‑3) were markedly increased in the Hut78 cell line and miR‑135a was markedly decreased (P<0.05). Based on bioinformatics, the target gene of miR‑135a was identified as GATA‑3. Dual luciferase and pre‑miR‑135a assays showed that miR‑135a regulated the translation of GATA‑3. In addition, the overexpression of miR‑135a mimics decreased the protein levels of GATA‑3 and thymocyte selection‑associated high mobility group box (TOX). The substantially increased mRNA and protein levels of GATA‑3 may be associated with the downregulation of miR‑135a, leading to T‑cell deregulation and proliferation through GATA‑3/TOX regulation and subsequently causing CTCL.
2012-01-03 | miR-122 Regulates p53/Akt Signalling and the Chemotherapy-Induced Apoptosis in Cutaneous T-Cell Lymphoma
Advanced cutaneous T-cell lymphoma (CTCL) is resistant to chemotherapy and presents a major area of medical need. In view of the known role of microRNAs (miRNAs) in the regulation of cellular signalling, we aimed to identify the functionally important miRNA species, which regulate apoptosis in CTCL. Using a recently established model in which apoptosis of CTCL cell lines is induced by Notch-1 inhibition by γ-secretase inhibitors (GSIs), we found that miR-122 was significantly increased in the apoptotic cells. miR-122 up-regulation was not specific for GSI-1 but was also seen during apoptosis induced by chemotherapies including doxorubicin and proteasome blockers (bortezomib, MG132). miR-122 was not expressed in quiescent T-cells, but was detectable in CTCL: in lesional skin in mycosis fungoides and in Sézary cells purified from peripheral blood. In situ hybridization results showed that miR-122 was expressed in the malignant T-cell infiltrate and increased in the advanced stage mycosis fungoides. Surprisingly, miR-122 overexpression decreased the sensitivity to the chemotherapy-induced apoptosis via a signaling circuit involving the activation of Akt and inhibition of p53. We have also shown that induction of miR-122 occurred via p53 and that p53 post-transcriptionally up-regulated miR-122. miR-122 is thus an amplifier of the antiapoptotic Akt/p53 circuit and it is conceivable that a pharmacological intervention in this pathway may provide basis for novel therapies for CTCL.
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2026-02-06 | A historical review of mycosis fungoides: from Alibert to mogamulizumab.
In 1806, French physician Baron Jean-Louis Alibert saw a man with a desquamating rash and skin tumours. Alibert considered this to be a variant of yaws. In 1829 Alibert named the condition mycosis fungoides (MF), meaning 'mushroom-like fungal disease'. Over 100 years later, French dermatologist Albert Sézary published papers from 1938 to 1949 detailing a mysterious disease containing 'cellules monstrueuses', describing cutaneous 'monster cells'. In 1961, these clinical findings were collated together into 'Sézary syndrome'. In the 1870s English dermatologist William Tilbury Fox published a dermatology atlas detailing cases similar to what we know now as MF, with the name 'fibroma fungoides'. The atlas described MF as a type of fungus, before giving a description of yaws and painting a clinical picture that differed from that of a lymphoma. Over the twentieth century, our understandings of the origins of MF were changing and by 1975 the classification system and term we now recognize as cutaneous T-cell lymphoma (CTCL) was developed. Neoplastic cells have been thought to arise from chronic activation of T cells via antigen-presenting cells due to inappropriate cytokines and C-C chemokine receptors. In 2018, the World Health Organization and European Organisation for Research and Treatment of Cancer officially recognized four variants of MF. These are the classic Alibert-Bazin variant and its three variants: folliculotropic MF, pagetoid reticulosis and granulomatous slack skin. Developments in immunohistochemistry for the T-cell receptor gene in the 1990s improved the diagnosis of CTCL; however, diagnosis is still challenging. Advanced MF therapies have evolved from cytotoxic chemotherapy to novel monoclonal antibodies such as mogamulizumab, targeting proteins on T-cell lymphoma cells.
2024-08-02 | Urticarial mycosis fungoides: A distinctive presentation with blood involvement and a peculiar immunophenotype.
Mycosis fungoides (MF) has been widely reported to mimick a considerable number of different dermatoses, including scarring alopecia, bullous dermatoses or cysts, and comedones. In atypical presentations, histopathology is essential for the diagnosis. We present two cases of MF with clinical urticarial lesions and a striking blood involvement that responded to mogamulizumab treatment. Histopathologically, both cases had classic MF features and shared a peculiar immunophenotype, with positivity for CD25 and FOXP3. Differential diagnoses included urticarial lymphomatoid drug reactions and other lymphomas, like T-cell prolymphocytic leukemia, atypical Sézary syndrome, or adult T-cell lymphocytic leukemia. A low suspicion threshold is necessary for the diagnosis of atypical presentations of MF.
2024-06-28 | P068 A history of mycosis fungoides: from Alibert to mogamulizumab
Abstract In 1806, French physician Baron Jean-Louis Alibert treated a 56-year-old man with a desquamating rash and skin tumours. Alibert considered this to be a variant of yaws. In 1829 Alibert named the condition mycosis fungoides (MF), meaning ‘mushroom-like fungal disease’. Over 100 years later, French dermatologist Albert Sézary published papers from 1938 to 1949 detailing a mysterious disease that caused erythroderma and ‘cellules monstrueuses’, describing cutaneous ‘monster cells’. In 1961, these clinical findings were collated together into ‘Sézary syndrome’. There was widespread confusion between these conditions, i.e. fungal infections and yaws. In the 1870s English dermatologist William Tilbury Fox published a dermatology atlas detailing cases similar to what we know now as MF, with the name ‘fibroma fungoides’. The atlas described MF as a type of fungus, before giving a description of yaws and painting a clinical picture that differed from that of a lymphoma. In 1975, Pierre-Antoine-Ernest Bazin and associates suggested the classification system and term we now recognize as cutaneous T-cell lymphoma (CTCL). Neoplastic cells have been thought to arise from chronic activation of T cells via antigen-presenting cells, yet the antigen to trigger this response remains unknown. Several potential bacterial, viral, fungal and iatrogenic causes have been studied, but no reliable triggers have been discovered. In 2018, the World Health Organization and European Organisation for Research and Treatment of Cancer officially recognized four types of MF. These are the classic Alibert–Bazin type (representing 88.6% of cases) and its three subtypes; folliculotropic MF (11.4%), Pagetoid reticulosis, and granulomatous slack skin (both with a combined 1% prevalence). CTCL has an incidence of approximately 0.2–0.6 per 100 000 person-years, with MF being the most common subtype. MF is twice as common in male as in female patients. It is twice as common in those of Black ethnic background than in White and Asian ethnicities. Development of immunohistochemistry and polymerase chain reaction for the T-cell receptor gene in the 1980s improved the diagnosis of CTCL. However, diagnosis of MF remains challenging due to its heterogeneous presentation, often mimicking inflammatory dermatoses. Advanced diseases therapies have evolved from cytotoxic chemotherapy in the 1970s to novel monoclonal antibodies such as mogamulizumab, targeting proteins on T-cell lymphoma cells (CCR4). Reflection on the past two centuries from Alibert to mogamulizumab offers insight into the challenges that accompany the aetiology, diagnosis, classification and management of MF.
2024-06-28 | H03 (P068) A history of mycosis fungoides: from Alibert to mogamulizumab
Abstract In 1806, French physician Baron Jean-Louis Alibert treated a 56-year-old man with a desquamating rash and skin tumours. Alibert considered this to be a variant of yaws. In 1829 Alibert named the condition mycosis fungoides (MF), meaning ‘mushroom-like fungal disease’. Over 100 years later, French dermatologist Albert Sézary published papers from 1938 to 1949 detailing a mysterious disease that caused erythroderma and ‘cellules monstrueuses’, describing cutaneous ‘monster cells’. In 1961, these clinical findings were collated together into ‘Sézary syndrome’. Over this time there was widespread confusion between these conditions, fungal infections and yaws. In the 1870s English dermatologist William Tilbury Fox published a dermatology atlas detailing cases similar to what we know now as MF, with the name ‘fibroma fungoides’. The atlas described MF as a type of fungus, before giving a description of yaws and painting a clinical picture that differed from that of a lymphoma. In 1975, Pierre-Antoine-Ernest Bazin and associates in suggested the classification system and term we now recognize as cutaneous T-cell lymphoma (CTCL). Neoplastic cells have been thought to arise from chronic activation of T cells via antigen-presenting cells, yet the antigen to trigger this response remains unknown. Several potential bacterial, viral, fungal and iatrogenic causes have been studied, but no reliable triggers have been discovered. In 2018, the World Health Organization and European Organisation for Research and Treatment of Cancer officially recognized four types of MF. These are the classic Alibert–Bazin type (representing 88.6% of cases) and its three subtypes; folliculotropic MF (11.4%), Pagetoid reticulosis, and granulomatous slack skin (both with a combined 1% prevalence). CTCL has an incidence of approximately 0.2–0.6 per 100 000 person-years, with MF being the most common subtype. MF is twice as common in male as in female patients. It is twice as common in those of Black ethnic background than in White and Asian ethnicities. Development of immunohistochemistry and polymerase chain reaction for the T-cell receptor gene in the 1980s improved the diagnosis of CTCL. However, diagnosis of MF remains challenging due to its heterogeneous presentation, often mimicking inflammatory dermatoses. Advanced disease therapies have evolved from cytotoxic chemotherapy in the 1970s to novel monoclonal antibodies such as mogamulizumab, targeting proteins on T-cell lymphoma cells (CCR4). Reflection on the past two centuries from Alibert to mogamulizumab offers insight into the challenges that accompany the aetiology, diagnosis, classification and management of MF.
2024-02-12 | Clinical and Real-World Effectiveness of Mogamulizumab: A Narrative Review
Mogamulizumab (MOG) is an antibody targeting the CCR4 receptor, authorized for relapsed or refractory peripheral T-cell (PTCL) and cutaneous T-cell lymphomas (CTCL). Its adoption in guidelines and endorsement by FDA and EMA established it as a systemic treatment, especially for advanced disease stages due to its comparatively lower toxicity. Clinical trials and real-world evidence have underscored its efficacy in advanced CTCLs, including mycosis fungoides and Sézary syndrome; PTCLs; and adult T-cell leukemia/lymphoma (ATLL), showcasing positive outcomes. Notably, the drug has demonstrated significant response rates, disease stability, and extended periods of progression-free survival, suggesting its applicability in cases with multiple treatment lines. Its safety profile is generally manageable, with adverse events (AEs) primarily related to the skin, infusion-related reactions, drug eruptions, autoimmune diseases, and skin disorders. The latter seem to appear as CCR4 can promote the skin-specific homing of lymphocytes, and MOG is directed against this receptor. While combination with immunostimulatory agents like interferon alpha and interleukin 12 has shown promising results, caution is urged when combining with PD1 inhibitors due to the heightened risk of immune-mediated AEs. The introduction of MOG as a systemic treatment implies a significant advancement in managing these diseases, supported by its favorable safety profile and complementary mechanisms.
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2023-10-30 | Use of Pegylated Interferon Alpha-2a in Cutaneous T-cell Lymphoma: A Retrospective Case Collection
Mycosis fungoides and Sézary syndrome are rare and largely incurable types of cutaneous T-cell lymphoma with limited therapeutic options. In 1984 Bunn et al. reported that interferon alpha is an efficient monotherapy in cutaneous T-cell lymphoma and 14 years later it was shown in a prospective, randomized trial that a combination of interferon alpha and psoralen plus ultraviolet A therapy (PUVA) is most efficient in the treatment of cutaneous T-cell lymphoma. Since then interferon alpha as single agent or, most often, in combination with phototherapy and/or retinoids has been integrated as standard of care in cutaneous T-cell lymphoma guidelines worldwide. However, production of interferon alpha was discontinued recently worldwide and pegylated interferon alpha-2a (PEG-IFNα) has been used as an alternative therapy. In contrast to numerous interferon alpha studies, only a few studies focusing on PEG-IFNα are available. Therefore, the aim of this study was to conduct a retrospective data collection to report on the efficacy, adverse events and therapy regimens of PEG-IFNα in cutaneous T-cell lymphoma. In 28 patients with cutaneous T-cell lymphoma treated in Germany and in the Netherlands, 36% of patients achieved complete remission, 36% partial remission and 29% stable disease. Eighteen percent of patients developed adverse events during therapy, which led to the discontinuation of PEG-IFNα therapy in 2 patients. The most common concomittant therapies were oral PUVA phototherapy and local radiotherapy. In conclusion, PEG-IFNα, especially in combination with skin-directed therapies, is an effective treatment option for cutaneous T-cell lymphoma in clinical practice.
2023-10-24 | What Is New in Cutaneous T Cell Lymphoma?
This review focuses on updates in prognosis, pathogenesis, and treatment of cutaneous T cell lymphoma (CTCL).Cohort studies indicate imaging may be necessary in early-stage CTCL. Risk factors for progression of CTCL have been identified. Interactions between malignant cells and the tumor microenvironment (TME) and the skin microbiome advance the understanding of pathogenesis and tumor cell dissemination. Studies support a hypothesis of circulating malignant tumor cells. MicroRNA (miR) influence tumor progression and prognosis; the IL22-STAT3-CCL20 cascade may be a novel target. IL-4, IL-5, and IL-31 cytokines are relevant for pruritus and could be targets for therapeutic interventions. Systemic therapies, such as JAK inhibitors, targeted antibodies, and checkpoint inhibitors, show promise in advanced stages. Allogenic hematopoietic stem cell transplantation provides a potential curative option for patients. Further investigations of prognosis and translational research are necessary to improve stratification of patients for treatment.
2022-07-01 | CD47/SIRPα axis: bridging innate and adaptive immunity
Myeloid immune cells are frequently present in the tumor environment, and although they can positively contribute to tumor control they often negatively impact anticancer immune responses. One way of inhibiting the positive contributions of myeloid cells is by signaling through the cluster of differentiation 47 (CD47)/signal regulatory protein alpha (SIRPα) axis. The SIRPα receptor is expressed on myeloid cells and is an inhibitory immune receptor that, upon binding to CD47 protein, delivers a ‘don’t eat me’ signal. As CD47 is often overexpressed on cancer cells, treatments targeting CD47/SIRPα have been under active investigation and are currently being tested in clinical settings. Interestingly, the CD47/SIRPα axis is also involved in T cell-mediated antitumor responses. In this perspective we provide an overview of recent studies showing how therapeutic blockade of the CD47/SIRPα axis improves the adaptive immune response. Furthermore, we discuss the interconnection between the myeloid CD47/SIRPα axis and adaptive T cell responses as well as the potential therapeutic role of the CD47/SIRPα axis in tumors with acquired resistance to the classic immunotherapy through major histocompatibility complex downregulation. Altogether this review provides a profound insight for the optimal exploitation of CD47/SIRPα immune checkpoint therapy.
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.
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Drug Discovery Landscape
7 orphan drug designations for Classic mycosis fungoides, including 2 approved therapies.
7 orphan drug designations for Classic mycosis fungoides, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
priliximab | antibodies | FDA | 2017-09-18 | — | Onco Therapies, Inc. |
MRG-106 oligonucleotide inhibitor of microRNA miR-155-5p | oligonucleotides | FDA | 2017-03-30 | — | miRagen Therapeutics, Inc. |
brentuximab vedotin [Adcetris] | antibodies | FDA | 2012-11-19 | 2017-11-09 | Seagen Inc. |
naloxone | small molecules | FDA | 2010-11-23 | — | Elorac, Inc. |
meclorethamine [Valchlor] | small molecules | FDA | 2004-08-17 | 2013-08-23 | Helsinn Birex Pharmaceuticals Ltd. |
human anti-CD4 monoclonal antibody | antibodies | FDA | 2004-08-13 | — | Emergent Product Development Seattle, LLC |
Methotrexate with laurocapram | small molecules | FDA | 1990-10-15 | — | Echo Therapeutics, Ltd. |
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