Study of CD160, an Activating NK Cell Receptor, in Melanoma: a Potential Therapeutic Target?

Study Overview
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Brief Summary
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Although immunotherapy revolutionized melanoma outcomes over the last 10 years, only 40-50% of patients respond to treatments and 25% develop acquired resistances. Natural Killer (NK) cells naturally recognize and kill tumor cells. However, the immunosuppressive micro-environment generated by the tumor decreases NK cells' killing activity. CD160 is a NK cell receptor identified and characterized in our laboratory. Engagement of the GPI isoform (CD160-GPI) initiates NK cell cytotoxic response. Upon NK cell activation, a transmembrane isoform (CD160-TM) is neo-synthesized which promotes the amplification of activated NK cell cytotoxicity. The aim of this study is to assess the phenotypic profile of advanced stages melanoma patients' NK cells (mainly CD160-TM expression or its induction) and therefore the therapeutic potential of the use of an anti-CD160-TM agonist antibody to boost the NK-dependent mechanism leading to tumor depletion.

Official Title
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Study of CD160, an Activating NK Cell Receptor, in Melanoma: a Potential Therapeutic Target?

Conditions
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Melanoma

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria : Patients aged18-years old or over ECOG score between 0-2 Inoperable stage III or stage IV melanoma Naïve of treatment or in progression after one or several treatment lines Give their written consent for the present study and be included in MelBase cohort. health insurance coverage. Supplementary inclusion criteria for part II : skin or subcutaneous melanoma lesions agree and inform consent for a cutaneous biopsy or a tumor sample if presenting lymph nodes involvement if part of the usual clinical practice. Exclusion Criteria: Pregnant and breastfeeding women Patients with psychiatric disorders Patients already included in another clinical trial Having received chemotherapy or radiotherapy during the last 4 weeks, Patient presenting another solid or blood cancer, chronic viral infection (e.g. HIV, HBV or HCV) Been treated with more than 10mg of steroids until the 4 weeks before inclusion. Refusal to participate to the study Patients under guardianship or curatorship Patients on state medical aid

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of effector cells activation and degranulation (CD69 and CD107a staining ) | Difference between cells incubated with the anti CD160-TM antibody and with isotipic control ab ( flow cytometry) | at inclusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival |  | at 1 year post inclusion | 
| Overall survival |  | at 2 years post inclusion | 
| Overall survival |  | at 3 years post inclusion | 
| Overall survival |  | at 4 years post inclusion | 
| Overall survival |  | at 5 years post inclusion | 
| Progression free survival |  | at 1 year | 
| Progression free survival |  | at 2 years | 
| Progression free survival |  | at 3 years | 
| Progression free survival |  | at 4 years | 
| Progression free survival |  | at 5 years | 
| Objective response rate |  | at one year | 
| Objective response rate |  | at 2 years | 
| Objective response rate |  | at 3 years | 
| Objective response rate |  | at 4 years | 
| Objective response rate |  | at 5 years | 
| Phenotypic characteristics of NK cells | Assessment by flow cytometry of the expression levels of activating or inhibitory receptors (e.g. CD160-GPI, NKp46), phenotypic markers (e.g CD16, CD3), as well as activation (CD69) and degranulation (CD107a) markers by the NK cell population (defined as CD3- CD56+ cell). Results will be expressed as the % of positive cells for each marker among the NK cell population | at inclusion | 
| cytokine profile | Assessment by flow cytometry using a cytokine beads array (BD Biosciences) of the Th1/Th2/Th17 cytokine content. The presence of the following cytokine will be assessed: IL17-A, IFN-g, TNF, IL10, IL-6, IL-4 and IL-2. The mean fluorescence intensities will be recorded and quantifications will be done, using an individual standard curve, for each cytokine. Results will be expressed in pg/ml. | at inclusion | 
| Détection and quantification of sCD160 in patients' serum |  | at inclusion |