The TERTIO trial will propose to determine the clinical interest and immunological efficacy of a treatment combining the CD4 helper T-inducer cancer anti-telomerase vaccine (UCPVax) with anti-PD-L1 therapy (atezolizumab) and bevacizumab in unresectable HCC by evaluation of the objective response rate at 6 months (randomized phase II, 10 centers, 105 patients)

Main inclusion Criteria:

1. Signed informed consent
2. Histologically confirmed hepatocellular carcinoma
3. Locally advanced, metastatic, or unresectable disease
4. Patient who had not previously received systemic anti-cancer treatment
5. Age ≥ 18 years
6. Measurable disease defined according to mRECIST guidelines (Note: Previously irradiated lesions can be considered as measurable disease only if disease progression has been unequivocally documented at that site since radiation.)
7. Patients who have received previous chemoembolization, radioembolization and/or radiotherapy should have recovered from any treatment related toxicity, to a level of ≤ grade 1 (according to National Cancer Institute [NCI] common terminology criteria for adverse events, version 5 (CTCAE v5) with the exception of Grade 2 alopecia
8. Performance status < 2
9. Child-Pugh Class A status
10. BCLC C stage or BCLC B stage not eligible to loco-regional therapy according to the Barcelona Clinic Liver Cancer (BCLC) staging system

Main exclusion Criteria:

Non-eligible to a clinical trial:

1. Patients previously exposed to anti-tumor immunotherapy as anti-PD-1, anti-PD-L1, or anti-CTLA4 agent or any immune therapy.

2. Diagnosis of additional malignancy within 3 years prior to the inclusion with the exception of curatively treated basal cell carcinoma of the skin and/or curatively resected in situ cervical or breast cancer

3. Patient with any medical or psychiatric condition or disease, which would make the patient inappropriate for entry into this study

4. Current participation in a study of an investigational agent or in the period of exclusion

5. Patient under guardianship, curatorship or under the protection of justice

   Cancer-specific exclusion criteria:

6. Know fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC

7. Uncontrolled pleural effusion, pericardial effusion, ascites or symptomatic fistula

8. Uncontrolled tumor-related pain: exposing patients to risk of exposure to corticoids or iterative hospitalizations. Symptomatic lesions amenable to palliative radiotherapy should be treated prior to inclusion. Patients should be recovered from the effects of radiation. There is no required minimum recovery period

9. Known active central nervous system metastases and/or carcinomatous meningitis. Subject with previously treated brain metastases and with radiological and clinical stability are allowed

   Non-eligible to treatment:

10. History of encephalopathy

11. Prior bleeding event due to untreated or incompletely treated esophageal and/or gastric varices within 6 months prior to randomization

12. Inadequate organ functions: known cardiac failure of unstable coronaropathy, respiratory failure, or uncontrolled infection or another life-risk condition