To improve the efficacy of immunotherapy for cancer, recent studies focused on specific targets to redirect the immune network toward eradicating a variety of tumors and ameliorating the self-destructive process.

A clinically relevant immune escape mechanism in melanoma is the activation of the Programmed cell Death-1 (PD-1) receptor on infiltrating T cells. By blocking PD-1 receptors with anti-PD-1 monoclonal antibodies (mAbs), T-cells are unaffected by the PD-L1 expressed on tumor cells and the patients T cells are free to respond to melanoma antigens and attack tumor cells. So the objective of this trial is to evaluate the safety and the efficacy of a combined therapy Nivolumab and adoptive T cell therapy in metastatic melanoma patients.

Inclusion Criteria:

• over 18 years old with a weight ≥ 40 kg
• Patients must have signed informed consent
• Patients with stage IIIb, IIIc or IV metastatic melanoma (AJCC 6th edition) with at least two lesions (lymph nodes relapse, or in transit metastasis, or unresectable cutaneous metastases, or visceral metastases except bone and brain metastases) including one easily accessible and no more than 2 lines of treatment of melanoma at the metastatic stage.
• Patients with a melanoma expressing a Braf V600 mutation can be included
• Measurable/assessable disease in 28 days which precede the first administration of the treatment
• A negative pregnancy test for women with childbearing potential
• Eastern Cooperative Oncology Group (ECOG) of 0-1, Karnofsky > 80%
• Laboratory results:

Haemoglobin ≥ 10 g/dl or ≥ 6,25 mmol/l; Neutrophils ≥ 1500/μl; Leukocytes ≥ 4000/μl; Lymphocytes ≥ 700/μl; Blood platelet ≥ 100.000/μl; Serum creatinine ≤ 1.5 x superior normal value or creatinine clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault formula); Serum bilirubin ≤ 2.0 mg/dl or ≤ 34.2 mol/l; Total bilirubin ≤ 1.5 x superior normal value (except subjects with Gilbert Syndrome, who can have total bilirubin < 3mg/dL); Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 2 x superior normal value; Lactate dehydrogenase (LDH) ≤ 1.5 x superior normal value

• Subjects affiliated to an appropriate health insurance
• Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception during the clinical trial. Furthermore WOCBP will be instructed to adhere to contraception for a period of 5 months after the last dose of Nivolumab.
• Men who are sexually active with WOCBP will be instructed to adhere to contraception during the clinical trial and for a period of 7 months after the last dose of Nivolumab.
• Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile) as well as azoospermic men do not require contraception.

Non inclusion Criteria:

• Brain or bone metastases

• Ocular melanoma

• Chemotherapy or radiotherapy within 4 weeks before baseline (6 weeks for nitroso-ureas and mitomycin C)

• Contraindication for the use of vasopressor agents

• For female: the patient is pregnant or breastfeeding or not using contraception

• For men: the patient is sexually active with WOCBP and not using contraception

• History or current manifestations of severe progressive heart disease (congestive heart failure, coronary artery disease, uncontrolled arterial hypertension, serious rhythm disorders or ECG signs of previous myocardial infarction)

• Patients should be excluded if they have had prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways except in the context of adjuvant or neoadjuvant

• History of allergies and Adverse Drug Reaction:

  • Hypersensitivity to human albumin, TIL excipient
  • Hypersensitivity to Nivolumab or related excipients
  • History of severe hypersensitivity reaction to any monoclonal antibody
  • Hypersensitivity to aldesleukin or to one of Proleukin excipients

• History of chronic autoimmune disease (Addison's disease, multiple sclerosis, Graves' disease, rheumatoid arthritis, systemic lupus erythematosus, etc…) except patient with active vitiligo or a history of vitiligo.

• History of uveitis or melanoma-associated retinopathy

• History of inflammatory bowel disease, celiac disease, or other chronic gastrointestinal conditions associated with diarrhea.

• Presence of a second active cancer, with the exception of an in situ cervical cancer or a skin cancer different from the treated melanoma

• Unchecked thyroid dysfunction

• Any serious, acute or chronic illness id est active infection asking for antibiotics administration, coagulation's disorders, or any state asking for an unauthorized concomitant treatment described in this study

• Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days before study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Subjects are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if > 10 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of nonautoimmune conditions (eg, delayed-type hypersensitivity reaction caused by contact allergen) is permitted.

• Adults under a legal protection regime (guardianship, trusteeship, "sauvegarde de justice")

Exclusion Criteria:

* Positive viral serology for HIV (human immunodeficiency virus) 1/2, p24 Ag, HTLV1, HTLV2, B and C hepatitis or syphilis