To evaluate the capability of basal and one-month differed white blood cells (WBC), neutrophil, lymphocyte and platelet values and their ratios (neutrophils-to-lymphocytes ratio, NLR, and ...platelets-to-lymphocytes ratio, PLR) in predicting the response to immune checkpoint inhibitors (ICI) in metastatic melanoma (MM).
We performed a retrospective study of 272 BRAF wild-type MM patients treated with first line ICI. Bivariable analysis was used to correlate patient/tumor characteristics with clinical outcomes. Variations between time 1 and time 0 (Δ) of blood parameters were also calculated and dichotomized using cut-off values assessed by ROC curve.
At baseline, higher neutrophils and NLR negatively correlated with PFS, OS and disease control rate (DCR). Higher PLR was also associated with worse OS. In multivariable analysis, neutrophils (p = 0.003), WBC (p = 0.069) and LDH (p = 0.07) maintained their impact on PFS, while OS was affected by LDH (p < 0.001), neutrophils (p < 0.001) and PLR (p = 0.022), while DCR by LDH (p = 0.03) and neutrophils (p = 0.004). In the longitudinal analysis, PFS negatively correlated with higher Δplatelets (p = 0.039), ΔWBC (p < 0.001), and Δneutrophils (p = 0.020), and with lower Δlymphocytes (p < 0.001). Moreover, higher ΔNLR and ΔPLR identified patients with worse PFS, OS and DCR. In the multivariable model, only ΔNLR influenced PFS (p = 0.004), while OS resulted affected by higher ΔWBC (p < 0.001) and lower Δlymphocytes (p = 0.038). Higher ΔWBC also affected the DCR (p = 0.003). When clustering patients in 4 categories using basal LDH and ΔNLR, normal LDH/lower ΔNLR showed a higher PFS than high LDH/higher ΔNLR (20 vs 5 months). Moreover, normal LDH/higher Δlymphocytes had a higher OS than high LDH/lower Δlymphocytes (50 vs. 10 months).
Baseline and early variations of blood cells, together with basal LDH, strongly predict the efficacy of ICI in MM. Our findings propose simple, inexpensive biomarkers for a better selection of patient treatments. Prospective multicenter studies are warranted to confirm these data.
The Sonic hedgehog (Shh) signaling pathway is an essential pathway in the human body that plays an important role in embryogenesis and tissue homeostasis. Aberrant activation of this pathway has been ...linked to the development of different diseases, ranging from cancer to immune dysregulation and infections.Uncontrolled activation of the pathway through sporadic mutations or other mechanisms is associated with cancer development and progression in various malignancies, such as basal cell carcinoma, medulloblastoma, pancreatic cancer, breast cancer and small-cell lung carcinoma. Targeted inhibition of the pathway components has therefore emerged as an attractive and validated therapeutic strategy for the treatment of a wide range of cancers. Currently, two main components of the pathway, the smoothened receptor and the glioma-associated oncogene homolog transcriptional factors, have been investigated for the development of targeted drugs, leading to the marketing authorization of three smoothened receptor inhibitors for the treatment of basal cell carcinoma and acute myeloid leukemia.The Shh pathway also seems to be involved in regulating the immune response, possibly playing a role in immune system evasions by tumors, development of autoimmune diseases, such as rheumatoid arthritis and Crohn’s disease, airway inflammation, and diseases related to aberrant activation of T-helper 2 cellular response, such as allergy, atopic dermatitis, and asthma.Finally, the Shh pathway is involved in pathogen-mediated infection, including influenza-A and, more recently, SARS-CoV-2 viruses. Therefore, agents that inhibit the Shh signaling pathway might be used to treat pathogenic infections, shifting the therapeutic approach from strain-specific treatments to host-based strategies that target highly conserved host targets.
Monoclonal antibodies targeting immune checkpoints improved clinical outcome of patients with malignant melanoma. However, the mechanisms are not fully elucidated. Since immune check-point receptors ...are also expressed by helper innate lymphoid cells (ILCs), we investigated the capability of immune checkpoints inhibitors to modulate ILCs in metastatic melanoma patients as well as melanoma cells effects on ILC functions. Here, we demonstrated that, compared to healthy donors, patients showed a higher frequency of total peripheral ILCs, lower percentages of CD117
ILC2s and CD117
ILCs as well as higher frequencies of CD117
ILCs. Functionally, melanoma patients also displayed an impaired TNFα secretion by CD117
ILCs and CD117
ILCs. Nivolumab therapy reduced the frequency of total peripheral ILCs but increased the percentage of CD117
ILC2s and enhanced the capability of ILC2s and CD117
ILCs to secrete IL-13 and TNFα, respectively. Before Nivolumab therapy, high CCL2 serum levels were associated with longer Overall Survival and Progression Free Survival. After two months of treatment, CD117
ILC2s frequency as well as serum concentrations of IL-6, CXCL8 and VEGF negatively correlated with both the parameters. Moreover, melanoma cells boosted TNFα production in all ILC subsets and increased the number of IL-13 producing ILC2s
. Our work shows for the first time that PD-1 blockade is able to affect ILCs proportions and functions in melanoma patients and that a specific subpopulation is associated with the therapy response.
Interestingly, the authors highlighted that for all positive cases no “viable virus” was detected on cultures and all their close contacts tested negative for the COVID-19, which suggested the lack ...of evidence of transmission from asymptomatic cases. ...the viral loads of SARS-CoV-2 were found similarly high in the four canonical symptomatic groups (presymptomatic, asymptomatic, typical symptoms and atypical symptoms); SARS-CoV-2 spreads in high concentrations from the nasal cavities prior to symptom development and viable virus was found in culture also in presymptomatic cases 4. No statistically significant differences were observed between symptomatic and asymptomatic cases for real-time PCR Ct median values of the N1, N2 and N3 regions (Fig. 1b, Table 2). In our opinion, these data underline that also the viral loads of asymptomatic cases may be sufficient to hypothesize the transmission of the SARS-CoV-2 infection from asymptomatic subjects; measuring not only the presence but also the amount of virus in infected subjects could be precious information to help control the pandemic.
The current therapeutic algorithm for Advanced Stage Melanoma comprises of alternating lines of Targeted and Immuno-therapy, mostly via Immune-Checkpoint blockade. While Comprehensive Genomic ...Profiling of solid tumours has been approved as a companion diagnostic, still no approved predictive biomarkers are available for Melanoma aside from BRAF mutations and the controversial Tumor Mutational Burden. This study presents the results of a Multi-Centre Observational Clinical Trial of Comprehensive Genomic Profiling on Target and Immuno-therapy treated advanced Melanoma.
82 samples, collected from 7 Italian Cancer Centres of FFPE-archived Metastatic Melanoma and matched blood were sequenced via a custom-made 184-gene amplicon-based NGS panel. Sequencing and bioinformatics analysis was performed at a central hub. Primary analysis was carried out via the Ion Reporter framework. Secondary analysis and Machine Learning modelling comprising of uni and multivariate, COX/Lasso combination, and Random Forest, was implemented via custom R/Python scripting.
The genomics landscape of the ACC-mela cohort is comparable at the somatic level for Single Nucleotide Variants and INDELs aside a few gene targets. All the clinically relevant targets such as BRAF and NRAS have a comparable distribution thus suggesting the value of larger scale sequencing in melanoma. No comparability is reached at the CNV level due to biotechnological biases and cohort numerosity. Tumour Mutational Burden is slightly higher in median for Complete Responders but fails to achieve statistical significance in Kaplan-Meier survival analysis via several thresholding strategies. Mutations on PDGFRB, NOTCH3 and RET were shown to have a positive effect on Immune-checkpoint treatment Overall and Disease-Free Survival, while variants in NOTCH4 were found to be detrimental for both endpoints.
The results presented in this study show the value and the challenge of a genomics-driven network trial. The data can be also a valuable resource as a validation cohort for Immunotherapy and Target therapy genomic biomarker research.
Extensive squamous cell carcinoma has few therapeutic options. In such cases, electrochemotherapy involving electroporation combined with antineoplastic drug appears to be a new potential option and ...may be considered as an alternative treatment. The aim of this retrospective single-center study was to evaluate electrochemotherapy efficacy in treatment of locally advanced stage III squamous cell carcinoma, in which surgical procedures would have entailed wide tissue sacrifice.
Clinical features, treatment response, and adverse effects were evaluated in 22 patients treated with electrochemotherapy with intravenous injection of bleomycin for extensive stage III cutaneous squamous cell carcinoma. Treatment of cutaneous lesions were performed according to the European Standard Operating Procedures of Electrochemotherapy.
Overall response to electrochemotherapy treatment was observed in 18 (81.8%) patients. Clinical response with necrosis of tumor mass was observed from the first session and lasted for all follow up period that ranged between 5 and 48 months with a median of 34 months. Overall the treatment was well tolerated with a very low complication rate.
Electrochemotherapy represents a safe and effective therapeutic approach, associated with a good tolerability.
Melanoma displays a rising incidence, and the mortality associated with metastatic form remains high. Monoclonal antibodies that block programmed death (PD-1) and PD Ligand 1 (PD-L1) network have ...revolutionized the history of metastatic disease. PD-L1 is expressed on several immune cells and can be also expressed on human neutrophils (PMNs). The role of peripheral blood PMNs as predictive biomarkers in anti-PD-1 therapy of melanoma is largely unknown. In this study, we aimed to determine activation status and PD-L1 expression on human neutrophils as possible novel biomarkers in stage IV melanoma patients (MPs). We found that PMNs from MPs displayed an activated phenotype and increased PD-L1 levels compared to healthy controls (HCs). Patients with lower PD-L1
+
PMN frequencies displayed better progression-free survival (PFS) and overall survival (OS) compared to patients with high PD-L1
+
PMN frequencies. Multivariate analysis showed that PD-L1
+
PMNs predicted patient outcome in BRAF wild type MP subgroup but not in BRAF mutated MPs. PD-L1
+
PMN frequency emerges as a novel biomarker in stage IV BRAF wild type MPs undergoing anti-PD-1 immunotherapy. Our findings suggest further evaluation of the role of neutrophil subsets and their mediators in melanoma patients undergoing immunotherapy.
Correspondence to Dr Jeffrey Weber; Jeffrey.Weber@nyulangone.org We wish to thank Eggermont et al1 for their thoughtful communication regarding our recently published article, ‘Adjuvant nivolumab for ...stage III/IV melanoma: evaluation of safety outcomes and association with recurrence-free survival’2 The authors appear to suggest that the differing conclusions of that article, that there was no significant association between outcome of relapse-free survival and immune-related toxicity, and their recent work based on the EORTC1325/Keynote-054 study indicating the opposite, was due to the differing definitions of toxicity in the two studies. By being overly selective in the choice of side effects of checkpoint inhibition to include in one’s analysis, one may indeed come to a different conclusion from that of Mandala et al, but we stand by the lack of association between immune-related side effects and relapse-free survival observed in the nivolumab data from Checkmate 238 and feel confident in its clinical relevance. Consulting or Advisory Role: AbbVie, Altor Bioscience, Amgen, AstraZeneca, Bristol Myers Squibb, CytomX Therapeutics, Daiichi Sankyo, Eisai, Genentech, GlaxoSmithKline, Medivation, Merck, Nektar Therapeutics, Novartis, Pieris Pharmaceuticals, Inc. Roche, SELLAS Life Sciences Group, WindMIL Therapeutics; Research Funding: Astellas Pharma, Bristol Myers Squibb, Genentech, Incyte Corporation, Merck, Novartis, Roche; Travel, Accommodations, and Expenses: Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Genentech, GlaxoSmithKline, Merck, Novartis, Pieris Pharmaceuticals, Roche; Honoraria: AbbVie, Altor Bioscience, Amgen, AstraZeneca, Bristol Myers Squibb, CytomX Therapeutics, Daiichi Sankyo, Eisai, Genentech, GlaxoSmithKline, Medivation, Merck, Nektar Therapeutics, Novartis, Pieris Pharmaceuticals, Inc., Roche, SELLAS Life Sciences Group, WindMIL Therapeutics; Stock/Ownership Interests: Biond; Named on a patent submitted by Moffitt Cancer Center for an ipilimumab biomarker; named on a patent submitted from Biodesix for a PD-1 antibody biomarker.
Immune checkpoint inhibitors have revolutionized treatment and outcome of melanoma and many other solid malignancies including non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC). ...Unfortunately, only a minority of patients have a long-term benefit, while the remaining demonstrate primary or acquired resistance. Recently, it has been demonstrated that the prevalence of programmed death-ligand 1 (PD-L1) and tumor-infiltrating lymphocytes (TILs) varies based on the anatomical site of metastases. In particular, liver seems to have more immunosuppressive microenvironment while both the presence of lymph nodal disease and lung metastases seem to have the highest prevalence of PD-L1 and TILs. The aim of the present study is to investigate the possible role of site of metastases as a predictive factor for response or resistance to immunotherapy in several types of cancer. In this multicenter retrospective study, we enrolled patients with metastatic NSCLC, melanoma, RCC, urothelial, merkel carcinoma, and colon cancer who received immunotherapy from April 2015 to August 2019. Major clinicopathological parameters were retrieved and correlated with patients' survival outcomes in order to assess their prognostic value and build a useful tool to assist in the decision-making process. A total of 291 patients were included in this study. One hundred eighty-seven (64%) patients were male and 104 (36%) female. The tumor histology was squamous NSCLC in 56 (19%) patients, non-squamous NSCLC in 99 (34%) patients, melanoma in 101 (35%) patients, RCC in 28 (10%) patients, and other tumors in the remaining 7 (2%) patients. The number of metastatic sites was 1 in 103 patients (35%), 2 in 104 patients (36%) and 3 in 84 patients (29%). Out of 183 valuable patients, the entity of response was complete response (CR), partial response (PR), stable disease (SD), and progression disease (PD) in 15, 53, 31, and 79 patients, respectively. Using an univariate analysis (UVA), tumor burden (
= 0.0004), the presence of liver (
= 0.0009), bone (
= 0.0016), brain metastases (
< 0.0001), the other metastatic sites (
= 0.0375), the number of metastatic sites (
= 0.0039), the histology (
= 0.0034), the upfront use of immunotherapy (
= 0.0032), and Eastern Cooperative Oncology Group (ECOG) Perfomance status (PS) ≥ 1 (
< 0.0001) were significantly associated with poor overall survival (OS). Using a multivariate analysis (MVA) the presence of liver (
= 0.0105) and brain (
= 0.0026) metastases, the NSCLC diagnosis (
< 0.0001) and the ECOG PS (
< 0.0001) resulted as significant prognostic factors of survival. Regarding the progression free survival (PFS), using a UVA of the tumor burden (
= 0.0004), bone (
= 0.0098) and brain (
= 0.0038) metastases, the presence of other metastatic sites (
= 0.0063), the number of metastatic sites (
= 0.0007), the histology (
= 0.0007), the use of immunotherapy as first line (
= 0.0031), and the ECOG PS ≥ 1 (
≤ 0.0001) were associated with a lower PFS rate. Using an MVA, the presence of brain (
= 0.0088) and liver metastases (
= 0.024) and the ECOG PS (
< 0.0001) resulted as predictors of poor PFS. Our study suggests that the site of metastases could have a role as prognostic and predictive factor in patients treated with immunotherapy. Indeed, regardless of the histology, the presence of liver and brain metastases was associated with a shorter PFS and OS, but these results must be confirmed in further studies. In this context, a deep characterization of microenvironment could be crucial to prepare patients through novel strategies with combination or sequential immunotherapy in order to improve treatment response.
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