Tebentafusp induces a T cell driven rash in melanocyte-bearing skin as an adverse event consistent with the mechanism of action.

Tebentafusp is a gp100xCD3 bispecific ImmTAC designed to redirect polyclonal T cells against cells presenting the melanocyte lineage specific antigen gp100 on HLA-A*02:01. Skin-related adverse events, predominantly rash, are frequent and occur within a few hours after initial infusions, yet the mechanisms are unknown. Here we analysed clinical data from the randomised phase 3 trial (NCT03070392) of tebentafusp (n=252) versus investigator's choice (n=126). Translational analyses were performed on paired on-treatment skin samples from 19 patients collected in the phase 1 trial (NCT01211262). Our analyses showed that rash is a clinical manifestation of tebentafusp-induced recruitment of T cells to cutaneous melanocytes. Development of rash depended on baseline expression levels of gp100 and other melanin pathway genes in the skin. On treatment, melanocyte number was reduced and expression of melanocytic genes decreased, while gene expression related to immunity and cytokine signalling increased. When adjusted for baseline prognostic features, patients with rash within the first week of tebentafusp treatment had the same overall survival compared to patients without a rash in the phase 3 randomized trial IMCgp100-202 (HR 0.84; 95% CI 0.53-1.32). In summary, skin rash is an off-tumour, on-target effect of tebentafusp against gp100+ melanocytes, in line with the mechanism of action.

Ustekinumab for pyoderma gangrenosum-like skin ulcerations in late-onset leukocyte adhesion deficiency.

Background: Leukocyte adhesion deficiency type 1 (LAD-1) is a congenital immunodeficiency leading to impaired trafficking of neutrophils to inflammation sites. Solitary or multiple pyoderma gangrenosum (PG)-like skin ulcers (PGLUs) have been reported previously in 13 children (aged 0.5-19 years) with LAD-1. Objective: Our aim was to report the case of a 10-year-old boy presenting with PGLUs as the first manifestation of LAD-1 treated with ustekinumab. Methods: We obtained in situ cytokine profiles. Results: PGLUs were triggered by cutaneous ringworm infection (Trichophyton tonsurans). Skin biopsy samples showed increased intralesional expression of IL-17A, Il-23, and IL-1ß as compared with their expression in healthy controls. After an unsuccessful attempt at treatment with oral methylprednisolone, ustekinumab induced regression of the ulcerations, associated with complete normalization of the cytokine profile. Conclusions: PGLUs, triggered by ringworm infection, can be a late harbinger of LAD-1. Ustekinumab is a safe and effective therapeutic option for patients with LAD-1 and PGLUs while bridging the time until stem cell transplantation.

Cutaneous Adverse Events of Systemic Melanoma Treatments: A Retrospective Single-Center Analysis.

Recent progress in the treatment of advanced melanoma has led to the improved survival of affected patients. However, novel treatments also lead to considerable and distinct skin toxicity. To further characterize cutaneous adverse events (AE) of systemic treatments, we conducted a single-center retrospective study of biopsy-proven cutaneous adverse events of melanoma treatment over a period of 10 years at the University Hospital of Zurich, Switzerland. In 102 identified patients, 135 individual skin AEs developed. Immune checkpoint blockade (ICB) was causal for 81 skin AEs, and 54 were related to targeted therapies (TT). Recorded types of skin AEs included lichenoid, maculopapular, acneiform, urticarial, panniculitis, folliculitis, psoriasiform, granulomatous, eczematous, and others. The incidence of skin AEs was higher with TT (18.54%) than with ICB (9.64%, p = 0.0029). Most AEs were low-grade, although 19.21% of AEs were common terminology criteria for adverse events (CTCAE) Grades 3 or 4. A large spectrum of skin AEs was documented during treatment of advanced melanoma, and distinct phenotypes were observed, depending on treatment classes. AEs occurred earlier during treatment with TT than with ICB, and distinct types of skin AEs were associated with respective treatment classes. This study comprehensively describes skin AEs occurring during systemic treatment for melanoma at a single center.

Cutaneous lichenoid drug eruptions: A narrative review evaluating demographics, clinical features and culprit medications.

Cutaneous lichenoid drug eruptions (LDE) are adverse drug reactions (ADR) characterized by symmetric, erythematous, violaceous papules reminiscent but rarely fully characteristic of lichen planus (LP). We aimed to analyse the literature describing cases of LDE within the last 20 years to provide additional insight into culprit drugs, typical latency to onset of the eruption, the spectrum of clinical presentations, severity and management. A literature search was conducted in MEDLINE between January 2000 and 27 January 2021. The keywords 'lichenoid drug rash' and 'lichenoid drug eruption' were used. Cases were included if LDE diagnosis was made, and culprit drugs were identified. A total of 323 cases with LDE were identified from 163 published case reports and studies. The mean patient age was 58.5 years (1 month to 92 years), and 135 patients (41.8%) were female. Checkpoint inhibitors (CKI) were the most frequently reported culprit drugs (136 cases; 42.1%), followed by tyrosine kinase inhibitors (TKI) (39 cases; 12.0%) and anti-TNF-α-monoclonal antibodies (13 cases; 4.0%). The latency between initiation of the drug and manifestation was 15.7 weeks (range: 0.1-208 weeks). After discontinuing the culprit drug, the median time to resolution was 14.2 weeks (range: 0.71-416 weeks). One hundred thirty-six patients (42.1%) were treated with topical, and 54 patients (16.7%) with systemic glucocorticoids. Overall, we conclude that, albeit rare, LDE is challenging to diagnose ADR induced by mostly CKI, TKI, and biologics. Treatment modalities resemble that of lichen planus, and the culprit drugs had to be discontinued in only 26%, which is low compared with other types of adverse drug reactions. This is probably due to the low risk of aggravation (e.g. toxic epidermal necrolysis) if the drug is continued and the benefit/risk ratio favouring the drug, as is often the case in cancer therapy.

Dermatofibrosarcoma Protuberans: The Current State of Multidisciplinary Management.

Dermatofibrosarcoma protuberans (DFSP) is a rare, infiltrative, soft tissue tumor. It has a propensity for deep invasion but a low risk for distant metastasis. The classic presentation is a slowly progressive, painless, and erythematous to purpuric patch on the trunk or arms. A deep, subcutaneous punch biopsy or incisional biopsy should be performed for diagnosis in all suspected cases; wide undermining of the skin is to be avoided for minimizing the risk of tumor seeding and for retaining the feasibility of histopathologic examination of re-excisions. Histopathologic distinction of DFSP from dermatofibroma requires immunohistochemical assessment for CD34, factor XIIIa, nestin, apolipoprotein D, and cathepsin K. Management of this cutaneous sarcoma involves a multidisciplinary oncologic approach. Surgical excision is usually the first step in management. DFSP has a high propensity for local recurrence, even when surgical margins are negative; therefore, radiation therapy or rarely systemic therapy is recommended, especially for locally advanced or metastatic cases. The indolent nature of DFSP requires lifelong surveillance for recurrence; however, most recurrences occur within 3 years of the primary excision. The median time for the development of a local recurrence is estimated to be 32 months. An emerging theragnostic transmembrane receptor target, folate hydrolase-1 (FOLH1; prostate-specific membrane antigen), has been expressed in benign dermatofibromas and in high-grade sarcomatous phenotypes. These findings suggest that DFSP may also express FOLH1, which could allow for surveillance with FOLH1 PET/CT and antibody-mediated brachytherapy.

IL-36γ drives skin toxicity induced by EGFR/MEK inhibition and commensal Cutibacterium acnes.

Epidermal growth factor receptor (EGFR) and MEK inhibitors (EGFRi/MEKi) are beneficial for the treatment of solid cancers but are frequently associated with severe therapy-limiting acneiform skin toxicities. The underlying molecular mechanisms are poorly understood. Using gene expression profiling we identified IL-36γ and IL-8 as candidate drivers of EGFRi/MEKi skin toxicity. We provide molecular and translational evidence that EGFRi/MEKi in concert with the skin commensal bacterium Cutibacterium acnes act synergistically to induce IL-36γ in keratinocytes and subsequently IL-8, leading to cutaneous neutrophilia. IL-36γ expression was the combined result of C. acnes-induced NF-κB activation and EGFRi/MEKi-mediated expression of the transcription factor Krüppel-like factor 4 (KLF4), due to the presence of both NF-κB and KLF4 binding sites in the human IL-36γ gene promoter. EGFRi/MEKi increased KLF4 expression by blockade of the EGFR/MEK/ERK pathway. These results provide an insight into understanding the pathological mechanism of the acneiform skin toxicities induced by EGFRi/MEKi and identify IL-36γ and the transcription factor KLF4 as potential therapeutic targets.

Newly Defined ATP-Binding Cassette Subfamily B Member 5 Positive Dermal Mesenchymal Stem Cells Promote Healing of Chronic Iron-Overload Wounds via Secretion of Interleukin-1 Receptor Antagonist.

In this study, we report the beneficial effects of a newly identified dermal cell subpopulation expressing the ATP-binding cassette subfamily B member 5 (ABCB5) for the therapy of nonhealing wounds. Local administration of dermal ABCB5+ -derived mesenchymal stem cells (MSCs) attenuated macrophage-dominated inflammation and thereby accelerated healing of full-thickness excisional wounds in the iron-overload mouse model mimicking the nonhealing state of human venous leg ulcers. The observed beneficial effects were due to interleukin-1 receptor antagonist (IL-1RA) secreted by ABCB5+ -derived MSCs, which dampened inflammation and shifted the prevalence of unrestrained proinflammatory M1 macrophages toward repair promoting anti-inflammatory M2 macrophages at the wound site. The beneficial anti-inflammatory effect of IL-1RA released from ABCB5+ -derived MSCs on human wound macrophages was conserved in humanized NOD-scid IL2rγ null mice. In conclusion, human dermal ABCB5+ cells represent a novel, easily accessible, and marker-enriched source of MSCs, which holds substantial promise to successfully treat chronic nonhealing wounds in humans. Stem Cells 2019;37:1057-1074.