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Chemotherapy + RFA + in situ immunotherapy in patients with non resectable CRC liver-only metastases.
Chemotherapy: (at the investigator’s choice) for ≥ 2 months before RFA (with controlled disease) and resumed 4-6 weeks after RFA to achieve 6-month total duration.
RFA : radio frequency ablation of liver mets.
In situ immunotherapy: TLR agonist and GM-CSF
Key inclusion criteria:
-4 to 10 liver metastases, at least 2 accessible to RFA (radio frequency ablation)
– No detectable extra-hepatic disease allowed.
The hypothesis of the study is that local immunotherapy may reduce recurrence rates after RFA in patients with unresectable liver metastases from CRC.

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Inclusion Criteria

Inclusion Criteria:

1. Written informed consent obtained from the patient prior to performing any protocol-related procedures, including screening evaluations;
2. Willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up;
3. Histologically or cytologically proven CRC;
4. Non-resectable liver metastases from CRC without detectable extra-hepatic disease, on abdomino-pelvic computed tomography (CT) or magnetic resonance imaging (MRI) and chest CT by the consulting hepatobiliary surgeon and radiologist. Unresectability is defined as no possibility to completely resect all tumor lesions;
5. Age ≥ 18 years;
6. ECOG PS 0-1;
7. Controlled disease (stability or objective response) with chemotherapy (≥ 2 months) for liver metastases;
8. Liver metastases ≥ 3 and <10, including ≥ 3 lesions accessible to RFA;
9. Maximum diameter of 4 cm for lesions to be treated by RFA;
10. Metastatic involvement of the liver ≤50%;
11. Complete treatment of all liver lesions judged possible, either by RFA alone or by combination with resection of resectable lesions and RFA of the remaining non-resectable liver deposits;
12. Measurable or evaluable (radiologically detectable disease which does not fulfill RECIST criteria for measurable disease) lesions according to RECIST v1.1 criteria (CT-scan < 4 weeks);
13. Adequate organ function, as defined by the following:

1. Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) < 3 x upper limit of normal (ULN);
2. Total serum bilirubin < 1.5 ULN; 3. Prothrombin ratio > 70%;
4. Serum albumin ≥ 30 g/L;
5. Hemoglobin ≥ 10.0 g/dl;
6. White blood cell count (WBC) ≥ 3,000/μL;
7. Absolute neutrophil count (ANC) ≥ 1,500/μL;
8. Platelets ≥ 150,000/μL;
9. Serum creatinine ≤ 1.5 ULN or creatinine clearance > 50 mL/min (MDRD);
14. Any other prior therapy directed at the malignant tumor, including chemotherapy; chemoembolization therapy, molecular targeted therapy (including antiangiogenics), and radiotherapy, must be discontinued at least 2 weeks prior to registration and at least 3 weeks before day 1 on trial;
15. Life expectancy ≥ 3 months;
16. Evidence of post-menopausal status, negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause;
17. Women participants of childbearing potential must have a negative serum pregnancy test within the 7 days prior to the first treatment administration;
18. Registration in a national health care system.

Exclusion Criteria

Exclusion Criteria:

1. Any other malignancy in the past 10 years (except carcinoma of the cervix in situ or no melanoma skin cancer);
2. Clinical significant cardiovascular disease;
3. Uncontrolled hypertension, bleeding disorders or coagulopathy, active infection;
4. Major surgical procedures within 28 days before RFA;
5. Concurrent enrolment in another clinical study, unless it is an observational (noninterventional) or supportive care clinical study or during the follow-up period of an interventional study;
6. Receipt of the last dose of anticancer therapy (investigational product, chemotherapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies) ≤ 21 days prior to the RFA. If sufficient wash-out time has not occurred due to the schedule or pharmacokinetics properties of an agent, a longer wash-out period will be required;
7. Histology other than adenocarcinoma;
8. Extensive tumor massively replacing both entire lobes;
9. Obstructive jaundice (bilirubin > 1.5 ULN) without adequate biliary drainage;
10. Any unresolved toxicity NCI CTCAE Grade ≥ 2 from previous anticancer therapy with the exception of alopecia, neuropathy, and the laboratory values defined in the inclusion criteria;
11. History of allogenic organ transplantation;
12. Any systemic steroid therapy whatever the duration of this corticotherapy;

Note: The following are exceptions to this criterion:
* Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
* Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication);
13. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies); Note: Patients with past HBV infection or resolved HBV infection (defined as having a negative HBsAg test and a positive hepatitis B core antigen [HBc] antibody test) are eligible.

Note: Patients positive for HCV antibody are eligible only if polymerase chain reaction testing is negative for HCV ribonucleic acid (RNA).
14. Diagnosis of any second malignancy within the last 5 years, except for adequately treated basal cell or squamous cell skin cancer, or in situ carcinoma of the cervix uteri;
15. Known active central nervous system metastases and/or carcinomatous meningitis; patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids > 10 mg/day of prednisone or equivalent for at least 14 days prior to trial treatment;
16. Uncontrolled massive pleural effusion or massive ascites;
17. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]), that has required systemic treatment (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); Note: Patients with vitiligo, alopecia, or any chronic skin condition that does not require systemic therapy are exception to this criterion.

History of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible. Controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible.
18. Uncontrolled undercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent;
19. Live vaccine administration, excepted BCG, within 30 days prior to the RFA;
20. Known or suspected allergy or hypersensitivity to any of the study component or any of the study vaccine excipients;
21. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with participation for the full duration of the trial, or is not in the best interest of the participant, in the opinion of the treating investigator;
22. Pregnancy/lactation;
23. Tutelage or guardianship.