Tebentafusp induces a T cell driven rash in melanocyte-bearing skin as an adverse event consistent with the mechanism of action
Jessica C. HasselSarah StanhopeAlexander Greenshields‐WatsonDevayani MachirajuAlexander EnkChristopher HollandShaad E. AbdullahAdel BenlahrechMarlana OrloffPaul NathanSophie Piperno‐NeumannRamon StaegerReinhard DummerBarbara Meier
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Abstract:
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. In this study, we analyzed clinical data from the randomized 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, whereas gene expression related to immunity and cytokine signaling increased. When adjusted for baseline prognostic features, patients with rash within the first week of tebentafusp treatment had the same overall survival as patients without a rash in the phase 3 randomized trial IMCgp100-202 (hazard ratio = 0.84, 95% confidence interval = 0.53-1.32). In summary, skin rash is an off-tumor, on-target effect of tebentafusp against gp100+ melanocytes, in line with the mechanism of action.Keywords:
Melanocyte
Mechanism of Action
Hair bulb melanocytes involved in the expression of the coat colors of mice are derived from epidermal melanocytes. The biological study of epidermal melanocytes is important to understand the expression of the coat color. Analysis of the melanocyte and melanoblast-melanocyte population in the mouse epidermis has shown marked strain differences, suggesting that the two populations are regulated by genetic factors. From the results of genetic crosses between C57BL/1OJ and C3H/He mice semidominant genes were shown to be involved in regulating the two populations. The two populations in C57BL/1OJ-A/A congenic mouse did not differ from those in C57BL/1OJ. The distributions of the two populations in C3H/He were gradually transferred to those in C57BL/1OJ by repeated backcrossing.The semidominant genes are thought to affect the melanocyte proliferation, melanocyte differentiation, or induction of tyrosinase activity by MSH. Such effects may change the pigmentation in the hair bulb and produce a variety of the hair color intensity of mice, which may in turn be influenced by selection, mutation, random mating, and environment.
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Epidermis (zoology)
Melanocortin 1 receptor
Pigmentation disorder
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Melanosome
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Autologous melanocyte transplantation plays an important role in the treatment of vitiligo.Previous studies have indicated that, compared with melanocytes growing in monolayers, melanocyte spheroids have a better survival in growth factor- and serum-deprived conditions.Melanocyte spheroids were obtained from human epidermis by repetitive long-term trypsinization and maintained an aggregated morphology for a short period in certain conditions.Melanocyte spheroids were capable of growing into normal dendritic melanocytes in monolayer when they were harvested and reinoculated in 24-well plates. Immunohistochemical analysis of the melanocyte spheroids revealed that they were positive for HMB45, a melanosome-specific marker. No melanomas occurred when melanocyte spheroids were transplanted into mice.Our study provides a promising approach for melanocyte transplantation to treat vitiligo.
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Objective To investigate the immunization status in children with measles rash. Methods Flow cytometry and ELISA was employed to investigate the changes of CD4+T,CD8+T,TL-2,TL-4,TL-6,TL-10 in early rash and after rash,and then compared with those in healthy children. Results CD4+T decreased,while CD8+T increased in early rash,and returned to normal after rash. TL-2 increased significantly in early rash(P0.01) ,and decreased after the rash,but still maintained high level(P0.05) . TL-4,TL-6 was low and increased immediately after the rash(P0.05) ,and TL-10 always maintained a high level in early rash and after rash(P0.05) . All the changes had no relation with gender and age,but in younger patients,the younger the patients,the greater CD4+T declined may be in the early rash. Conclusion There is the brief reversible immunosuppression in children with measles,TH1 dominates the early while TH2 plays an important role after rash. TL-10 plays an important regulatory role in children with measles immunization. Immune disorders may be more serious in younger patients
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Objective:To evaluate the relationship between erlotinib-induced skin rash and clinical outcome and explore the effective way to prevent skin rash.Methods:The data from 76 non-small cell lung cancer(NSCLC) patients who experienced erlotinib-induced skin rash from Dec 2005 to Sep 2008 were collected.All the patients were confirmed with NSCLC by pathological and cytological examination and received erlotinib 150 mg/d till they had progressive disease or intolerable adverse reaction.The severity of skin rash was recorded and graded according to National Cancer Institute-Common Toxicity Criteria(NCI-CTC).The therapeutic outcome of skin rash was observed.Results:The skin rash develops as early as 3 days after commencement of erlotinib therapy,with median onset at 8 days.Twenty-seven(35.5%) patients experienced grade 1 skin rash,44 patients(57.9%) had grade 2 and 5 cases(6.6%) had grade 3 skin rash.A statistically significant correlation was observed between skin rash and erlotinib therapy.The disease-controlling rate was 63.0% for grade 1 skin rash patients including 5 cases with partial remission and 12 cases with stable disease and 91.8% for grade 2/3 skin rash patients including 32 cases with partial remission and 13 cases with stable disease(P0.05).The median time to progression(TTP) and median overall survival(OS) were prolonged in patients experienced grade 2/3 skin rash compared with those in patients with grade 1 skin rash(TTP:5.1 months vs 9.7 months,P0.01;OS:10.0 months vs 14.6 months,P0.01).The skin rash was alleviated in 60 out of 76 patients(78.9%).Conclusion:Skin rash is a potent surrogate marker of favorable outcome in patients who received erlotinib treatment.It was tolerable to most patients.Appropriate therapy may be useful in decreasing the severity of skin rash.
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It is not uncommon for tuberculosis patients taking 3 or 4 kinds of antituberculous agents long-term to develop adverse effects such as rash or hepatic dysfunction.However,the frequency of rash is unclear because many cases are based on patients' self-reports.The purpose of this study was to clarify the incidence of rash caused by antituberculous agent as well as the relationship between rash and other factors such as other adverse effects,clinical test values and period of taking antituberculous agents until appearance of rash.We conducted a retrospective search of medical records for inpatients with tuberculosis at Tokyo Hospital from October 1,2004 to September 30,2006.There were 266 subjects and rash developed in 100 of them (38%).In most cases,the rash was only mild and easily controlled with antiallergics.However,rash was severe in 26 patients requiring the reduction or discontinuation of antituberculous agents.We noted no difference in rash occurrence rate among prescriptions for antituberculous agents and no relationship between rash and other factors was observed.These results indicate that the frequency of rash caused by antituberculous agents is high and that it is important to judge the severity of each case in order to perform appropriate treatment.
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Objective To summarize the experience of identifying rash of the pediatric patients and improve the recognition rate of rash.Methods A total of 419 pediatric outpatients with rash were recruited.The characteristics of rash,accompanying symptoms,doctors diagnose and the status of identify triage wereanalyzed.Results The average accuracy of triage of rash Was 76.13%.11le accuracy of triage of rash in allersic skin diseases was 82.4% and in viral or bacterial infectious disases was 66.3%.The top five triage diseases were eczenma,acute urticaria,drug rash,chicken pox,hand,foot and mouth disease.Conclusions Since the pediatric patients'rash con be found in a vailety of diseases,triage nurses should carefully observe the performance and characteristics of the rash in order to prevent errors triage.
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Children; Rash; Triage
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The survival benefit from gemcitabine plus erlotinib was on average marginal for advanced pancreatic cancer (APC) patients. Skin rash developed shortly after starting treatment seemed to be associated with better efficacy and might be used to assist clinical decision-making, but the results across studies were inconsistent. Thus, we conducted a systematic review and meta-analysis.PubMed, Embase, Cochrane Central Register of Controlled Trials, three Chinese databases, and the abstracts of important conferences were searched for eligible studies. The primary outcome was overall survival (OS), and the secondary outcomes were progression-free survival (PFS) and objective response. The random-effects model was used to pool results across studies if heterogeneity was substantial. Otherwise, the fixed-effect model was used.A total of 16 studies with 1,776 patients were included. Patients who developed skin rash during treatment had longer OS (8.9 vs 4.9 months, HR=0.57, 95% CI 0.50-0.64) and longer PFS (4.5 vs 2.4 months, HR=0.53, 95% CI 0.40-0.68) than those who did not. A dose- response relationship was also observed for both OS (HR=0.64 for grade-1 rash vs no rash and HR=0.46 for ≥grade-2 rash vs no rash) and PFS (HR=0.72 for grade-1 rash vs no rash and HR=0.43 for ≥grade-2 rash vs no rash).Skin rash was associated with better OS and PFS in APC patients treated with gemcitabine plus erlotinib. It might be used as a marker for efficacy to guide clinical decision-making toward a more precise and personalized treatment.
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Summary Hair follicle reconstitution analysis was used to test the contribution of melanocytes or their precursors to regenerated hair follicles. In this study, we first confirmed the process of chimeric hair follicle regeneration by both hair keratinocytes and follicular melanocytes. Then, as first suggested from the differential growth requirements of epidermal skin melanocytes and non‐cutaneous or dermal melanocytes, we confirmed the inability of the latter to be involved as follicular melanocytes to regenerate hair follicles during the hair reconstitution assay. This clear functional discrimination between non‐cutaneous or dermal melanocytes and epidermal melanocytes suggests the presence of two different melanocyte cell lineages, a finding that might be important in the pathogenesis of melanocyte‐related diseases and melanomas.
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Dermal papillae
Follicular cell
Epidermis (zoology)
Hair cycle
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