Vitiligo-Specific Soluble Biomarkers as Early Indicators of Response to Immune Checkpoint Inhibitors in Metastatic Melanoma Patients

2021 ◽  
Author(s):  
Maria Luigia Carbone ◽  
Gabriele Madonna ◽  
Marianna Bove ◽  
Simona Mastroeni ◽  
Lauretta Levati ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Checkpoint Inhibitors ◽  
Serum Levels ◽  
Response To Treatment ◽  
Number Of Patients ◽  
Treatment Characteristic ◽  
Favorable Prognostic Factor ◽  
Melanoma Patients ◽  
Pre Treatment ◽  
Early Indicators

Abstract Background: Immunotherapy with checkpoint inhibitors strongly improved the outcome of metastatic melanoma patients. However, not all the patients respond to treatment and identification of prognostic biomarkers able to select patients who would respond to this therapy is of outmost importance. Considering that development of vitiligo-like depigmentation in melanoma patients represents both an adverse event of immunotherapy and a favorable prognostic factor for overall survival, we analyzed known soluble biomarkers of vitiligo to validate them as early indicators of response to checkpoint inhibitors in metastatic melanoma.Methods: Fifty-seven patients with metastatic melanoma receiving anti-PD-1 checkpoint inhibitor immunotherapy were enrolled. Patient sera and plasma were evaluated for vitiligo biomarkers at pre-treatment and after 1 and 3 months of therapy. Patients were divided and analyzed according to the best overall response to treatment. Characteristic vitiligo proteins were analyzed by ELISA, while expression of circulating microRNAs, distinctive of vitiligo, was determined using real-time RT-PCR.Results: Basal serum CD25 levels were higher in stable and responder melanoma patients and remained higher during the first 3 months of anti-PD-1 therapy compared to non-responder patients. The chemokine CXCL9 was absent in non-responder patients before therapy beginning. Moreover, an increase of CXCL9 levels was observed at 1 and 3 months of therapy for all patients, although higher CXCL9 amounts were present in stable and responder compared to non-responder patients. Finally, higher levels of miR-19b, miR-25 and miR-16 were observed after 1 month of therapy in plasma of stable and responder compared to non-responder patients.Conclusions: Serum levels of CD25 and CXCL9 before and during the first months of treatment could represent biomarkers of response to anti-PD-1 immunotherapy in metastatic melanoma patients. Plasmatic miR-19b, miR-25 and miR-16 could also represent possible early biomarkers of response to anti-PD-1 treatment, but they must be validated in a higher number of patients.

VEGF serum levels during bevacizumab plus paclitaxel combination in metastatic melanoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8534-8534 ◽  
Author(s):  
S. Viteri ◽  
A. Diaz-Lagares ◽  
A. González ◽  
S. Martin Algarra ◽  
P. Redondo ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Serum Levels ◽  
Median Number ◽  
Hematological Toxicity ◽  
The Novel ◽  
Response Evaluation ◽  
Previously Treated ◽  
Melanoma Patients ◽  
Pre Treatment ◽  
One Year

8534 Background: Angiogenesis has an important role in melanoma progression. A prognostic value has been suggested for serum VEGF in melanoma. The novel agent bevacizumab (Bev) has demonstrated in combination with chemotherapy high activity in other tumors. We studied the combination of weekly paclitaxel (TXL) and bevacizumab (Bev) in previously treated metastatic melanoma patients (pts) and analyzed serum VEGF levels before and during treatment. Methods: TXL 70 mg/m2 weekly and Bev 10 mg/kg biweekly during 5 consecutive weeks every six weeks. VEGF levels pre-treatment and at response evaluation were analyzed with enzyme-linked immunoassays. Results: 13 pts have been treated: male/female: 4/9, median age: 45 (29–71), median PS ECOG: 2 (0–3), stage distribution M1b/ M1c: 2/11, high LDH levels: 8 pts. Median number of previous lines: 3 (1–6). Hematological toxicity: G III lymphopenia in 6 pts, G III leucopenia in 2 pts, G III thrombocytopenia in 1 pt and G I anemia in 3 pts. Non-hematological toxicities: alopecia in 7 pts, diarrhea G I in 4 pts, epistaxis G I in 8 pts. Response (and time to progression, months [m]): 2/12 PR (6 m and 4 m), 1/12 MR (6 m), 7/12 SD (7+ m, 7 m, 4 m, 4+ m, 3 m, 3 m, 3+ m), 2/12 PD. Responses were seen in soft tissue, lung and brain metastases. Overall survival at 12 months was 43.3%. Pre-treatment serum levels were high in five patients and they became negative at response evaluation (1 pt achieved MR, 3 pts SD and 1 pt PD). Unexpectedly patients with high pre-treatment VEGF levels had long survival: 4/5 patients remain alive and 2 pts have survived over one year: 12+ m, 12+ m, 5 m, 3+ m, 3.5+ m.VEGF was undetectable pre-treatment and at response evaluation in 7 pts, only 2/7 pts remained alive: 15+ m, 8 m, 7.5 m, 7 m, 6.8+ m, 3 m, 2.6 m. Conclusions: The combination of Bev and weekly TXL is active in melanoma and it has a good tolerance profile. Serum VEGF could be a good marker in this setting. Further research is needed to confirm these results. No significant financial relationships to disclose.

scholarly journals Circulating mucosal-associated invariant T cells identify patients responding to anti-PD-1 therapy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sara De Biasi ◽  
Lara Gibellini ◽  
Domenico Lo Tartaro ◽  
Simone Puccio ◽  
Claudio Rabacchi ◽  
...  
Keyword(s):  
T Cells ◽  
Metastatic Melanoma ◽  
Checkpoint Inhibitors ◽  
Granzyme B ◽  
In Silico Analysis ◽  
Response To Treatment ◽  
Multiparameter Flow Cytometry ◽  
Mait Cells ◽  
Single Cell Rna Sequencing ◽  
Silico Analysis

AbstractImmune checkpoint inhibitors are used for treating patients with metastatic melanoma. Since the response to treatment is variable, biomarkers are urgently needed to identify patients who may benefit from such therapy. Here, we combine single-cell RNA-sequencing and multiparameter flow cytometry to assess changes in circulating CD8+ T cells in 28 patients with metastatic melanoma starting anti-PD-1 therapy, followed for 6 months: 17 responded to therapy, whilst 11 did not. Proportions of activated and proliferating CD8+ T cells and of mucosal-associated invariant T (MAIT) cells are significantly higher in responders, prior to and throughout therapy duration. MAIT cells from responders express higher level of CXCR4 and produce more granzyme B. In silico analysis support MAIT presence in the tumor microenvironment. Finally, patients with >1.7% of MAIT among peripheral CD8+ population show a better response to treatment. Our results thus suggest that MAIT cells may be considered a biomarker for patients responding to anti-PD-1 therapy.

scholarly journals 90. Fecal Microbiota Transplantation in Metastatic Melanoma Patients Resistant to Anti-PD-1 Treatment

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S7-S7 ◽  
Author(s):  
Ilan Youngster ◽  
Erez Baruch ◽  
Lior Katz ◽  
Adi Lahat ◽  
Tal Brosh-Nissimov ◽  
...  
Keyword(s):  
T Cell ◽  
Gut Microbiota ◽  
Metastatic Melanoma ◽  
Cell Activity ◽  
Complete Response ◽  
Fecal Microbiota ◽  
Post Treatment ◽  
Response To Treatment ◽  
Durable Response ◽  
Melanoma Patients

Abstract Background Most metastatic melanoma patients treated with Programed cell Death (PD)-1 blockers fail to achieve a durable response. The gut microbiota profoundly affects host immunity, and fecal microbiota transplantations (FMT) have been shown to enhance anti-PD-1 effectiveness in murine models. We report initial safety and efficacy results from the first patients treated in a Phase I study of FMT and re-induction anti-PD-1 therapy in anti-PD-1 refractory metastatic melanoma. Methods FMT donors were two metastatic melanoma patients who achieved a durable complete response to treatment. FMT recipients were metastatic melanoma patients who failed at least one anti-PD-1 line of treatment. FMT was conducted by both colonoscopic and oral administration, followed by anti-PD-1 re-treatment. Each recipient underwent pre- and post-treatment stool sampling, tissue biopsy of both gut and tumor, and total body imaging. Results Five patients with treatment-resistant metastatic melanoma were recruited. No FMT-related or immunotherapy-related adverse events were observed. To assess engraftment of the new microbiota, recipients were paired with their respective donors and stool 16S rDNA gene sequence analysis was performed. Sequencing results demonstrated post-FMT compositional dissimilarity (Unweighted UniFrac, P = 0.04, FDR q = 0.22) between the two recipient–donor groups. Specific taxonomic dynamics included post-FMT increased abundance of Paraprevotellaceae, previously associated in descriptive studies with responsiveness to treatment, and significant reductions in abundance of β-proteobacteria, previously associated with reduced response to treatment. Immunohistochemical stains of biopsies demonstrated an increased post-FMT infiltration of antigen presenting cells (CD68+) in the gut (paired T-test, P = 0.008) and in the tumor (P = 0.0076). Post-treatment intra-tumoral CD8+ T-cell infiltration was also increased. Three patients had a partial or complete response to treatment post-FMT. Conclusion FMT in metastatic melanoma patients seems to be safe and may alter recipient gut microbiota to resemble that of a responder donor. This alteration may result in intra-tumoral T-cell activity, and conferred clinical and radiological benefit in several recipients previously unresponsive to treatment. Disclosures All Authors: No reported Disclosures.

Prognostic relevance of neutrophil to lymphocyte ratio (NLR) before anti-PD1 therapy in metastatic melanoma patients.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e21045-e21045
Author(s):  
Daniel Vilarim Araujo ◽  
Rafael Vanin de Moraes ◽  
Victor Aurelio Ramos Sousa ◽  
Mauro Daniel Spina Donadio ◽  
Aline Fusco Fares ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Metastatic Melanoma ◽  
Proportional Hazards ◽  
Checkpoint Inhibitors ◽  
Prognostic Significance ◽  
Multivariable Analysis ◽  
Continuous Variable ◽  
Cox Proportional Hazards ◽  
Rank Test ◽  
Melanoma Patients

e21045 Background: Biomarkers to select the patients most likely to benefit from checkpoint inhibitors are urged. NLR is a simple way of measuring systemic inflammation and is an independent predictor of survival before Anti-CTLA4 therapy. We hypothesized if NLR is also a predictor of survival before Anti-PD1 therapy. Methods: We performed a retrospective review of the medical records of all consecutive metastatic melanoma patients who received Nivolumab treatment from January/2014 – February/2017, including 53 patients prospectively collected from an Expanded Access Program. Of 86 patients, 83 patients were included for demographic and efficacy analysis, and 74 had information about baseline pre-treatment NLR. We analyzed NLR as a continuous variable and categorised ≥ 5 vs. < 5. Kaplan-Meier method was used for survival analysis. Long-rank test compared categories and Cox proportional hazards regression model was used to assess the prognostic significance of baseline NLR in univariate and multivariable analysis. Results: Median PFS for the entire population was 6,407 months (3,28 – 9,52) and median OS was not reached (NR) with a median FU of 10,74 months. The median NLR ratio was 3,11 (0,87 – 19). 18 patients (24,3%) had a ≥ 5 NLR vs. 56 (75,7%) < 5. Median PFS for NLR ≥ 5 was: 2,3 (1,75 – 2,84) vs. 12,02 (5,11 – 18,93) for < 5 (HR = 3,11; IC95% 1,52 – 6,27; p = 0,001). Median OS ≥ 5: 3,05 (2,06 – 4,04) vs. NR for < 5 (HR = 5,88; IC95% 2,60 – 13,29; p = 0,001). NLR categorised remained statistically significant in multivariate analysis for PFS and NLR as a continuous variable remained statistically significant for both PFS and OS in multivariate analysis (Table 1). Conclusions: Baseline NLR is a rapid, simple, and cost-free predictor of survival before Anti-PD1 therapy. These results should be validated in a larger cohort of patients. [Table: see text]

Using autoantibody signatures to predict immunotherapy discontinuation in melanoma patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3069-3069
Author(s):  
Iman Osman ◽  
Keith M. Giles ◽  
Yingzhi Qian ◽  
Megan Wind-Rotolo ◽  
John Loffredo ◽  
...  
Keyword(s):  
Clinical Laboratory ◽  
Checkpoint Inhibitors ◽  
Characteristic Curve ◽  
Treatment Discontinuation ◽  
Functional Enrichment ◽  
Phase Iii ◽  
Protein Targets ◽  
Phase Iii Trial ◽  
Melanoma Patients ◽  
Pre Treatment

3069 Background: Immune checkpoint inhibitors (ICIs), e.g., ipilimumab (IPI) and/or nivolumab (NIVO), produce durable survival benefit in a substantial proportion of melanoma patients but can also induce severe immune-related adverse events (irAEs) requiring treatment discontinuation. There is no biomarker to predict irAEs in ICI-treated melanoma patients. Given the similar clinical manifestation between irAEs and autoimmune disorders, we hypothesized that a subset of patients possess a subclinical baseline predisposition to developing irAEs that is characterized by specific autoantibodies (autoAbs). Methods: Pre-treatment melanoma patient sera from the CheckMate-238 Phase III trial of adjuvant IPI vs. NIVO were used for autoAb profiling with HuProt proteomic arrays (CDI Labs). The outcome of interest is to predict toxicity events that caused treatment discontinuation. For each treatment arm, we allocated patients to training and testing datasets in a 3:1 ratio. We calculated the area under the curve (AUC) of the receiver operating characteristic curve to select a probability threshold, which was applied to the testing dataset to assess accuracy, sensitivity, and specificity. Functional enrichment among autoAb protein targets was assessed using Metascape. Results: There were 707 irAEs among 597 patients (IPI = 423, NIVO = 174), of which 355 required treatment discontinuation (IPI = 287, NIVO = 68). In the training sets, we identified a 170 autoAbs signature consisting of 102 autoAbs for IPI treatment and 68 autoAbs for NIVO treatment. In the independent testing set, the signatures showed AUC of 0.85 (0.78, 0.92), 82% sensitivity, 78% specificity, and overall accuracy of 81% to predict IPI discontinuation, and AUC of 0.87 (0.74, 0.99), 75% sensitivity, 97% specificity, and overall accuracy of 88% to predict NIVO discontinuation. Enrichment of nuclear lumen-associated protein targets was identified among autoAb signatures that predict IPI or NIVO discontinuation. Conclusions: The identified signature within a large Phase III trial cohort highlights the potential utility of pre-treatment autoAbs for prediction of patients at high risk of developing irAEs in the adjuvant setting necessitating treatment termination. We are currently validating and refining toxicity-associated autoAb signatures with the goal of developing a Clinical Laboratory Improvement Amendments (CLIA)-certified assay to enable clinicians to optimize immunotherapy delivery and patient selection.

scholarly journals Clinical Categorization Algorithm (CLICAL) and Machine Learning Approach (SRF-CLICAL) to Predict Clinical Benefit to Immunotherapy in Metastatic Melanoma Patients: Real-World Evidence from the Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4164
Author(s):  
Gabriele Madonna ◽  
Giuseppe V. Masucci ◽  
Mariaelena Capone ◽  
Domenico Mallardo ◽  
Antonio Maria Grimaldi ◽  
...  
Keyword(s):  
Machine Learning ◽  
Metastatic Melanoma ◽  
Learning Algorithm ◽  
Checkpoint Inhibitors ◽  
Real Life ◽  
Previous Treatment ◽  
Clinical Decision ◽  
Neutrophil Lymphocyte Ratio ◽  
Real World Evidence ◽  
Melanoma Patients

The real-life application of immune checkpoint inhibitors (ICIs) may yield different outcomes compared to the benefit presented in clinical trials. For this reason, there is a need to define the group of patients that may benefit from treatment. We retrospectively investigated 578 metastatic melanoma patients treated with ICIs at the Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale” of Napoli, Italy (INT-NA). To compare patients’ clinical variables (i.e., age, lactate dehydrogenase (LDH), neutrophil–lymphocyte ratio (NLR), eosinophil, BRAF status, previous treatment) and their predictive and prognostic power in a comprehensive, non-hierarchical manner, a clinical categorization algorithm (CLICAL) was defined and validated by the application of a machine learning algorithm—survival random forest (SRF-CLICAL). The comprehensive analysis of the clinical parameters by log risk-based algorithms resulted in predictive signatures that could identify groups of patients with great benefit or not, regardless of the ICI received. From a real-life retrospective analysis of metastatic melanoma patients, we generated and validated an algorithm based on machine learning that could assist with the clinical decision of whether or not to apply ICI therapy by defining five signatures of predictability with 95% accuracy.

scholarly journals Treatment of Advanced Metastatic Melanoma

2021 ◽  
pp. 2021164S
Author(s):  
Pietro Quaglino ◽  
Paolo Fava ◽  
Luca Tonella ◽  
Marco Rubatto ◽  
Simone Ribero ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Targeted Therapies ◽  
Checkpoint Inhibitors ◽  
Performance Status ◽  
Survival Rates ◽  
National Health System ◽  
Stage Iv ◽  
Daily Practice ◽  
Long Term Results ◽  
Melanoma Patients

The introduction in clinical practice of new drug compounds both targeted therapies anti-BRAF and checkpoint inhibitors have largely improved our potential to manage advanced metastatic melanoma patients. This has led to a significant improvement in terms of response rates and particularly in the overall survival (OS). The long-term results of trials with follow-up data of patients treated with targeted or immunotherapies reported median OS rates around 24 months, with 5-year survival rates around 35-40%. As to the drugs currently available and reimbursed by the Italian National Health System, 3 combinations of anti-BRAF/anti-MEK inhibitors are available (dabrafenib/trametinib, vemurafenib/cobimetinib and the most recently introduced encorafenib/binimetinib). As for checkpoint inhibitors, first line immunotherapy is represented by anti-PD1 blockers (nivolumab and pembrolizumab), whilst the anti-CTLA-4 ipilimumab can be used as second line immunotherapy. The decision-making factors that define the best treatment approach in stage IV patients with metastatic melanoma include the mutation pattern, performance status, high/low tumor load, brain metastases, progression pattern (low/fast), and availability of clinical trials. This review will analyze the current therapeutic tools adopted for the treatment of metastatic melanoma patients. It will then focus on the latest results obtained by novel treatments (checkpoint inhibitors and targeted therapies) which can be used in the clinical daily practice.

scholarly journals Optimal treatment strategy for metastatic melanoma patients harboring BRAF-V600 mutations

2020 ◽  
Vol 12 ◽  
pp. 175883592092521
Author(s):  
Emilio Francesco Giunta ◽  
Vincenzo De Falco ◽  
Stefania Napolitano ◽  
Giuseppe Argenziano ◽  
Gabriella Brancaccio ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Checkpoint Inhibitors ◽  
First Line ◽  
Therapeutic Choice ◽  
Therapeutic Algorithm ◽  
Melanoma Patients ◽  
Biological Aspects ◽  
New Biomarkers ◽  
Line Setting ◽  
Optimal Treatment Strategy

BRAF-V600 mutations occur in approximately 50% of patients with metastatic melanoma. Immune-checkpoint inhibitors and targeted therapies are both active as first-line treatments in these patients regardless of their mechanisms of action and toxicities. However, an upfront therapeutic strategy is still controversial. In fact, waiting for results of ongoing clinical trials and for new biomarkers, clinicians should base their decision on the clinical characteristics of the patient and on the biological aspects of the tumor. This review provides an overview on BRAF-V600 mutations in melanoma and will discuss their prognostic and clinical significance. Moreover, it will suggest a therapeutic algorithm that can drive therapeutic choice in a first-line setting for BRAF-V600 mutant melanoma patients.

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