Cryotherapy With in Situ Immunotherapy in Melanoma Metastasis

Inclusion Criteria:

1. Subject with previously treated (or unknown) primary stage IIIB/IIIC melanoma with lymph node metastases, with at least one ≥1 cm3 that is accessible to cryotherapy under interventional radiology (IR), assessed at the inclusion visit (V1).
2. ECOG performance status (0 to 2) at the selection visit (V0)
3. If woman or man are of reproductive age, they should have no desire to procreate for the duration of their participation in the study, agreeing to use a highly effective contraception method\*, with at least one barrier method (condom or diaphragm), and for 5 months after the infusion of Nivolumab for women and 7 months for men
4. Leukocytes \>2000/mm3, neutrophils \>1500/mm3, platelets \>100,000/mm3, haemoglobin \>9g/dl at the selection visit (V0)
5. Total bilirubin \<1.5 mg/dl except for patients with Gilbert's syndrome who may have total bilirubin \<3.0 mg/dl at the selection visit (V0)
6. Liver function: SGOT, SGPT, ALP \<2.5 N, if liver metastases SGOT and SGPT \<5 N at the selection visit (V0)
7. Serum creatinine \<1.5 N or creatinine clearance \>40 ml/min (using the Cockcroft-Gault equation) at the selection visit (V0)

Exclusion Criteria:

1. Pregnancy (women of childbearing potential : positive blood pregnancy test at the selection visit (V0) or breastfeeding
2. History of hypersensitivity to ipilimumab, nivolumab or one of the excipients
3. History of severe hypersensitivity to a monoclonal antibody
4. History of positive tests for HIV or Acquired Immunodeficiency Syndrome (HIV assessed at the selection visit (V0))
5. Positive tests for HCV or HBV indicating an acute or chronic infection at the selection visit (V0)
6. Patient presenting with an active, known or suspected autoimmune disease. The following, however, may participate:

   * patient with type 1 diabetes or hypothyroidism requiring substitute hormone therapy only;
   * patient with psoriasis, vitiligo or alopecia;
   * patient with conditions that are not known to reoccur without an exogenous triggering agent.
7. History of active neoplasia during the last 3 years with the exception of localised curable cancers considered to be cured, such as basal or squamous cell carcinomas, superficial bladder cancer and prostate, colon or breast carcinoma in situ.
8. Active systemic infection
9. Patient with a condition requiring systemic steroid treatment (at a dose \>10 mg/prednisone equivalent or at unstable dose) or another immunosuppressant within/following 14 days of study drugs administration. Inhaled steroids and treatment for adrenal insufficiency, however, are permitted.
10. Contraindication for the cryotherapy procedure as assessed by the radiologist (due to tumour size or proximity to a vascular or nerve structure giving the procedure an unacceptable level of risk) at the inclusion visit (V1)
11. Clotting disorder that may interfere with the cryoablation, assessed at the selection visit (V0)
12. Contraindication for MRI with gadolinium-based contrast media
13. History of uveal melanoma
14. Patient having received prior treatment for their melanoma, in particular, patient previously treated with interferon fewer than 3 months ago or with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD-137 or anti-CTLA-4 antibody. Patients who have undergone primary melanoma surgery and the excision of in-transit metastases, as well as adjuvant therapy with interferon if completed over 3 months ago are eligible.
15. Contraindication for general and/or local anaesthesia
16. Patient operated on under general anaesthesia, within the 4 weeks prior to the planned Nivolumab infusion.
17. Patient operated on epidural anaesthesia, within the 72 h prior to the planned Nivolumab infusion.
18. History of anterior organ transplantation, including allograft stem cell transplantation.
19. History of interstitial lung disease