Cryoablation with liver-directed immunotherapy and targeted therapy for melanoma liver metastases

Inclusion Criteria:

* Age 18-70 years;
* Patients with pathologically confirmed metastatic malignant melanoma after failure of standard treatment;
* Presence of liver metastases, with at least one lesion assessed as suitable for cryoablation;
* The largest diameter of each intrahepatic metastatic lesion \< 5 cm;
* At least one target lesion suitable for efficacy assessment according to RECIST 1.1 (when no appropriate extrahepatic target lesion is available, a non-ablated intrahepatic lesion may serve as the observation lesion);
* ECOG performance status score of 0;
* No history of autoimmune disease;
* Life expectancy of more than 3 months;
* Laboratory test results meeting the following criteria:

  1. Neutrophil count \>= 1.8 × 10⁹/L;
  2. White blood cell count \>= 3.0 × 10⁹/L;
  3. Platelet count \>= 100 × 10⁹/L; Hemoglobin \>= 90 g/L;
  4. Serum ALT and AST \<= 2.5 × the upper limit of normal (ULN);
  5. Serum creatinine \<= 1.5 × ULN;
  6. INR \< 1.3 or prothrombin time \< ULN + 2 seconds;
  7. Albumin \>= 35 g/L;
  8. Total bilirubin \<= 1.0 × ULN.

Exclusion Criteria:

* Liver metastases previously treated with radiotherapy, microwave ablation, radiofrequency ablation, or irreversible electroporation;
* ECOG performance status score \>= 2;
* Child-Pugh score \>= 7; decompensated liver function, such as massive ascites, gastric fundal or esophageal varices with upper gastrointestinal bleeding within the previous year, hepatic encephalopathy, or bilirubin encephalopathy;
* Known central nervous system metastases that are clinically unstable, or acute meningitis (except patients with central nervous system metastases who have received treatment and are clinically stable).

Clinical stability requires all of the following:

1. no new brain lesions and no enlargement of existing lesions, confirmed by MRI;
2. no glucocorticoid treatment for at least 2 weeks;
3. no new neurological symptoms, and previous neurological symptoms have returned to normal.

   * Previous treatment with immune checkpoint inhibitors complicated by grade 3 or higher immune-related adverse events;
   * Pregnant or breastfeeding women;
   * History of HIV infection;
   * History of another malignancy within 5 years (excluding early-stage basal cell carcinoma, carcinoma in situ of the cervix, and papillary thyroid carcinoma);
   * Any of the following within 12 months before study initiation: myocardial infarction, severe or unstable angina, congestive heart failure, cerebrovascular accident, or pulmonary embolism;
   * Severe hepatic or renal impairment; uncontrolled diabetes, pulmonary fibrosis, interstitial lung disease, or acute pulmonary disease; poorly controlled hypertension (systolic blood pressure \> 160 mmHg and/or diastolic blood pressure \> 90 mmHg); clinically significant cardiovascular or cerebrovascular disease, such as cerebrovascular accident or myocardial infarction within 6 months, unstable angina, NYHA class II or higher congestive heart failure, severe arrhythmia not controlled by medication, clinically significant electrocardiographic abnormalities on three consecutive recordings obtained at least 5 minutes apart, psychiatric disorders, or drug abuse; or any condition that the investigator considers likely to increase risk to the subject or interfere with study results;
   * History of organ transplantation;
   * Other severe acute or chronic physical or psychiatric illnesses, or laboratory abnormalities, that may increase study-related risk or interfere with interpretation of results and make the patient unsuitable for enrollment;
   * Uncontrolled concurrent diseases or infectious diseases. Patients with active hepatitis B must receive antiviral therapy to achieve HBV DNA \< 500 copies/mL and remain stable for at least 2 weeks before the investigator assesses eligibility, and must continue antiviral therapy throughout the study after enrollment;
   * History of severe adverse reactions to contrast agents;
   * Any active autoimmune disease, or a history of autoimmune disease judged by the investigator to make the patient unsuitable for this study, including but not limited to systemic lupus erythematosus, immune-related neuropathy, multiple sclerosis, Guillain-Barre syndrome, myasthenia gravis, connective tissue diseases, and inflammatory bowel disease including Crohn's disease and ulcerative colitis;
   * Previous treatment with lenvatinib or other multi-target tyrosine kinase inhibitors;
   * Previous systemic chemotherapy containing dacarbazine or temozolomide complicated by grade 3 or higher myelosuppression or hepatotoxicity during treatment;
   * Total intrahepatic lesion volume assessed by the investigator as exceeding 50% of the total liver volume;
   * Use of therapeutic anticoagulants (such as warfarin, direct oral anticoagulants, or low-molecular-weight heparin) or dual antiplatelet therapy (such as aspirin combined with clopidogrel) within 7 days before enrollment, if the medications cannot be safely discontinued and bridged before cryoablation and arterial infusion.