Combined Therapy of 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 atleast two lesions (lymph nodes relapse, or in transit metastasis, or unresectablecutaneous metastases, or visceral metastases except bone and brain metastases)including one easily accessible and no more than 2 lines of treatment of melanoma atthe 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 thetreatment
• 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 normalvalue 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); Aspartateaminotransferase (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) ofcontraception during the clinical trial. Furthermore WOCBP will be instructed toadhere 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 contraceptionduring the clinical trial and for a period of 7 months after the last dose ofNivolumab.
• Women who are not of childbearing potential (ie, who are postmenopausal or surgicallysterile) 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-ureasand 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 (congestiveheart failure, coronary artery disease, uncontrolled arterial hypertension, seriousrhythm 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 drugspecifically targeting T-cell costimulation or immune checkpoint pathways except inthe 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 withactive vitiligo or a history of vitiligo.
• History of uveitis or melanoma-associated retinopathy
• History of inflammatory bowel disease, celiac disease, or other chronicgastrointestinal conditions associated with diarrhea.
• Presence of a second active cancer, with the exception of an in situ cervical canceror a skin cancer different from the treated melanoma
• Unchecked thyroid dysfunction
• Any serious, acute or chronic illness id est active infection asking for antibioticsadministration, coagulation's disorders, or any state asking for an unauthorizedconcomitant treatment described in this study
• Patients should be excluded if they have a condition requiring systemic treatment witheither corticosteroids (> 10 mg daily prednisone equivalents) or otherimmunosuppressive medications within 14 days before study drug administration. Inhaledor topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalentsare permitted in the absence of active autoimmune disease. Subjects are permitted touse topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemiccorticosteroids are permitted, even if > 10 mg/day prednisone equivalents. A briefcourse of corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatmentof nonautoimmune conditions (eg, delayed-type hypersensitivity reaction caused bycontact allergen) is permitted.
• Adults under a legal protection regime (guardianship, trusteeship, "sauvegarde dejustice")

Exclusion Criteria:

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