Evaluation of radio-immunotherapy sequence on immunological responses and clinical outcomes in patients with melanoma brain metastases (ELEKTRA).

In patients with melanoma brain metastases (MBM), a combination of radiotherapy (RT) with immune checkpoint inhibitors (ICI) is routinely used. However, the best sequence of radio-immunotherapy (RIT) remains unclear. In an exploratory phase 2 trial, MBM patients received RT (stereotactic or whole-brain radiotherapy depending on the number of MBM) combined with ipilimumab (ipi) ± nivolumab (nivo) in different sequencing (Rad-ICI or ICI-Rad). Comparators arms included patients treated with ipi-free systemic treatment or without RT (in MBM-free patients). The primary endpoints were radiological and immunological responses in the peripheral blood. Secondary endpoints were progression-free survival (PFS) and overall survival (OS). Of 106 screened, 92 patients were included in the study. Multivariate analysis revealed an advantage for patients starting with RT (Rad-ICI) for overall response rate (RR: p = .007; HR: 7.88 (95%CI: 1.76-35.27)) and disease control rate (DCR: p = .036; HR: 6.26 (95%CI: 1.13-34.71)) with a trend for a better PFS (p = .162; HR: 1.64 (95%CI: 0.8-3.3)). After RT plus two cycles of ipi-based ICI in both RIT sequences, increased frequencies of activated CD4, CD8 T cells and an increase in melanoma-specific T cell responses were observed in the peripheral blood. Lasso regression analysis revealed a significant clinical benefit for patients treated with Rad-ICI sequence and immunological features, including high frequencies of memory T cells and activated CD8 T cells in the blood. This study supports increasing evidence that sequencing RT followed by ICI treatment may have better effects on the immunological responses and clinical outcomes in MBM patients.

Tebentafusp for the treatment of metastatic uveal melanoma.

Uveal melanoma is a rare disease; nevertheless, it is the most common primary intraocular malignancy among adults. Approximately half of affected patients will suffer from metastatic disease, mostly to the liver. No standard-of-care treatment exists for these patients. Median progression-free survival and overall survival for all types of treatment, including checkpoint inhibitors, have remained poor. However, the most recent phase III study results for tebentafusp, a member of a new-in-class molecule, are raising hopes for stage IV uveal melanoma patients. In this review, we examine the current literature, focusing on the most recent trial results for this new reagent. We evaluate the latest clinical results for tebentafusp and aim to shed light on its immunological strategy.

Uveal melanoma is a rare disease but is the most common tumor of the eye among adults. In approximately half patients who have uveal melanoma, it will spread to other parts of the body, mostly to the liver. There is no standard type of therapy for these patients. So far, all existing therapies have shown poor outcomes. However, the new treatment tebentafusp has shown encouraging results in a recent clinical study. In this review, we discuss the latest study results for tebentafusp and outline how it works as a treatment for uveal melanoma.

Complete Metabolic Response in FDG-PET-CT Scan before Discontinuation of Immune Checkpoint Inhibitors Correlates with Long Progression-Free Survival.

Checkpoint inhibitors have revolutionized the treatment of patients with metastasized melanoma. However, it remains unclear when to stop treatment. We retrospectively analyzed 45 patients (median age 64 years; 58% male) with metastasized melanoma from 3 cancer centers that received checkpoint inhibitors and discontinued therapy due to either immune-related adverse events or patient decision after an (18F)2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) combined with a low-dose CT scan (FDG-PET-CT) scan without signs for disease progression. After a median of 21 (range 1-42) months of immunotherapy an FDG-PET-CT scan was performed to evaluate disease activity. In these, 32 patients (71%) showed a complete metabolic response (CMR) and 13 were classified as non-CMR. After a median follow-up of 34 (range 1-70) months, 3/32 (9%) of CMR patients and 6/13 (46%) of non-CMR patients had progressed (p = 0.007). Progression-free survival (PFS), as estimated from the date of last drug administration, was significantly longer among CMR patients than non-CMR (log-rank: p = 0.001; hazard ratio: 0.127; 95% CI: 0.032-0.511). Two-year PFS was 94% among CMR patients and 62% among non-CMR patients. Univariable Cox regression showed that metabolic response was the only parameter which predicted PFS (p = 0.004). Multivariate analysis revealed that metabolic response predicted disease progression (p = 0.008). In conclusion, our findings suggest that patients with CMR in an FDG-PET-CT scan may have a favorable outcome even if checkpoint inhibition is discontinued.

Soluble immune checkpoints and T-cell subsets in blood as biomarkers for resistance to immunotherapy in melanoma patients.

Different mechanisms lead to immune checkpoint inhibitor (ICI) resistance. Identifying clinically useful biomarkers might improve drug selection and patients' therapy. We analyzed the soluble immune checkpoints sPD1, sPDL1, sLAG3, and sTIM3 using ELISA and their expression on circulating T cells using FACS in pre- and on-treatment blood samples of ICI treated melanoma patients. In addition, pre-treatment melanoma metastases were stained for TIM3 and LAG3 expression by IHC. Results were correlated with treatment response and progression-free survival (PFS). Resistance to anti-PD1 treatment (n = 48) was associated with high pre-treatment serum levels of sLAG3 (DCR: p = .009; PFS: p = .018; ROC cutoff >148 pg/ml) but not sPD1, sPDL1 or sTIM3. In contrast, resistance to ipilimumab plus nivolumab (n = 42) was associated with high levels of sPD1 (DCR: p = .019, PFS: p = .046; ROC cutoff >167 pg/ml) but not sPDL1, sLAG3 or sTIM3. Both treatment regimens shared a profound increase of sPD1 serum levels with treatment (p < .0001). FACS analysis revealed reduced frequencies of CD3+ CD8+ PD1 + T cells (p = .028) in anti-PD1-resistant patients, whereas increased frequencies of CD3+ CD4+ LAG3 + T cells characterized patients resistant to ipilimumab plus nivolumab (p = .033). Unlike anti-PD1 monotherapy, combination blockade significantly increased proliferating T cells (CD3+ CD8+ Ki67 + T cells; p < .0001) and eosinophils (p = .001). In melanoma metastases, an increased infiltration with TIM3+ or LAG3 + T cells in the tumor microenvironment correlated with a shorter PFS under anti-PD1 treatment (TIM3: p = .019, LAG3: p = .07). Different soluble immune checkpoints characterized checkpoint inhibitor-resistant melanoma. Measuring these serum markers may have the potential to be used in clinical routine.

Physicians' level of hindrance by body hair in dermatoscopy and clinical benefit of an automated hair removal algorithm.

BACKGROUND AND OBJECTIVES: Dermatoscopy may be hindered by body hair, and the development of an automated hair removal algorithm (AuHRA) might improve the diagnostic accuracy. However, the physicians' exact level of hindrance and the clinical benefit attained by AuHRA has not been assessed. The objectives of this study are to quantify the physicians' level of hindrance by body hair and the level of improvement in the visibility of underlying dermatoscopic patterns after application of AuHRA to digital images of hair-covered nevi. PATIENTS AND METHODS: A cross-sectional reader study including 59 sets of dermatoscopic images of benign nevi that were presented to six dermatologists. Each set included three images of one individual nevus (unshaved/physically shaved/digitally shaved with AuHRA), which were compared to each other within each set to assess the level of improvement caused by hair removal. RESULTS: In comparison to unshaved lesions, dermatologists attributed the highest mean level of improvement to a physical shave (+1.36, p < 0.001) followed by AuHRA's digital shave (+0.79, p < 0.001). The majority of dermatologists considered the application of AuHRA as helpful and confirmed a medical need. CONCLUSIONS: The dermatologists in our study confirmed a substantial impairment of the dermatoscopic examination by body hair. We demonstrated a clinical benefit attained by AuHRA in comparison to unshaved or physically shaved lesions.

Immunotherapies for the Treatment of Uveal Melanoma-History and Future.

BACKGROUND: Uveal melanoma is the most common primary intraocular malignancy among adults. It is, nevertheless, a rare disease, with an incidence of approximately one case per 100,000 individuals per year in Europe. Approximately half of tumors will eventually metastasize, and the liver is the organ usually affected. No standard-of-care treatment exists for metastasized uveal melanoma. Chemotherapies or liver-directed treatments do not usually result in long-term tumor control. Immunotherapies are currently the most promising therapy option available. METHODS: We reviewed both relevant recent literature on PubMed concerning the treatment of uveal melanoma with immunotherapies, and currently investigated drugs on ClinicalTrials.gov. Our own experiences with immune checkpoint blockers are included in a case series of 20 patients. RESULTS: Because few clinical trials have been conducted for metastasized uveal melanoma, no definitive treatment strategy exists for this rare disease. The outcomes of most immunotherapies are poor, especially compared with cutaneous melanoma. However, encouraging results have been found for some very recently investigated agents such as the bispecific tebentafusp, for which a remarkably increased one-year overall survival rate, and similarly increased disease control rate, were observed in early phase studies. CONCLUSIONS: The treatment of metastatic uveal melanoma remains challenging, and almost all patients still die from the disease. Long-term responses might be achievable by means of new immunological strategies. Patients should therefore be referred to large medical centers where they can take part in controlled clinical studies.

In vitro osteogenic differentiation of adipose-derived mesenchymal stem cell spheroids impairs their in vivo vascularization capacity inside implanted porous polyurethane scaffolds.

Undifferentiated adipose-derived mesenchymal stem cell (adMSC) spheroids are attractive vascularization units for tissue engineering. Their osteogenic differentiation further offers the possibility of directed generation of bone constructs. The aim of this study was to analyze how this differentiation affects their in vivo vascularization capacity. Green fluorescent protein (GFP)-positive adMSCs were isolated from C57BL/6-TgN(ACTB-EGFP)1Osb/J mice for the generation of undifferentiated and differentiated spheroids using the liquid overlay technique. Subsequently, polyurethane scaffolds were seeded with these spheroids and successful osteogenic differentiation was proven by von Kossa staining and high-resolution microtomography. The scaffolds were then implanted into dorsal skinfold chambers of C57BL/6 wild-type mice to analyze their vascularization and incorporation using intravital fluorescence microscopy, histology and immunohistochemistry. Scaffolds seeded with differentiated spheroids exhibited a markedly impaired vascularization. Immunohistochemical analyses revealed that this was caused by the lost ability of differentiated spheroids to form GFP-positive microvascular networks inside the scaffolds. This was associated with a reduced tissue incorporation of the implants. Moreover, they no longer exhibited a mineralized matrix after the 14day implantation period, indicating the dedifferentiation of the spheroids under the given in vivo conditions. These findings indicate that osteogenic differentiation of adMSC spheroids markedly impairs their vascularization capacity. Hence, it may be reasonable to combine adMSC spheroids of varying differentiation stages in scaffolds for bone tissue engineering to promote both vascularization and bone formation.