RARE DISEASE
Cutaneous neuroendocrine carcinoma
Cutaneous neuroendocrine carcinoma
Cutaneous neuroendocrine carcinoma
Synonyms: MCC, Merkel cell carcinoma
Synonyms: MCC, Merkel cell carcinoma
Synonyms: MCC, Merkel cell carcinoma
Drug discovery
15
drugs
With orphan designations
Overview
Cutaneous neuroendocrine carcinoma (CNEC), primarily Merkel cell carcinoma (MCC), is a rare, aggressive malignancy arising from neuroendocrine cells in sun-exposed skin. It presents as rapidly growing, painless nodules, often in elderly or immunocompromised individuals. Diagnosis requires biopsy and immunohistochemistry (CK20+/TTF-1– in most cases). Prognosis remains poor due to high recurrence and metastatic rates, with staging (tumor size, nodal/distant spread) being the strongest survival predictor [1][2][12].
Therapies
Localized disease: Wide excision ± adjuvant radiation (reduces recurrence) [8][14]
Advanced/metastatic: Immune checkpoint inhibitors (avelumab, pembrolizumab) as first-line systemic therapy; chemotherapy (carboplatin/etoposide) reserved for refractory cases [8][18][13]
Emerging options: Targeted therapies (VEGF inhibitors), peptide receptor radionuclide therapy (PRRT) [8][13][18]
Categories: rare endocrine diseases, rare neoplastic diseases, rare skin diseases
Research Papers
1,683 drug discovery papers about Cutaneous neuroendocrine carcinoma, with 4 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,683 drug discovery papers about Cutaneous neuroendocrine carcinoma, with 4 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-27 | Anatomical lymphatic drainage basin and sentinel lymph node positivity in Merkel cell carcinoma: a 37-year single-center cohort study of 400 patients.
Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous neuroendocrine malignancy with increasing incidence due to UV exposure and improved diagnostics. It spreads rapidly via lymphatics and has high mortality, surpassing melanoma in lethality. Management includes surgical excision, sentinel lymph node biopsy (SLNB), radiotherapy, and immunotherapy. SLNB is an established staging tool for detecting occult nodal metastases; however, the influence of anatomical drainage basin location on SLNB positivity and the role of completion lymph node dissection (CLND) remain incompletely understood. This study evaluated patterns of nodal involvement according to drainage basin location and assessed the diagnostic yield of CLND in a large single-center MCC cohort. A retrospective analysis was performed of 400 patients with MCC treated at a tertiary referral center between 1986 and 2023. SLNB positivity rates were compared across cervical, axillary, and inguinal drainage basins. Associations between anatomical location and nodal involvement were assessed using univariable and multivariable logistic regression models. Adjusted analyses included year of diagnosis, lymphovascular invasion and immunosuppression status, with Firth's penalized regression applied where appropriate. Among 400 patients, 244 underwent SLNB, of whom 71 (29.1%) had at least one positive SLN. In univariable analysis, inguinal SLNB was associated with higher odds of positivity compared with axillary SLNB (OR 3.31, 95% CI 1.49-7.35; p = 0.003) and cervical SLNB (OR 2.10, 95% CI 1.04-4.24; p = 0.040). After adjustment for lymphovascular invasion, immunosuppression, and year of diagnosis, inguinal drainage remained associated with SLNB positivity compared with axillary drainage (OR 3.08; 95% CI 1.36-6.98; p = 0.007). Lymphovascular invasion (OR 3.29; 95% CI 1.66-6.54; p = 0.001) and immunosuppression (OR 2.38; 95% CI 1.12-5.06; p = 0.025) were also associated with SLNB positivity in the adjusted model. SLNB remains a valuable staging procedure in MCC, identifying occult nodal disease in nearly one-third of patients. Inguinal drainage basin remained associated with SLNB positivity after adjustment for clinicopathological factors. These findings may help inform clinical decision-making regarding nodal staging in patients with MCC. The substantial rate of additional nodal involvement detected by CLND supports its continued role as a staging procedure in selected patients with MCC. As this study focuses on lymphatic dissemination assessed by SLNB and lymph node dissection (LND), no conclusions can be drawn regarding hematogenous metastatic spread.
2026-08-19 | Lineage plasticity in Merkel cell carcinoma
Merkel cell carcinoma (MCC) is a rare and highly aggressive skin cancer characterized by neuroendocrine features. Efforts to define the cell of origin have remained inconclusive, largely because MCC displays overlapping epithelial, neuroendocrine, and immune-associated differentiation programs. Moreover, MCC carcinogenesis is either due to UV mutagenesis or the clonal integration of the Merkel cell polyomavirus (MCPyV). Increasing evidence, however, suggests that MCC is best understood as a lineage-plastic cancer in which cellular identity is dynamically regulated rather than irreversibly fixed. In this thesis focusing on virus-positive MCC, we investigate the mechanisms underlying lineage plasticity, and examine how both intrinsic oncogenic pathways and extrinsic environmental cues shape tumor cell states, immune interactions, and therapeutic responses. MCPyV-encoded T antigens play a central role in maintaining a stem-like, poorly differentiated cell state, extending beyond their canonical function in cell-cycle control. The suppression of T antigens leads to coordinated downregulation of E2F-driven transcriptional programs associated with cell-cycle progression and stemness, accompanied by a metabolic shift from glycolysis toward mitochondrial oxidative phosphorylation. Concomitant with the loss of stem-like features, MCC cells activate neurogenesis-associated transcriptional programs and display enhanced neural differentiation, uncovering latent differentiation pathways that are actively repressed in the presence of T antigens. In parallel, we show that pharmacological inhibition of the epigenetic co-activators CBP/p300 phenocopies T-antigen loss, including repression of stemness-associated gene networks and induction of neurogenesis-related pathways. These findings identify CBP/p300-mediated epigenetic maintenance of lineage identity as a critical vulnerability in MCC. Collectively, this work establishes that stemness and neuroendocrine features in MCC are actively enforced by oncogenic and epigenetic mechanisms. Beyond tumor-intrinsic regulation, we demonstrate that environmental cues exert a profound influence on MCC cell identity. Close vicinity to normal keratinocytes by localization of MCC cells within the epidermal niche promotes epithelial differentiation programs, indicating that local tissue context can partially override oncogenic signaling and redirect tumor cell fate. This observation highlights the capacity for context-dependent lineage reprogramming in MCC. In line with this notion, the immune microenvironment, e.g. the cellular neighborhood of MCC cells with tertiary lymphoid structures (TLS) also acts as a regulator of tumor cell state. MCC cells in close proximity to TLS exhibit sustained activation of interferon-responsive pathways, upregulation of antigen processing and presentation machinery, and increased expression of apoptosis-associated genes. These findings suggest that TLS constrain immune-evasive plasticity and stabilize immunogenic tumor phenotypes, thereby supporting durable responses to immune checkpoint blockade. Overall, this work reframes MCC as a malignancy defined by dynamic lineage plasticity governed by oncogenic, epigenetic, and immune-mediated forces. A deeper understanding of these plastic states, and their therapeutic targeting, offers new opportunities to treat MCC patients.
2026-08-07 | Clinical Reasoning: A 79-Year-Old Man With Subacute Onset Involuntary Facial Movements and Discoordination.
A 79-year-old man with metastatic Merkel cell carcinoma undergoing cancer-directed treatment was admitted to the hospital with 1 week of bilateral upper and lower extremity tremor and nearly continuous involuntary facial movements. These abnormal movements of his face, head, and limbs were exacerbated by purposeful movement. Examination revealed dysarthria with tremulous speech, intention tremors of the head and all extremities, distally diminished vibration sense with hyporeflexia, bilateral upper extremity dysdiadochokinesis, bilateral lower extremity dysmetria on heel-to-shin testing, and truncal ataxia. MRI of the brain showed no acute abnormalities. CSF and serum testing showed evidence of CNS inflammation with a CSF lymphocytic pleocytosis and elevated total protein. Diagnosis was ultimately made using serum and CSF studies. Here, we discuss the differential diagnosis of 2 weeks of diffuse intention tremor, involuntary facial movements, and ataxia. We discuss the workup, diagnosis, acute and nonacute management of this condition, as well as important clinical points regarding the broader category into which this diagnosis falls.
2026-07-28 | The Nicotinic Acetylcholine Receptor-Macrophage Axis in Merkel Cell Carcinoma: Evidence, Limitations, and Therapeutic Hypotheses.
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin malignancy characterized by high mortality and a rising incidence. Although immune checkpoint inhibitors have significantly improved patient outcomes, many patients exhibit primary or acquired resistance, frequently in the setting of an immunosuppressive tumor microenvironment (TME) enriched for myeloid populations. This review synthesizes current evidence and proposes a testable model in which nicotinic acetylcholine receptor (nAChR) signaling may intersect with tumor-associated macrophage (TAM) biology to reinforce immune exclusion in MCC. Direct MCC-specific evidence currently supports nAChR-subunit expression in tumor tissues and the association of CD163+/CD14+/S100A8+ myeloid populations with resistance to PD-1 pathway blockade; however, functional nAChR signaling in MCC tumor cells, TAMs, or dendritic cells has not yet been demonstrated. We therefore distinguish established MCC observations from mechanistic hypotheses extrapolated from macrophage biology, cholinergic anti-inflammatory signaling, and other cancer models. Within this framework, α7-nAChR signaling on TAMs may activate the cholinergic anti-inflammatory pathway and favor suppressive myeloid states, whereas α3- and α5-containing receptors detected in MCC tumor cells may represent tumor-cell-associated candidates for future mechanistic testing. By integrating evidence on TAM plasticity, spatial immune exclusion, and cholinergic signaling, we propose that the nAChR-macrophage axis is a rational but unproven therapeutic hypothesis that warrants systematic validation in MCC models.
2026-07-20 | Merkel cell carcinoma in a patient on ruxolitinib treatment for polycythemia vera
Merkel cell carcinoma (MCC) is a rare aggressive neuroendocrine skin cancer derived from Merkel cells located in the basal layer of the epidermis and follicular epithelium. MCC predominantly affects elderly patients, particularly white males, and results from a combination of risk factors including genetic, molecular, age-related-immune decline, and environmental factors.1 Long-term ultraviolet radiation is a key risk factor for MCC, particularly for tumors arising on sun-exposed areas such as the head and neck, although less advanced lesions at diagnosis are more often seen on the limbs.
proteins
2026-09-26 | Lanreotide, a Somatostatin Analogue, in Advanced Merkel Cell Carcinoma: A Prospective Single-Arm Phase II Study.
Merkel Cell Carcinoma (MCC) is a rare, aggressive neuroendocrine and epithelial skin cancer. Somatostatin analogues, such as lanreotide, have shown efficacy in managing other neuroendocrine tumors. Retrospective studies suggest that lanreotide may induce partial response or disease stabilization in patients with advanced MCC. To test this hypothesis, we conducted a Phase II, non-randomized, open trial investigating lanreotide in MCC patients with advanced disease (ClinicalTrials.gov identifier: NCT02351128). Patients with Stage IIIB-IV MCC received lanreotide monotherapy (120 mg every 28 days) at any line of systemic therapy, until disease progression or unacceptable toxicity. The primary endpoint was disease control rate (DCR) (defined as the proportion of patients with complete response, partial response, and stable disease) at 3 months. Secondary endpoints included progression-free survival (PFS), overall survival (OS), somatostatin receptor (SSTR) tumor expression, and treatment safety. Between April, 2015, and November, 2016, 35 patients received lanreotide, with 12 evaluable at 3 months. The DCR at 3 months was 33.3% (4) among evaluable patients (all with stable disease) and 11.4% for the full cohort. Statistical analyses showed no significant difference from the expected 20% response rate (p = 0.205 for intention-to-treat; p = 0.939 for per-protocol). Kaplan-Meier analysis revealed median OS and PFS of 3.1 months (95% CI, 2-5.5) and 3.5 months (95% CI, 2.3-5.5), respectively. SSTR tumor expression did not correlate with treatment response. Although limited by its implementation before the era of immunotherapy, this non-randomized study shows the limited effectiveness of lanreotide as monotherapy in treating patients with advanced MCC. Identifier: NCT02351128.
2026-02-03 | Giant Merkel cell carcinoma of the scalp
None declared. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
2025-09-03 | Impact of UV Exposure and Incidence of Merkel Cell Carcinoma Between 1990 and 2018 in Austria
Background: To describe i) patients´ demographic, ii) Austrian UV-data and iii) to analyze a possible relationship between UV exposure and onset of disease in Austria between 1990 and 2018. Methods: We included all patients with MCC diagnosed and clinical and demographic data to compare to UV radiation. Results: A total of 538 cases were identified and the incidence (per 100.000/y) increased from 0.04 to 3.45. The MCC incidence was significantly higher in West- (mean incidence 0.269 ± 0.04) compared to East-Austria (0.180 ± 0.02 p=0.005). Notably, the mean and maximum UV radiation values were higher in the Western (p< 0.001) compared to the Eastern part of Austria. The sum (p=0.033; r: 0.503) and mean (p=0.019; r: 0.546) UV values correlated significantly to the MCC incidence. Conclusions: MCC incidence increased significantly and a higher UV radiation in West- compared to East-Austria that subsequently resulted in a higher MCC incidence could be determined.
2025-08-22 | Atypical presentation of Merkel cell carcinoma with pulmonary embolism.
Merkel cell carcinoma (MCC) is a rare aggressive neuroendocrine malignancy that typically presents in the skin and rapidly progresses to other body parts. MCC is typically found in sun-exposed areas, mainly the head and neck region as well as the upper limbs and shoulders. It typically affects fair-skinned elderly males. In this report, we present an unusual MCC case of a 48-year-old Caucasian male with an initial presentation of a massive pulmonary embolism. Further work-up of our patient indicated no typical MCC skin presentation, but rather metastases of the disease. The goal of this report is to highlight the importance of considering MCC as a differential even when patients do not present with common MCC risk factors or skin presentations.
2025-08-12 | Molecular regulatory mechanisms of Merkel cell differentiation.
Merkel cells are specialized oval-shaped epithelial cells located in the basal epidermis and hair follicles, connected with afferent nerve endings responsible for sensory perception of light touch. Recent advances in developmental biology have shed light on the complex regulatory networks governing Merkel cell maturation. The most recent evidence indicates a crosstalk among epigenetic pathways, notably Polycomb multi-subunit complexes, Merkel cell-lineage transcription factors such as atonal BHLH transcription factor 1 (ATOH1), SRY-box transcription factor 2 (SOX2), ISL LIM homeobox 1 (ISL1) and additional players in the regulation of Merkel cell developmental programs. At the same time, the implications of dysregulated Merkel cell-lineage transcription factors during Merkel cell carcinoma (MCC) onset is under investigation. This review offers a comprehensive overview of the current understanding of the genetic and epigenetic pathways crucial for Merkel cell differentiation. It covers the implication of Merkel cell-specific developmental programs, the role of epigenetic regulatory Polycomb complexes, and how genetic and epigenetic mechanisms converge to orchestrate Merkel cell differentiation.
oligonucleotides
2026-09-19 | Synthetic consensus DNA vaccines against Merkel cell polyomavirus large and small T antigens induce robust polyfunctional T cell responses.
Merkel cell carcinoma (MCC) is an aggressive form of skin cancer with a high mortality rate and limited therapeutic options. Approximately 80% of MCC cases are associated with Merkel cell polyomavirus (MCPyV). The Large T antigen (LTAg) and Small T antigen (STAg) of MCPyV are persistently expressed in tumors and important for viral maintenance and oncogenic transformation of infected cells, making them attractive targets for therapeutic vaccination. Here, we describe the development and preclinical evaluation of DNA vaccines against MCPyV LTAg (LTAgvax) and STAg (STAgvax). Vaccines were designed based on highly conserved regions across MCPyV strains and demonstrated robust expression in vitro. Immunization elicited strong antigen specific polyfunctional immune responses, including both CD4+ and CD8+ T cells producing IFNγ, TNFα, and IL2. We observed CD8+ T cells with cytotoxic potential, evidenced by expression of T-bet and CD107a. Importantly, these immune responses were observed in inbred and outbred mouse models, suggesting broad immunogenicity across diverse genetic backgrounds, enhancing the translational relevance of both vaccines. In a minimal residual disease challenge, LTAgvax controlled growth of B16 tumors transduced to express LTAg in mice, improving survival of tumor bearing mice. In a therapeutic challenge, LTAgvax extensively remodeled the tumor microenvironment, with fewer immunosuppressive immune cells and enhanced CD4+ and CD8+ T cell infiltration. The intratumoral CD8+ T cells were more activated and a greater percentage of them had the effector memory phenotype suggesting greater capacity to fight the tumor. This led to improved survival of mice which was further enhanced when mice were co-treated with LTAgvax and anti-PD1 antibody. Together, these findings demonstrate that MCPyV T antigen targeting DNA vaccines induce robust, multifunctional immune responses and control tumor growth. Further development of these vaccines for immunotherapy of MCPyV+ MCC is warranted.
2026-06-21 | mRNA vaccine design targeting Merkel cell polyomavirus for immunotherapy of Merkel cell carcinoma.
The pathogenesis of Merkel cell polyomavirus (MCPyV) is characterized by ubiquitous and most likely silent childhood infection that may cause Merkel cell carcinoma (MCC). This mRNA vaccine includes the capsid proteins VP1 and VP2, as well as the Large T antigen and small T antigen, which are highly immunogenic. This has led to the development of mRNA vaccines against these T and Capsid peptides. Different computational methods was used to identify the epitopes of helper CD4 + lymphocytes and CD8 + lymphocytes. All of selected epitopes was analyzed for their toxicity, allergenicity, and immunogenicity. The MD simulation was carried out in an orthorhombic TIP3P water box with a buffer region of 10 Å, and Na+/Cl- counter ions at a physiological amount of salt (150 mM) were added to neutralize the system. Once the NVT and NPT aggregates were equilibrated, a 100 ns manufacturing run at 310 K and 1 atm was performed. Our vaccine has 19 epitopes in the vaccine construct, including HTLs and CTLs. The vaccine was found to have an increased hydrophilicity, and the average hydropathicity score was - 8.95. The Ramachandran plot revealed potential stability, 94.6% of the amino acid units were found in the allowed region. The vaccine showed potentially high affinity with the TLR3 receptor as the docking score was - 318.56 KJ/mol, and the confidence score was 0.9668. After codon optimization, there was a knowing improvement in the expression in E. coli vectors that produced vaccines, as indicated by the increase in GC content to 53.41. MM-GBSA analysis showed that there was a uniform binding affinity of TLR3 between - 1500 and - 2000 kcal/mol. Our vaccine construct against MCPyV showed potential immune responses and should be advanced to in vitro and in vivo clinical experiments.
2026-04-12 | Transforming tumor cells into professional antigen-presenting cells using poly(β-amino ester) nanoparticles to deliver CD80-encoding mRNA.
Effective T-cell activation requires both antigen recognition and co-stimulatory signaling. However, tumor cells typically lack the necessary co-stimulatory molecules, rendering T-cell receptor engagement with tumor antigens insufficient to induce potent anti-tumor immune responses. To overcome this limitation, we converted tumor cells into professional antigen-presenting cell (APC)-like cells by equipping them with the co-stimulatory molecule CD80. Electroporation of melanoma and lung cancer cell lines with CD80-encoding mRNA significantly increased their ability to stimulate tumor-antigen-specific T cells, as indicated by increased activation markers and cytokine secretion. Most importantly, CD80 expression converted melanoma cells into APC-like cells capable of priming and expanding naïve T cells that recognize endogenous tumor antigens. To enable clinical application, we subsequently used poly-(beta aminoester) (pBAE) polymers, which efficiently encapsulate mRNA into nanometric polyplexes. As previously reported, pBAE nanoparticles (NPs) efficiently penetrate plasma membranes and escape endosomal degradation both in vitro and in vivo. Here, we evaluated pBAE NPs encapsulating GFP-encoding mRNA in human cell lines derived from melanoma, lung cancer, leukemia, adenocarcinoma, uveal melanoma, and Merkel cell carcinoma. The pBAE NPs effectively transfected adherent tumor cells, and tumor spheroids in vitro and in ovo. When delivering CD80 mRNA, NPs achieved expression rates of more than 50% in most cell lines, which lasted for at least 72 h. Here as well, nanoparticle-mediated CD80 expression enabled melanoma cells to prime and expand naïve T cells recognizing endogenous tumor antigens. Importantly, T cells primed by CD80-expressing tumor cells were also capable of killing tumor cells that had not been transfected. In line with these findings, T cells stimulated with untransfected tumor cells showed high levels of checkpoint receptors CTLA-4 and PD-1, whereas the expression was significantly lower when using CD80-transfected tumor cells. This proof-of-concept study indicates that conversion of tumor cells into professional APC-like cells with CD80 mRNA is feasible and results in potent anti-tumor CD8+ T-cell responses. With the use of mRNA-loaded pBAEs, the prerequisites for a future application in vivo are given. Therefore, the application of pBAE NPs encapsulating CD80 mRNA to specifically transfect tumor cells presents a new promising strategy for the in vivo treatment of various cancers.
2025-10-03 | Targeting an essential viral oncoprotein with an IL-7-enhanced mRNA vaccine induces durable immunity to Merkel cell carcinoma.
Although mRNA technologies have reinvigorated cancer vaccine development, the identification of strong antigens with consistent tumor cell expression and generation of durable antigen-specific CD8+ T cell memory remain key challenges. We identified the Merkel cell carcinoma (MCC) large T antigen (LTA) as an optimal vaccine target, essential for tumor cell survival and immunogenic in a cancer with high unmet clinical need. We developed an mRNA vaccine to MCC-LTA in murine studies and patient samples. We showed that antigen loss develops rapidly and causes resistance in mouse models when immunogenic, but non-essential antigens are targeted. To improve T cell response durability, we co-encoded LTA and IL-7, co-localizing proliferative and memory signals spatially and temporally with antigen exposure. IL-7-containing mRNA vaccines improved antigen-specific T cell expansion, memory differentiation, and tumor control. We propose that the principles of antigen essentiality and memory signal co-encoding may be adapted to improve the efficacy of mRNA therapeutics.
2025-07-28 | Phase 1b/2 study evaluating safety, efficacy and immune effects of TLR9 agonist cavrotolimod with anti-PD-1 antibodies among patients with advanced solid tumors.
There is an unmet need for novel immunotherapies to overcome immune evasion in patients with advanced skin cancers resistant to programmed death (PD)-1 / PD-ligand 1 (PD-L1) blockade. Cavrotolimod is a novel spherical nucleic acid configuration of a toll-like receptor 9 agonist oligonucleotide, designed to trigger innate and adaptive immune responses to tumors. The safety, pharmacokinetics, pharmacodynamics and preliminary efficacy of intratumoral cavrotolimod, first dosed alone and then in combination with anti-PD-1 antibodies (pembrolizumab or cemiplimab), were assessed in a combined Phase 1b/2 dose escalation/dose expansion study in patients with advanced skin cancers, including melanoma, Merkel cell carcinoma and cutaneous squamous cell carcinoma (www. gov; NCT03684785). A total of 58 patients (20 in dose-escalation and 38 in expansion cohorts) were enrolled. 55 (95%) of the 58 patients experienced progressive disease on prior anti-PD-(L)1 therapy. Cavrotolimod, in combination with anti-PD-1 therapy, produced objective responses in 6 (12%) and stable disease (SD) in 8 (16%) of 51 evaluable patients on this study, leading to a disease control rate of 27% (14/51). 5 of 6 (83%) patients with an objective response and 13 of 14 (93%) patients with disease control had progressed on prior anti-PD-(L)1 therapy. Disease control was durable, with median duration of 54 (range 24-88+) weeks for responses and 24 (range 11-35+) weeks for SD. Regression of both injected and non-injected tumors was observed. Cavrotolimod, alone and in combination with anti-PD-1 therapy, had a manageable safety profile with mostly transient adverse events (AEs). The most frequent Grade 3/4 cavrotolimod-related AEs were fatigue and injection site reactions. Cavrotolimod dosing was associated with robust chemokine/cytokine induction and lymphocyte activation in peripheral blood. Serial tumor biopsies of injected tumors suggested upregulation of genes associated with the interferon pathway, antiviral proteins, immune checkpoints, chemokines, granzymes and costimulatory proteins, along with increases in certain immune cell populations. Cavrotolimod had a manageable safety profile and showed clinical activity in anti-PD-(L)1 refractory cutaneous malignancies, suggesting potential for further development as an antitumor immunotherapy in combination with other agents. NCT03684785.
antibodies
2026-09-23 | PD-L1 in Merkel Cell Carcinoma: From Tumor Microenvironment to Pathological Interpretation
Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous neuroendocrine carcinoma in which Merkel cell polyomavirus (MCPyV) oncoproteins and ultraviolet-induced mutations provide distinct sources of tumor immunogenicity. This narrative review examines the biological determinants, immunohistochemical assessment, and prognostic and therapeutic relevance of programmed death ligand 1 (PD-L1) in MCC, linking tumor immunobiology to pathological interpretation. PD-L1 expression on tumor and immune cells is often concentrated at tumor–immune interfaces, consistent with interferon-γ-driven adaptive immune resistance. Reported associations with survival and treatment response vary across studies, partly reflecting differences in tissue sampling, assays, scoring compartments, and treatment context. Immune checkpoint blockade can produce durable responses in both PD-L1-positive and PD-L1-negative tumors, while baseline PD-L1 expression alone is not a validated criterion for treatment selection. Resistance mechanisms and emerging biomarkers are discussed alongside viral status, T-cell architecture, antigen-presentation defects, and alternative immune checkpoints. A reporting framework should emphasize specimen characteristics, assay documentation, separate assessment of PD-L1 expression in tumor and immune cells, and spatial heterogeneity. Interpreting PD-L1 within this biological and pathological context supports informative reporting and highlights the potential of integrated spatial biomarkers to improve understanding of immune responsiveness in MCC.
2026-09-22 | Clinical characteristics and immunotherapy in Chinese patients with Merkel cell carcinoma: a retrospective analysis
Purpose Merkel cell carcinoma (MCC) is a rare but highly aggressive cutaneous malignancy with limited epidemiological and therapeutic data in Asian populations. While immunotherapy works in Western patients, its efficacy in Chinese MCC patients remains unexplored. Methods We retrospectively analyzed 40 histologically confirmed MCC cases treated at our institution between November 2011 to November 2024. Sixteen patients with complete records underwent detailed analysis of demographics, treatments, and responses. Results The cohort included 25 female and 15 male patients (median age 71 years, range 25-91). Of the 16 patients with detailed information, 15 (94%) patients underwent extensive resection while 1 did not. Among surgical patients, 1 (7%) patient operative area received postoperative adjuvant radiotherapy, and 2 (13%) had additional lymph node dissection. Immunohistochemical analysis showed that out of 10 evaluable patients, 8 (80%) were MCPyV positive and 3 (30%) were PD-L1 positive. Among the patients receiving systemic treatment, four were administered Pembrolizumab at a dose of 200 mg every three weeks. Remarkably, three of these patients (75%) achieved a complete response (CR) by radiographic evaluation, with two of the treated specimens showed no residual malignant cells detected in post-treatment biopsy specimens. The treatment was well-tolerated, with no grade 3 or higher adverse events reported during the observation period. Conclusion This study describes MCC characteristics in Chinese patients, with preliminary indications of female predominance and favorable immunotherapy responses. The findings highlight the need for standardized treatment approaches.
2026-08-21 | Complete metabolic response in stage IV Merkel cell carcinoma after combined avelumab and radiotherapy: a case report suggestive of an abscopal effect.
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with limited therapeutic options once it reaches metastatic stages. While immune checkpoint inhibitors like avelumab have improved outcomes, achieving a complete and durable response in stage IV disease remains challenging. We report the case of a 75-year-old male diagnosed with stage IV MCC, negative for Merkel cell polyomavirus (MCPyV) and with 1% PD-L1 tumor cell expression, presenting with a primary tumor in the right thigh, a regional inguinal nodal conglomerate, and a distant mediastinal lymph node metastasis. Initial treatment with first-line avelumab resulted in a discordant response, with a near-complete metabolic response of the mediastinal lesion but persistence of the primary tumor. Localized radiotherapy (RT) - 66 Gy in 33 fractions delivered by intensity-modulated radiotherapy (IMRT), encompassing the primary tumor, the inguinal nodal conglomerate, and at-risk regional nodal basins - was subsequently added while avelumab was continued. Following completion of RT and the fourteenth cycle of avelumab, a complete metabolic and morphological response was documented by FDG PET-CT across all disease sites, including the non-irradiated mediastinal node, consistent with an abscopal effect. Treatment was reasonably well tolerated, with grade 3 radiodermatitis and grade 1 radiation cystitis as the only reported adverse events, and no immune-related toxicity. The patient has since maintained a durable remission under surveillance with maintenance RT. This case suggests a potent synergistic interaction between avelumab and RT, potentially mediated by an abscopal effect at the non-irradiated distant site. The strategic combination of these therapies may overcome initial resistance to immunotherapy in advanced MCC, highlighting the need for further clinical investigation into radio-immunotherapy protocols for this malignancy.
2026-08-14 | Merkel cell carcinoma: A clinically oriented mini-review for dermatologists.
Merkel cell carcinoma (MCC) is a rare but highly aggressive cutaneous neuroendocrine malignancy with mortality rates exceeding melanoma at comparable stages. Its incidence is increasing worldwide, particularly among elderly, immunosuppressed, and fairskinned individuals. Clinically, MCC often presents as a rapidly enlarging, asymptomatic nodule on sun-exposed skin, although atypical locations and morphologic variants may delay recognition. This clinically oriented mini-review summarizes current evidence most relevant to dermatologists regarding the epidemiology, risk factors, clinical presentation, histopathology, immunohistochemical diagnosis, staging, imaging, prognostic factors, circulating biomarkers, and treatment of MCC. Diagnosis relies on histopathology and immunohistochemistry, with cytokeratin 20 and Merkel cell polyomavirus (MCPyV)-related markers playing important roles in distinguishing MCC from other small round blue cell tumors. Imaging modalities, particularly FDG-PET/CT, are essential for accurate staging and surveillance. Prognosis is influenced by tumor size, stage, immune status, age, and viral status. Emerging biomarkers such as circulating tumor DNA and MCPyV oncoprotein antibody titers are increasingly relevant for disease monitoring. Management is stage-specific and multidisciplinary, involving surgical excision, radiotherapy, and immune checkpoint inhibitors such as avelumab, pembrolizumab, nivolumab, and retifanlimab, which have improved outcomes in advanced disease. MCC is an uncommon but highly lethal skin cancer that requires early recognition, accurate staging, and multidisciplinary management. Dermatologists should be aware of both classic and atypical presentations to avoid delayed diagnosis. Recent advances in imaging, biomarkers, and immunotherapy have improved disease monitoring and treatment, but important global disparities remain in access to diagnostic tools and modern therapies.
2026-07-29 | An immunocompetent model of MCPyV-driven Merkel cell carcinoma reveals tumor evolution under immune selection.
Merkel cell carcinoma (MCC) is a neuroendocrine skin tumor that is frequently driven by integration of Merkel cell polyomavirus (MCPyV). In MCC, the MCPyV genome is truncated, but expression of the viral tumor antigens, truncated large tumor antigen (LTT) and small tumor antigen (sT), is maintained and drives uncontrolled proliferation. We introduced constitutive expression of the MCPyV T antigens (TAs) into primary mouse dermal fibroblasts (MDFs) to determine whether these cells are susceptible to MCPyV-driven transformation. TA expression alone in MDFs induced key MCC markers, cytokeratin-20 (CK20) and Sry-box transcription factor 2 (SOX2), and promoted anchorage-independent growth indicative of cellular transformation. Subcutaneous implantation of TA-transformed fibroblasts produced high-grade MCC-like tumors that grew persistently in immunodeficient NSG mice but not in immunocompetent C57BL/6 mice. Serial in vivo passaging of the tumor cell line enhanced tumor growth, reduced expression of p53-target genes and MHC-1, and was accompanied by a shift in T antigen isoform expression, with decreased LTT and increased sT expression. Our data demonstrate that MCPyV-driven tumors acquire immune-evasive adaptions during tumor progression in vivo and suggest that the anti-tumor immune response exerts selective pressure in MCC that favors expression of sT rather than LTT. The model established in this study provides a unique platform for studying evolution of MCPyV-driven tumors under immune pressure and identifying mechanisms of immune evasion in MCC that could be used to develop new therapeutic strategies. MCPyV tumor antigen expression transforms mouse dermal fibroblasts to generate MCC-like tumors. Serial in vivo passaging reveals tumor evolution under immune pressure, providing a model to study immune evasion mechanisms in MCC.
other
2026-09-09 | Reprogramming engineered autologous T cells to overcome resistance in patients with Merkel cell carcinoma.
Immune checkpoint inhibitors (ICIs) have transformed Merkel cell carcinoma (MCC) outcomes, but most patients with MCC develop resistance. We identified T cell receptor (TCR)MCC1, a highly avid, HLA-A*02:01-restricted TCR targeting the Merkel cell polyomavirus (MCPyV) oncoprotein large-T antigen15-23. Seven patients with ICI-refractory metastatic MCPyV+ MCC received TCRMCC1-transduced cells (TTCR-MCC1 cells) after lymphodepleting chemotherapy or HLA-enhancing interventions [radiation or interferon gamma-1b (Actimmune)], with concurrent ICIs (NCT03747484). TTCR-MCC1 cells trafficked to tumor sites and expressed a gene expression profile compatible with T cell activation, with tumor regression observed in two patients. However, therapeutic activity was limited by HLA class I silencing, a common mechanism of immune escape in MCC. In one patient, delayed tumor regression coincided with endogenous effector immune activation and restoration of MCC HLA expression, implying that robust local responses could reverse HLA silencing. To overcome this barrier, we engineered CD4 and CD8 TTCR-MCC1 cells to coexpress CD8αβ and a CD200R-CD28 switch receptor, enabling CD4 T cell engagement and T cell costimulation. These modifications enhanced tumor infiltration, increased HLA expression, and improved control of HLAlow MCC in vivo in mice. These findings support the feasibility of TCR-engineered cell therapy for MCPyV+ MCC and provide a blueprint for overcoming immune evasion via targeted localized enhancement of antigen presentation.
2026-04-17 | Systemic Therapies for the Treatment of Cutaneous Malignancies in Solid Organ Transplant Recipients.
Solid organ transplant recipients (SOTRs) face frequent advanced cutaneous malignancies, yet data guiding systemic therapy are limited. We conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses systematic review of immune checkpoint inhibitors (ICIs), talimogene laherparepvec (T-VEC), and Sonic Hedgehog Pathway Inhibitors (HPIs) for locally advanced or metastatic cutaneous squamous cell carcinoma, melanoma, Merkel cell carcinoma, and basal cell carcinoma in SOTRs, including a novel case from our institution. Outcomes included tumor response, graft rejection, and graft failure. Among 196 SOTRs treated with ICIs (101 cutaneous squamous cell carcinoma, 83 melanoma, 12 Merkel cell carcinoma), the overall response rate (ORR) was 39.3%, and lack of progression occurred in 58.0%. Graft rejection occurred in 36.9% and graft failure in 22.3%. A higher number of baseline immunosuppressive agents decreased odds of rejection (OR 0.55) and failure (OR 0.38). Tacrolimus was associated with reduced tumor response (OR 0.41), whereas mTOR-based regimens and cemiplimab were associated with fewer transplant rejection. T-VEC was reported in 10 SOTRs with an ORR of 90% and no graft rejection or failure. HPIs in six SOTRs with basal cell carcinoma demonstrated ORR of 83% without graft loss. ICIs provide antitumor activity but substantial graft-related risk, while T-VEC and HPIs show high response rates with no reported rejection.
2026-03-04 | Response of B Cells Specific for Polyomavirus-Derived Oncoprotein Is Predictive of Merkel Cell Carcinoma Tumor Control.
Merkel cell carcinomas (MCC) typically arise from the clonal integration of the Merkel cell polyomavirus. Immunogenic viral oncoproteins then lead to tumorigenesis. Oncoprotein-specific T cells are essential for anti-MCC immunity, but it is unclear whether B cells promote tumor control. In this study, we analyzed the frequency and phenotype of viral oncoprotein-specific and total B cells in blood samples from 47 patients with MCC and tumor samples from another 19 patients with MCC. The phenotype of blood B cells did not correlate with the outcomes of patients with MCC. In contrast, all 11 patients with robust oncoprotein-specific antibody-secreting and/or germinal center B cells in tumors experienced long-term MCC control. In vitro, B cells engineered to be specific for viral oncoproteins increased the sensitivity of oncoprotein-specific CD4+ T cells by more than 50-fold. Together, our findings suggest that cancer-specific B cells promote antitumor immunity via increased responses by T cells and that cancer-specific augmentation of B cells could be therapeutically relevant. See related Spotlight, p. 716.
2026-03-03 | ASO Visual Abstract: Evaluation of Talimogene Laherparepvec for the Treatment of Advanced Nonmelanoma Skin Cancers.
Our visual abstract highlights the primary question of our work, which was to evaluate the outcomes of patients who received talimogene laherparepvec (T-VEC), an oncolytic herpes virus, for advanced Merkel cell carcinoma (MCC) and squamous cell carcinoma (SCC). While T-VEC has been approved for use in melanoma, it is currently only being used in the off-label setting for nonmelanoma skin cancer (NMSC). In addition, many of our patients received T-VEC with concurrent immune therapy, which is a patient population that has not been thoroughly studied. Data were obtained through a retrospective chart review of patients with MCC or SCC who received T-VEC at our NCI-designated comprehensive cancer center. The cohort included ten patients with MCC and three with SCC; six patients received T-VEC alone and seven received T-VEC with concurrent immune therapy. Of note, all three patients who had SCC also received immune therapy. The overall response rate (ORR) of the cohort, defined as the percentage of complete and partial responses to therapy, was 53.8%, with six complete responses and one partial response. Of the six complete responses, four patients were disease-free at their date of last follow-up, which was an average of 25 months from completion of T-VEC treatment. Our work highlights the fact that durable response to T-VEC for patients with advanced NMSC is possible in the setting of a high rate of concurrent immune therapy administration. Further work should more rigorously explore the role that T-VEC may play in NMSC, with particular attention to its use with immune therapy ( https://doi.org/10.1245/s10434-026-19182-3 ).
2026-02-23 | Evaluation of Talimogene Laherparepvec for the Treatment of Advanced Nonmelanoma Skin Cancers.
Talimogene laherparepvec (T-VEC) is an intralesional, injectable oncolytic herpes virus that is FDA-approved to treat Stage III-IV melanoma. The utility of T-VEC for nonmelanoma skin cancers (NMSC), including Merkel cell carcinoma (MCC) and squamous cell carcinoma (SCC), as well as its use with concurrent immune therapy (IO), is poorly defined. The purpose of this study is to evaluate outcomes of T-VEC for MCC and SCC with and without concurrent immune therapy. This retrospective study included patients at a single institution with MCC or SCC and treated with T-VEC between May 2016 and May 2023. Abstracted cohort data were reported using descriptive statistics. Ten MCC and three SCC patients were eligible. Four MCC patients and all three SCC patients received concurrent pembrolizumab. Overall, six patients achieved complete response (CR), one had partial response (PR), and six had progressive disease (PD). Of the six patients who achieved CR, two recurred at 8 and 56 months. Those without recurrence had a durable response at a median follow-up of 25 months. Our initial experience with a small, single-institution cohort demonstrated tumor response to intralesional T-VEC with or without immunotherapy in some patients with NMSC. Nearly 50% of participants had a complete response; two-thirds of responders remained relapse-free at the time of follow-up. Some observed responses are not attributable to T-VEC alone due to high usage rates of IO. Future work should expand to larger cohorts and focus on its use with and without immune therapy.
small molecules
2026-08-27 | Anatomical lymphatic drainage basin and sentinel lymph node positivity in Merkel cell carcinoma: a 37-year single-center cohort study of 400 patients.
Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous neuroendocrine malignancy with increasing incidence due to UV exposure and improved diagnostics. It spreads rapidly via lymphatics and has high mortality, surpassing melanoma in lethality. Management includes surgical excision, sentinel lymph node biopsy (SLNB), radiotherapy, and immunotherapy. SLNB is an established staging tool for detecting occult nodal metastases; however, the influence of anatomical drainage basin location on SLNB positivity and the role of completion lymph node dissection (CLND) remain incompletely understood. This study evaluated patterns of nodal involvement according to drainage basin location and assessed the diagnostic yield of CLND in a large single-center MCC cohort. A retrospective analysis was performed of 400 patients with MCC treated at a tertiary referral center between 1986 and 2023. SLNB positivity rates were compared across cervical, axillary, and inguinal drainage basins. Associations between anatomical location and nodal involvement were assessed using univariable and multivariable logistic regression models. Adjusted analyses included year of diagnosis, lymphovascular invasion and immunosuppression status, with Firth's penalized regression applied where appropriate. Among 400 patients, 244 underwent SLNB, of whom 71 (29.1%) had at least one positive SLN. In univariable analysis, inguinal SLNB was associated with higher odds of positivity compared with axillary SLNB (OR 3.31, 95% CI 1.49-7.35; p = 0.003) and cervical SLNB (OR 2.10, 95% CI 1.04-4.24; p = 0.040). After adjustment for lymphovascular invasion, immunosuppression, and year of diagnosis, inguinal drainage remained associated with SLNB positivity compared with axillary drainage (OR 3.08; 95% CI 1.36-6.98; p = 0.007). Lymphovascular invasion (OR 3.29; 95% CI 1.66-6.54; p = 0.001) and immunosuppression (OR 2.38; 95% CI 1.12-5.06; p = 0.025) were also associated with SLNB positivity in the adjusted model. SLNB remains a valuable staging procedure in MCC, identifying occult nodal disease in nearly one-third of patients. Inguinal drainage basin remained associated with SLNB positivity after adjustment for clinicopathological factors. These findings may help inform clinical decision-making regarding nodal staging in patients with MCC. The substantial rate of additional nodal involvement detected by CLND supports its continued role as a staging procedure in selected patients with MCC. As this study focuses on lymphatic dissemination assessed by SLNB and lymph node dissection (LND), no conclusions can be drawn regarding hematogenous metastatic spread.
2026-08-19 | Lineage plasticity in Merkel cell carcinoma
Merkel cell carcinoma (MCC) is a rare and highly aggressive skin cancer characterized by neuroendocrine features. Efforts to define the cell of origin have remained inconclusive, largely because MCC displays overlapping epithelial, neuroendocrine, and immune-associated differentiation programs. Moreover, MCC carcinogenesis is either due to UV mutagenesis or the clonal integration of the Merkel cell polyomavirus (MCPyV). Increasing evidence, however, suggests that MCC is best understood as a lineage-plastic cancer in which cellular identity is dynamically regulated rather than irreversibly fixed. In this thesis focusing on virus-positive MCC, we investigate the mechanisms underlying lineage plasticity, and examine how both intrinsic oncogenic pathways and extrinsic environmental cues shape tumor cell states, immune interactions, and therapeutic responses. MCPyV-encoded T antigens play a central role in maintaining a stem-like, poorly differentiated cell state, extending beyond their canonical function in cell-cycle control. The suppression of T antigens leads to coordinated downregulation of E2F-driven transcriptional programs associated with cell-cycle progression and stemness, accompanied by a metabolic shift from glycolysis toward mitochondrial oxidative phosphorylation. Concomitant with the loss of stem-like features, MCC cells activate neurogenesis-associated transcriptional programs and display enhanced neural differentiation, uncovering latent differentiation pathways that are actively repressed in the presence of T antigens. In parallel, we show that pharmacological inhibition of the epigenetic co-activators CBP/p300 phenocopies T-antigen loss, including repression of stemness-associated gene networks and induction of neurogenesis-related pathways. These findings identify CBP/p300-mediated epigenetic maintenance of lineage identity as a critical vulnerability in MCC. Collectively, this work establishes that stemness and neuroendocrine features in MCC are actively enforced by oncogenic and epigenetic mechanisms. Beyond tumor-intrinsic regulation, we demonstrate that environmental cues exert a profound influence on MCC cell identity. Close vicinity to normal keratinocytes by localization of MCC cells within the epidermal niche promotes epithelial differentiation programs, indicating that local tissue context can partially override oncogenic signaling and redirect tumor cell fate. This observation highlights the capacity for context-dependent lineage reprogramming in MCC. In line with this notion, the immune microenvironment, e.g. the cellular neighborhood of MCC cells with tertiary lymphoid structures (TLS) also acts as a regulator of tumor cell state. MCC cells in close proximity to TLS exhibit sustained activation of interferon-responsive pathways, upregulation of antigen processing and presentation machinery, and increased expression of apoptosis-associated genes. These findings suggest that TLS constrain immune-evasive plasticity and stabilize immunogenic tumor phenotypes, thereby supporting durable responses to immune checkpoint blockade. Overall, this work reframes MCC as a malignancy defined by dynamic lineage plasticity governed by oncogenic, epigenetic, and immune-mediated forces. A deeper understanding of these plastic states, and their therapeutic targeting, offers new opportunities to treat MCC patients.
2026-08-07 | Clinical Reasoning: A 79-Year-Old Man With Subacute Onset Involuntary Facial Movements and Discoordination.
A 79-year-old man with metastatic Merkel cell carcinoma undergoing cancer-directed treatment was admitted to the hospital with 1 week of bilateral upper and lower extremity tremor and nearly continuous involuntary facial movements. These abnormal movements of his face, head, and limbs were exacerbated by purposeful movement. Examination revealed dysarthria with tremulous speech, intention tremors of the head and all extremities, distally diminished vibration sense with hyporeflexia, bilateral upper extremity dysdiadochokinesis, bilateral lower extremity dysmetria on heel-to-shin testing, and truncal ataxia. MRI of the brain showed no acute abnormalities. CSF and serum testing showed evidence of CNS inflammation with a CSF lymphocytic pleocytosis and elevated total protein. Diagnosis was ultimately made using serum and CSF studies. Here, we discuss the differential diagnosis of 2 weeks of diffuse intention tremor, involuntary facial movements, and ataxia. We discuss the workup, diagnosis, acute and nonacute management of this condition, as well as important clinical points regarding the broader category into which this diagnosis falls.
2026-07-28 | The Nicotinic Acetylcholine Receptor-Macrophage Axis in Merkel Cell Carcinoma: Evidence, Limitations, and Therapeutic Hypotheses.
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin malignancy characterized by high mortality and a rising incidence. Although immune checkpoint inhibitors have significantly improved patient outcomes, many patients exhibit primary or acquired resistance, frequently in the setting of an immunosuppressive tumor microenvironment (TME) enriched for myeloid populations. This review synthesizes current evidence and proposes a testable model in which nicotinic acetylcholine receptor (nAChR) signaling may intersect with tumor-associated macrophage (TAM) biology to reinforce immune exclusion in MCC. Direct MCC-specific evidence currently supports nAChR-subunit expression in tumor tissues and the association of CD163+/CD14+/S100A8+ myeloid populations with resistance to PD-1 pathway blockade; however, functional nAChR signaling in MCC tumor cells, TAMs, or dendritic cells has not yet been demonstrated. We therefore distinguish established MCC observations from mechanistic hypotheses extrapolated from macrophage biology, cholinergic anti-inflammatory signaling, and other cancer models. Within this framework, α7-nAChR signaling on TAMs may activate the cholinergic anti-inflammatory pathway and favor suppressive myeloid states, whereas α3- and α5-containing receptors detected in MCC tumor cells may represent tumor-cell-associated candidates for future mechanistic testing. By integrating evidence on TAM plasticity, spatial immune exclusion, and cholinergic signaling, we propose that the nAChR-macrophage axis is a rational but unproven therapeutic hypothesis that warrants systematic validation in MCC models.
2026-07-20 | Merkel cell carcinoma in a patient on ruxolitinib treatment for polycythemia vera
Merkel cell carcinoma (MCC) is a rare aggressive neuroendocrine skin cancer derived from Merkel cells located in the basal layer of the epidermis and follicular epithelium. MCC predominantly affects elderly patients, particularly white males, and results from a combination of risk factors including genetic, molecular, age-related-immune decline, and environmental factors.1 Long-term ultraviolet radiation is a key risk factor for MCC, particularly for tumors arising on sun-exposed areas such as the head and neck, although less advanced lesions at diagnosis are more often seen on the limbs.
proteins
2026-09-26 | Lanreotide, a Somatostatin Analogue, in Advanced Merkel Cell Carcinoma: A Prospective Single-Arm Phase II Study.
Merkel Cell Carcinoma (MCC) is a rare, aggressive neuroendocrine and epithelial skin cancer. Somatostatin analogues, such as lanreotide, have shown efficacy in managing other neuroendocrine tumors. Retrospective studies suggest that lanreotide may induce partial response or disease stabilization in patients with advanced MCC. To test this hypothesis, we conducted a Phase II, non-randomized, open trial investigating lanreotide in MCC patients with advanced disease (ClinicalTrials.gov identifier: NCT02351128). Patients with Stage IIIB-IV MCC received lanreotide monotherapy (120 mg every 28 days) at any line of systemic therapy, until disease progression or unacceptable toxicity. The primary endpoint was disease control rate (DCR) (defined as the proportion of patients with complete response, partial response, and stable disease) at 3 months. Secondary endpoints included progression-free survival (PFS), overall survival (OS), somatostatin receptor (SSTR) tumor expression, and treatment safety. Between April, 2015, and November, 2016, 35 patients received lanreotide, with 12 evaluable at 3 months. The DCR at 3 months was 33.3% (4) among evaluable patients (all with stable disease) and 11.4% for the full cohort. Statistical analyses showed no significant difference from the expected 20% response rate (p = 0.205 for intention-to-treat; p = 0.939 for per-protocol). Kaplan-Meier analysis revealed median OS and PFS of 3.1 months (95% CI, 2-5.5) and 3.5 months (95% CI, 2.3-5.5), respectively. SSTR tumor expression did not correlate with treatment response. Although limited by its implementation before the era of immunotherapy, this non-randomized study shows the limited effectiveness of lanreotide as monotherapy in treating patients with advanced MCC. Identifier: NCT02351128.
2026-02-03 | Giant Merkel cell carcinoma of the scalp
None declared. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
2025-09-03 | Impact of UV Exposure and Incidence of Merkel Cell Carcinoma Between 1990 and 2018 in Austria
Background: To describe i) patients´ demographic, ii) Austrian UV-data and iii) to analyze a possible relationship between UV exposure and onset of disease in Austria between 1990 and 2018. Methods: We included all patients with MCC diagnosed and clinical and demographic data to compare to UV radiation. Results: A total of 538 cases were identified and the incidence (per 100.000/y) increased from 0.04 to 3.45. The MCC incidence was significantly higher in West- (mean incidence 0.269 ± 0.04) compared to East-Austria (0.180 ± 0.02 p=0.005). Notably, the mean and maximum UV radiation values were higher in the Western (p< 0.001) compared to the Eastern part of Austria. The sum (p=0.033; r: 0.503) and mean (p=0.019; r: 0.546) UV values correlated significantly to the MCC incidence. Conclusions: MCC incidence increased significantly and a higher UV radiation in West- compared to East-Austria that subsequently resulted in a higher MCC incidence could be determined.
2025-08-22 | Atypical presentation of Merkel cell carcinoma with pulmonary embolism.
Merkel cell carcinoma (MCC) is a rare aggressive neuroendocrine malignancy that typically presents in the skin and rapidly progresses to other body parts. MCC is typically found in sun-exposed areas, mainly the head and neck region as well as the upper limbs and shoulders. It typically affects fair-skinned elderly males. In this report, we present an unusual MCC case of a 48-year-old Caucasian male with an initial presentation of a massive pulmonary embolism. Further work-up of our patient indicated no typical MCC skin presentation, but rather metastases of the disease. The goal of this report is to highlight the importance of considering MCC as a differential even when patients do not present with common MCC risk factors or skin presentations.
2025-08-12 | Molecular regulatory mechanisms of Merkel cell differentiation.
Merkel cells are specialized oval-shaped epithelial cells located in the basal epidermis and hair follicles, connected with afferent nerve endings responsible for sensory perception of light touch. Recent advances in developmental biology have shed light on the complex regulatory networks governing Merkel cell maturation. The most recent evidence indicates a crosstalk among epigenetic pathways, notably Polycomb multi-subunit complexes, Merkel cell-lineage transcription factors such as atonal BHLH transcription factor 1 (ATOH1), SRY-box transcription factor 2 (SOX2), ISL LIM homeobox 1 (ISL1) and additional players in the regulation of Merkel cell developmental programs. At the same time, the implications of dysregulated Merkel cell-lineage transcription factors during Merkel cell carcinoma (MCC) onset is under investigation. This review offers a comprehensive overview of the current understanding of the genetic and epigenetic pathways crucial for Merkel cell differentiation. It covers the implication of Merkel cell-specific developmental programs, the role of epigenetic regulatory Polycomb complexes, and how genetic and epigenetic mechanisms converge to orchestrate Merkel cell differentiation.
oligonucleotides
2026-09-19 | Synthetic consensus DNA vaccines against Merkel cell polyomavirus large and small T antigens induce robust polyfunctional T cell responses.
Merkel cell carcinoma (MCC) is an aggressive form of skin cancer with a high mortality rate and limited therapeutic options. Approximately 80% of MCC cases are associated with Merkel cell polyomavirus (MCPyV). The Large T antigen (LTAg) and Small T antigen (STAg) of MCPyV are persistently expressed in tumors and important for viral maintenance and oncogenic transformation of infected cells, making them attractive targets for therapeutic vaccination. Here, we describe the development and preclinical evaluation of DNA vaccines against MCPyV LTAg (LTAgvax) and STAg (STAgvax). Vaccines were designed based on highly conserved regions across MCPyV strains and demonstrated robust expression in vitro. Immunization elicited strong antigen specific polyfunctional immune responses, including both CD4+ and CD8+ T cells producing IFNγ, TNFα, and IL2. We observed CD8+ T cells with cytotoxic potential, evidenced by expression of T-bet and CD107a. Importantly, these immune responses were observed in inbred and outbred mouse models, suggesting broad immunogenicity across diverse genetic backgrounds, enhancing the translational relevance of both vaccines. In a minimal residual disease challenge, LTAgvax controlled growth of B16 tumors transduced to express LTAg in mice, improving survival of tumor bearing mice. In a therapeutic challenge, LTAgvax extensively remodeled the tumor microenvironment, with fewer immunosuppressive immune cells and enhanced CD4+ and CD8+ T cell infiltration. The intratumoral CD8+ T cells were more activated and a greater percentage of them had the effector memory phenotype suggesting greater capacity to fight the tumor. This led to improved survival of mice which was further enhanced when mice were co-treated with LTAgvax and anti-PD1 antibody. Together, these findings demonstrate that MCPyV T antigen targeting DNA vaccines induce robust, multifunctional immune responses and control tumor growth. Further development of these vaccines for immunotherapy of MCPyV+ MCC is warranted.
2026-06-21 | mRNA vaccine design targeting Merkel cell polyomavirus for immunotherapy of Merkel cell carcinoma.
The pathogenesis of Merkel cell polyomavirus (MCPyV) is characterized by ubiquitous and most likely silent childhood infection that may cause Merkel cell carcinoma (MCC). This mRNA vaccine includes the capsid proteins VP1 and VP2, as well as the Large T antigen and small T antigen, which are highly immunogenic. This has led to the development of mRNA vaccines against these T and Capsid peptides. Different computational methods was used to identify the epitopes of helper CD4 + lymphocytes and CD8 + lymphocytes. All of selected epitopes was analyzed for their toxicity, allergenicity, and immunogenicity. The MD simulation was carried out in an orthorhombic TIP3P water box with a buffer region of 10 Å, and Na+/Cl- counter ions at a physiological amount of salt (150 mM) were added to neutralize the system. Once the NVT and NPT aggregates were equilibrated, a 100 ns manufacturing run at 310 K and 1 atm was performed. Our vaccine has 19 epitopes in the vaccine construct, including HTLs and CTLs. The vaccine was found to have an increased hydrophilicity, and the average hydropathicity score was - 8.95. The Ramachandran plot revealed potential stability, 94.6% of the amino acid units were found in the allowed region. The vaccine showed potentially high affinity with the TLR3 receptor as the docking score was - 318.56 KJ/mol, and the confidence score was 0.9668. After codon optimization, there was a knowing improvement in the expression in E. coli vectors that produced vaccines, as indicated by the increase in GC content to 53.41. MM-GBSA analysis showed that there was a uniform binding affinity of TLR3 between - 1500 and - 2000 kcal/mol. Our vaccine construct against MCPyV showed potential immune responses and should be advanced to in vitro and in vivo clinical experiments.
2026-04-12 | Transforming tumor cells into professional antigen-presenting cells using poly(β-amino ester) nanoparticles to deliver CD80-encoding mRNA.
Effective T-cell activation requires both antigen recognition and co-stimulatory signaling. However, tumor cells typically lack the necessary co-stimulatory molecules, rendering T-cell receptor engagement with tumor antigens insufficient to induce potent anti-tumor immune responses. To overcome this limitation, we converted tumor cells into professional antigen-presenting cell (APC)-like cells by equipping them with the co-stimulatory molecule CD80. Electroporation of melanoma and lung cancer cell lines with CD80-encoding mRNA significantly increased their ability to stimulate tumor-antigen-specific T cells, as indicated by increased activation markers and cytokine secretion. Most importantly, CD80 expression converted melanoma cells into APC-like cells capable of priming and expanding naïve T cells that recognize endogenous tumor antigens. To enable clinical application, we subsequently used poly-(beta aminoester) (pBAE) polymers, which efficiently encapsulate mRNA into nanometric polyplexes. As previously reported, pBAE nanoparticles (NPs) efficiently penetrate plasma membranes and escape endosomal degradation both in vitro and in vivo. Here, we evaluated pBAE NPs encapsulating GFP-encoding mRNA in human cell lines derived from melanoma, lung cancer, leukemia, adenocarcinoma, uveal melanoma, and Merkel cell carcinoma. The pBAE NPs effectively transfected adherent tumor cells, and tumor spheroids in vitro and in ovo. When delivering CD80 mRNA, NPs achieved expression rates of more than 50% in most cell lines, which lasted for at least 72 h. Here as well, nanoparticle-mediated CD80 expression enabled melanoma cells to prime and expand naïve T cells recognizing endogenous tumor antigens. Importantly, T cells primed by CD80-expressing tumor cells were also capable of killing tumor cells that had not been transfected. In line with these findings, T cells stimulated with untransfected tumor cells showed high levels of checkpoint receptors CTLA-4 and PD-1, whereas the expression was significantly lower when using CD80-transfected tumor cells. This proof-of-concept study indicates that conversion of tumor cells into professional APC-like cells with CD80 mRNA is feasible and results in potent anti-tumor CD8+ T-cell responses. With the use of mRNA-loaded pBAEs, the prerequisites for a future application in vivo are given. Therefore, the application of pBAE NPs encapsulating CD80 mRNA to specifically transfect tumor cells presents a new promising strategy for the in vivo treatment of various cancers.
2025-10-03 | Targeting an essential viral oncoprotein with an IL-7-enhanced mRNA vaccine induces durable immunity to Merkel cell carcinoma.
Although mRNA technologies have reinvigorated cancer vaccine development, the identification of strong antigens with consistent tumor cell expression and generation of durable antigen-specific CD8+ T cell memory remain key challenges. We identified the Merkel cell carcinoma (MCC) large T antigen (LTA) as an optimal vaccine target, essential for tumor cell survival and immunogenic in a cancer with high unmet clinical need. We developed an mRNA vaccine to MCC-LTA in murine studies and patient samples. We showed that antigen loss develops rapidly and causes resistance in mouse models when immunogenic, but non-essential antigens are targeted. To improve T cell response durability, we co-encoded LTA and IL-7, co-localizing proliferative and memory signals spatially and temporally with antigen exposure. IL-7-containing mRNA vaccines improved antigen-specific T cell expansion, memory differentiation, and tumor control. We propose that the principles of antigen essentiality and memory signal co-encoding may be adapted to improve the efficacy of mRNA therapeutics.
2025-07-28 | Phase 1b/2 study evaluating safety, efficacy and immune effects of TLR9 agonist cavrotolimod with anti-PD-1 antibodies among patients with advanced solid tumors.
There is an unmet need for novel immunotherapies to overcome immune evasion in patients with advanced skin cancers resistant to programmed death (PD)-1 / PD-ligand 1 (PD-L1) blockade. Cavrotolimod is a novel spherical nucleic acid configuration of a toll-like receptor 9 agonist oligonucleotide, designed to trigger innate and adaptive immune responses to tumors. The safety, pharmacokinetics, pharmacodynamics and preliminary efficacy of intratumoral cavrotolimod, first dosed alone and then in combination with anti-PD-1 antibodies (pembrolizumab or cemiplimab), were assessed in a combined Phase 1b/2 dose escalation/dose expansion study in patients with advanced skin cancers, including melanoma, Merkel cell carcinoma and cutaneous squamous cell carcinoma (www. gov; NCT03684785). A total of 58 patients (20 in dose-escalation and 38 in expansion cohorts) were enrolled. 55 (95%) of the 58 patients experienced progressive disease on prior anti-PD-(L)1 therapy. Cavrotolimod, in combination with anti-PD-1 therapy, produced objective responses in 6 (12%) and stable disease (SD) in 8 (16%) of 51 evaluable patients on this study, leading to a disease control rate of 27% (14/51). 5 of 6 (83%) patients with an objective response and 13 of 14 (93%) patients with disease control had progressed on prior anti-PD-(L)1 therapy. Disease control was durable, with median duration of 54 (range 24-88+) weeks for responses and 24 (range 11-35+) weeks for SD. Regression of both injected and non-injected tumors was observed. Cavrotolimod, alone and in combination with anti-PD-1 therapy, had a manageable safety profile with mostly transient adverse events (AEs). The most frequent Grade 3/4 cavrotolimod-related AEs were fatigue and injection site reactions. Cavrotolimod dosing was associated with robust chemokine/cytokine induction and lymphocyte activation in peripheral blood. Serial tumor biopsies of injected tumors suggested upregulation of genes associated with the interferon pathway, antiviral proteins, immune checkpoints, chemokines, granzymes and costimulatory proteins, along with increases in certain immune cell populations. Cavrotolimod had a manageable safety profile and showed clinical activity in anti-PD-(L)1 refractory cutaneous malignancies, suggesting potential for further development as an antitumor immunotherapy in combination with other agents. NCT03684785.
antibodies
2026-09-23 | PD-L1 in Merkel Cell Carcinoma: From Tumor Microenvironment to Pathological Interpretation
Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous neuroendocrine carcinoma in which Merkel cell polyomavirus (MCPyV) oncoproteins and ultraviolet-induced mutations provide distinct sources of tumor immunogenicity. This narrative review examines the biological determinants, immunohistochemical assessment, and prognostic and therapeutic relevance of programmed death ligand 1 (PD-L1) in MCC, linking tumor immunobiology to pathological interpretation. PD-L1 expression on tumor and immune cells is often concentrated at tumor–immune interfaces, consistent with interferon-γ-driven adaptive immune resistance. Reported associations with survival and treatment response vary across studies, partly reflecting differences in tissue sampling, assays, scoring compartments, and treatment context. Immune checkpoint blockade can produce durable responses in both PD-L1-positive and PD-L1-negative tumors, while baseline PD-L1 expression alone is not a validated criterion for treatment selection. Resistance mechanisms and emerging biomarkers are discussed alongside viral status, T-cell architecture, antigen-presentation defects, and alternative immune checkpoints. A reporting framework should emphasize specimen characteristics, assay documentation, separate assessment of PD-L1 expression in tumor and immune cells, and spatial heterogeneity. Interpreting PD-L1 within this biological and pathological context supports informative reporting and highlights the potential of integrated spatial biomarkers to improve understanding of immune responsiveness in MCC.
2026-09-22 | Clinical characteristics and immunotherapy in Chinese patients with Merkel cell carcinoma: a retrospective analysis
Purpose Merkel cell carcinoma (MCC) is a rare but highly aggressive cutaneous malignancy with limited epidemiological and therapeutic data in Asian populations. While immunotherapy works in Western patients, its efficacy in Chinese MCC patients remains unexplored. Methods We retrospectively analyzed 40 histologically confirmed MCC cases treated at our institution between November 2011 to November 2024. Sixteen patients with complete records underwent detailed analysis of demographics, treatments, and responses. Results The cohort included 25 female and 15 male patients (median age 71 years, range 25-91). Of the 16 patients with detailed information, 15 (94%) patients underwent extensive resection while 1 did not. Among surgical patients, 1 (7%) patient operative area received postoperative adjuvant radiotherapy, and 2 (13%) had additional lymph node dissection. Immunohistochemical analysis showed that out of 10 evaluable patients, 8 (80%) were MCPyV positive and 3 (30%) were PD-L1 positive. Among the patients receiving systemic treatment, four were administered Pembrolizumab at a dose of 200 mg every three weeks. Remarkably, three of these patients (75%) achieved a complete response (CR) by radiographic evaluation, with two of the treated specimens showed no residual malignant cells detected in post-treatment biopsy specimens. The treatment was well-tolerated, with no grade 3 or higher adverse events reported during the observation period. Conclusion This study describes MCC characteristics in Chinese patients, with preliminary indications of female predominance and favorable immunotherapy responses. The findings highlight the need for standardized treatment approaches.
2026-08-21 | Complete metabolic response in stage IV Merkel cell carcinoma after combined avelumab and radiotherapy: a case report suggestive of an abscopal effect.
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with limited therapeutic options once it reaches metastatic stages. While immune checkpoint inhibitors like avelumab have improved outcomes, achieving a complete and durable response in stage IV disease remains challenging. We report the case of a 75-year-old male diagnosed with stage IV MCC, negative for Merkel cell polyomavirus (MCPyV) and with 1% PD-L1 tumor cell expression, presenting with a primary tumor in the right thigh, a regional inguinal nodal conglomerate, and a distant mediastinal lymph node metastasis. Initial treatment with first-line avelumab resulted in a discordant response, with a near-complete metabolic response of the mediastinal lesion but persistence of the primary tumor. Localized radiotherapy (RT) - 66 Gy in 33 fractions delivered by intensity-modulated radiotherapy (IMRT), encompassing the primary tumor, the inguinal nodal conglomerate, and at-risk regional nodal basins - was subsequently added while avelumab was continued. Following completion of RT and the fourteenth cycle of avelumab, a complete metabolic and morphological response was documented by FDG PET-CT across all disease sites, including the non-irradiated mediastinal node, consistent with an abscopal effect. Treatment was reasonably well tolerated, with grade 3 radiodermatitis and grade 1 radiation cystitis as the only reported adverse events, and no immune-related toxicity. The patient has since maintained a durable remission under surveillance with maintenance RT. This case suggests a potent synergistic interaction between avelumab and RT, potentially mediated by an abscopal effect at the non-irradiated distant site. The strategic combination of these therapies may overcome initial resistance to immunotherapy in advanced MCC, highlighting the need for further clinical investigation into radio-immunotherapy protocols for this malignancy.
2026-08-14 | Merkel cell carcinoma: A clinically oriented mini-review for dermatologists.
Merkel cell carcinoma (MCC) is a rare but highly aggressive cutaneous neuroendocrine malignancy with mortality rates exceeding melanoma at comparable stages. Its incidence is increasing worldwide, particularly among elderly, immunosuppressed, and fairskinned individuals. Clinically, MCC often presents as a rapidly enlarging, asymptomatic nodule on sun-exposed skin, although atypical locations and morphologic variants may delay recognition. This clinically oriented mini-review summarizes current evidence most relevant to dermatologists regarding the epidemiology, risk factors, clinical presentation, histopathology, immunohistochemical diagnosis, staging, imaging, prognostic factors, circulating biomarkers, and treatment of MCC. Diagnosis relies on histopathology and immunohistochemistry, with cytokeratin 20 and Merkel cell polyomavirus (MCPyV)-related markers playing important roles in distinguishing MCC from other small round blue cell tumors. Imaging modalities, particularly FDG-PET/CT, are essential for accurate staging and surveillance. Prognosis is influenced by tumor size, stage, immune status, age, and viral status. Emerging biomarkers such as circulating tumor DNA and MCPyV oncoprotein antibody titers are increasingly relevant for disease monitoring. Management is stage-specific and multidisciplinary, involving surgical excision, radiotherapy, and immune checkpoint inhibitors such as avelumab, pembrolizumab, nivolumab, and retifanlimab, which have improved outcomes in advanced disease. MCC is an uncommon but highly lethal skin cancer that requires early recognition, accurate staging, and multidisciplinary management. Dermatologists should be aware of both classic and atypical presentations to avoid delayed diagnosis. Recent advances in imaging, biomarkers, and immunotherapy have improved disease monitoring and treatment, but important global disparities remain in access to diagnostic tools and modern therapies.
2026-07-29 | An immunocompetent model of MCPyV-driven Merkel cell carcinoma reveals tumor evolution under immune selection.
Merkel cell carcinoma (MCC) is a neuroendocrine skin tumor that is frequently driven by integration of Merkel cell polyomavirus (MCPyV). In MCC, the MCPyV genome is truncated, but expression of the viral tumor antigens, truncated large tumor antigen (LTT) and small tumor antigen (sT), is maintained and drives uncontrolled proliferation. We introduced constitutive expression of the MCPyV T antigens (TAs) into primary mouse dermal fibroblasts (MDFs) to determine whether these cells are susceptible to MCPyV-driven transformation. TA expression alone in MDFs induced key MCC markers, cytokeratin-20 (CK20) and Sry-box transcription factor 2 (SOX2), and promoted anchorage-independent growth indicative of cellular transformation. Subcutaneous implantation of TA-transformed fibroblasts produced high-grade MCC-like tumors that grew persistently in immunodeficient NSG mice but not in immunocompetent C57BL/6 mice. Serial in vivo passaging of the tumor cell line enhanced tumor growth, reduced expression of p53-target genes and MHC-1, and was accompanied by a shift in T antigen isoform expression, with decreased LTT and increased sT expression. Our data demonstrate that MCPyV-driven tumors acquire immune-evasive adaptions during tumor progression in vivo and suggest that the anti-tumor immune response exerts selective pressure in MCC that favors expression of sT rather than LTT. The model established in this study provides a unique platform for studying evolution of MCPyV-driven tumors under immune pressure and identifying mechanisms of immune evasion in MCC that could be used to develop new therapeutic strategies. MCPyV tumor antigen expression transforms mouse dermal fibroblasts to generate MCC-like tumors. Serial in vivo passaging reveals tumor evolution under immune pressure, providing a model to study immune evasion mechanisms in MCC.
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2026-09-09 | Reprogramming engineered autologous T cells to overcome resistance in patients with Merkel cell carcinoma.
Immune checkpoint inhibitors (ICIs) have transformed Merkel cell carcinoma (MCC) outcomes, but most patients with MCC develop resistance. We identified T cell receptor (TCR)MCC1, a highly avid, HLA-A*02:01-restricted TCR targeting the Merkel cell polyomavirus (MCPyV) oncoprotein large-T antigen15-23. Seven patients with ICI-refractory metastatic MCPyV+ MCC received TCRMCC1-transduced cells (TTCR-MCC1 cells) after lymphodepleting chemotherapy or HLA-enhancing interventions [radiation or interferon gamma-1b (Actimmune)], with concurrent ICIs (NCT03747484). TTCR-MCC1 cells trafficked to tumor sites and expressed a gene expression profile compatible with T cell activation, with tumor regression observed in two patients. However, therapeutic activity was limited by HLA class I silencing, a common mechanism of immune escape in MCC. In one patient, delayed tumor regression coincided with endogenous effector immune activation and restoration of MCC HLA expression, implying that robust local responses could reverse HLA silencing. To overcome this barrier, we engineered CD4 and CD8 TTCR-MCC1 cells to coexpress CD8αβ and a CD200R-CD28 switch receptor, enabling CD4 T cell engagement and T cell costimulation. These modifications enhanced tumor infiltration, increased HLA expression, and improved control of HLAlow MCC in vivo in mice. These findings support the feasibility of TCR-engineered cell therapy for MCPyV+ MCC and provide a blueprint for overcoming immune evasion via targeted localized enhancement of antigen presentation.
2026-04-17 | Systemic Therapies for the Treatment of Cutaneous Malignancies in Solid Organ Transplant Recipients.
Solid organ transplant recipients (SOTRs) face frequent advanced cutaneous malignancies, yet data guiding systemic therapy are limited. We conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses systematic review of immune checkpoint inhibitors (ICIs), talimogene laherparepvec (T-VEC), and Sonic Hedgehog Pathway Inhibitors (HPIs) for locally advanced or metastatic cutaneous squamous cell carcinoma, melanoma, Merkel cell carcinoma, and basal cell carcinoma in SOTRs, including a novel case from our institution. Outcomes included tumor response, graft rejection, and graft failure. Among 196 SOTRs treated with ICIs (101 cutaneous squamous cell carcinoma, 83 melanoma, 12 Merkel cell carcinoma), the overall response rate (ORR) was 39.3%, and lack of progression occurred in 58.0%. Graft rejection occurred in 36.9% and graft failure in 22.3%. A higher number of baseline immunosuppressive agents decreased odds of rejection (OR 0.55) and failure (OR 0.38). Tacrolimus was associated with reduced tumor response (OR 0.41), whereas mTOR-based regimens and cemiplimab were associated with fewer transplant rejection. T-VEC was reported in 10 SOTRs with an ORR of 90% and no graft rejection or failure. HPIs in six SOTRs with basal cell carcinoma demonstrated ORR of 83% without graft loss. ICIs provide antitumor activity but substantial graft-related risk, while T-VEC and HPIs show high response rates with no reported rejection.
2026-03-04 | Response of B Cells Specific for Polyomavirus-Derived Oncoprotein Is Predictive of Merkel Cell Carcinoma Tumor Control.
Merkel cell carcinomas (MCC) typically arise from the clonal integration of the Merkel cell polyomavirus. Immunogenic viral oncoproteins then lead to tumorigenesis. Oncoprotein-specific T cells are essential for anti-MCC immunity, but it is unclear whether B cells promote tumor control. In this study, we analyzed the frequency and phenotype of viral oncoprotein-specific and total B cells in blood samples from 47 patients with MCC and tumor samples from another 19 patients with MCC. The phenotype of blood B cells did not correlate with the outcomes of patients with MCC. In contrast, all 11 patients with robust oncoprotein-specific antibody-secreting and/or germinal center B cells in tumors experienced long-term MCC control. In vitro, B cells engineered to be specific for viral oncoproteins increased the sensitivity of oncoprotein-specific CD4+ T cells by more than 50-fold. Together, our findings suggest that cancer-specific B cells promote antitumor immunity via increased responses by T cells and that cancer-specific augmentation of B cells could be therapeutically relevant. See related Spotlight, p. 716.
2026-03-03 | ASO Visual Abstract: Evaluation of Talimogene Laherparepvec for the Treatment of Advanced Nonmelanoma Skin Cancers.
Our visual abstract highlights the primary question of our work, which was to evaluate the outcomes of patients who received talimogene laherparepvec (T-VEC), an oncolytic herpes virus, for advanced Merkel cell carcinoma (MCC) and squamous cell carcinoma (SCC). While T-VEC has been approved for use in melanoma, it is currently only being used in the off-label setting for nonmelanoma skin cancer (NMSC). In addition, many of our patients received T-VEC with concurrent immune therapy, which is a patient population that has not been thoroughly studied. Data were obtained through a retrospective chart review of patients with MCC or SCC who received T-VEC at our NCI-designated comprehensive cancer center. The cohort included ten patients with MCC and three with SCC; six patients received T-VEC alone and seven received T-VEC with concurrent immune therapy. Of note, all three patients who had SCC also received immune therapy. The overall response rate (ORR) of the cohort, defined as the percentage of complete and partial responses to therapy, was 53.8%, with six complete responses and one partial response. Of the six complete responses, four patients were disease-free at their date of last follow-up, which was an average of 25 months from completion of T-VEC treatment. Our work highlights the fact that durable response to T-VEC for patients with advanced NMSC is possible in the setting of a high rate of concurrent immune therapy administration. Further work should more rigorously explore the role that T-VEC may play in NMSC, with particular attention to its use with immune therapy ( https://doi.org/10.1245/s10434-026-19182-3 ).
2026-02-23 | Evaluation of Talimogene Laherparepvec for the Treatment of Advanced Nonmelanoma Skin Cancers.
Talimogene laherparepvec (T-VEC) is an intralesional, injectable oncolytic herpes virus that is FDA-approved to treat Stage III-IV melanoma. The utility of T-VEC for nonmelanoma skin cancers (NMSC), including Merkel cell carcinoma (MCC) and squamous cell carcinoma (SCC), as well as its use with concurrent immune therapy (IO), is poorly defined. The purpose of this study is to evaluate outcomes of T-VEC for MCC and SCC with and without concurrent immune therapy. This retrospective study included patients at a single institution with MCC or SCC and treated with T-VEC between May 2016 and May 2023. Abstracted cohort data were reported using descriptive statistics. Ten MCC and three SCC patients were eligible. Four MCC patients and all three SCC patients received concurrent pembrolizumab. Overall, six patients achieved complete response (CR), one had partial response (PR), and six had progressive disease (PD). Of the six patients who achieved CR, two recurred at 8 and 56 months. Those without recurrence had a durable response at a median follow-up of 25 months. Our initial experience with a small, single-institution cohort demonstrated tumor response to intralesional T-VEC with or without immunotherapy in some patients with NMSC. Nearly 50% of participants had a complete response; two-thirds of responders remained relapse-free at the time of follow-up. Some observed responses are not attributable to T-VEC alone due to high usage rates of IO. Future work should expand to larger cohorts and focus on its use with and without immune therapy.
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Drug Discovery Landscape
15 orphan drug designations for Cutaneous neuroendocrine carcinoma, including 4 approved therapies.
15 orphan drug designations for Cutaneous neuroendocrine carcinoma, including 4 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
a humanized bispecific monoclonal antibody against PD-L1 and 4-1BB | antibodies | FDA | Nanjing Leads Biolabs Co., Ltd. | |
topotecan liposome injection | small molecules | FDA | Fujifilm Pharmaceuticals U.S.A., Inc. | |
Retifanlimab [ZYNYZ] | antibodies | EMA | Approved | Incyte Biosciences Distribution B.V. |
bi-specific fragment crystallizable region (Fc) fusion protein containing cluster of differentiation 80 ectodomain as an N-terminal moiety and interleukin-2 variant as a C-terminal moiety conjugated with human immunoglobulin G4 Fc | proteins | FDA | — | GI Innovation, Inc. |
Navtemadlin | small molecules | EMA | Yes Pharmaceutical Development Services GmbH | |
cavrotolimod | oligonucleotides | FDA | Exicure, Inc. | |
retifanlimab-dlwr [Zynyz] | antibodies | FDA | Approved | Incyte Corporation |
navtemadlin | small molecules | FDA | Kartos Therapeutics, Inc. | |
activated natural killer[aNK]) | cell therapies | FDA | ImmunityBio, Inc. | |
pembrolizumab [Keytruda] | antibodies | FDA | Approved | MSD International Business GmbH |
Live-attenuated non-replicative Pseudomonas aeruginosa strain expressing large T antigen of Merkel cell polyomavirus | vaccines | EMA | — | APCure SAS |
Avelumab [Bavencio] | antibodies | EMA | Merck Europe B.V. | |
avelumab (Recombinant human monoclonal IgG1 antibody against programmed death ligand-1) [Bavencio] | antibodies | FDA | Approved | EMD Serono Research and Development Institute, Inc. |
Lorvotuzumab mertansine [IMGN901 (BB-10901 and huN901-DM1)] | antibodies | EMA | ImmunoGen Europe Limited | |
maytansinoid DM1-conjugated humanized monoclonal antibody N901 | antibodies | FDA | ImmunoGen, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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