Microbiota Modification for Immuno-oncology in Hepatocellular Carcinoma

Inclusion Criteria: 1. Male and Female 2. Age ≥18 years at time of signing informed consent 3. Presenting with HCC, diagnosed either by histological or radiological criteria as described by EASL 4. Locally advanced or metastatic and/or unresectable HCC according a Multidisciplinary Team meeting 5. Progressive disease after exposure to standard-of-care approved first-line immunotherapy 6. Decision made by the physician to continue the same standard-of-care approved first-line immunotherapy beyond progression 7. Child-Pugh A within 7 days prior to inclusion 8. ECOG performance status 0 to 1 9. Adequate hematological (Hemoglobin \>8.5g/dL, platelets \>60G/L, neutrophils \>1.5G/L) and renal (creatinine clearance \> 50 mL/min according to Cockcroft or MDRD formula) functions 10. Disease measurable by RECIST 1.1 11. Signed written Informed consent Exclusion Criteria: 1. Partial response achieved under standard-of-care approved first-line immunotherapy 2. CTCAE Grade ≥3 or more toxicity under standard-of-care approved first-line immunotherapy, or persistent toxicity Grade \>1 3. Liver involvement \> 50% 4. Presence of major macro vascular invasion (except Vp1/Vp2) 5. Pregnant woman, or breastfeeding or women of child-bearing potential with no adequate contraception (see §4.3.1) 6. Under curatorship, guardianship, safeguard of justice or deprived of liberty 7. History of serious autoimmune disease 8. Interstitial lung disease 9. HBV chronic infection with HBV DNA \> 100 IU/mL or without antiviral therapy; HBV patients with cirrhosis should be treated 10. HIV infection 11. Immunosuppression, including subjects with a condition requiring systemic treatment with either corticosteroids (\> 10 mg/day prednisone equivalent) 12. Transplanted liver, or patient with intent for transplantation 13. Has difficulties in swallowing. 14. Has undergone major surgery or significant trauma ≤4 weeks prior to Screening. Note: Participants who had surgery \>4 weeks prior to Screening must have recovered adequately from any toxicity and/or complications from the surgery or trauma prior to starting study intervention. 15. Is currently participating in or has participated in a study with an investigational compound or device within 3 months prior to the first dose of study intervention. Note: Participants who have entered the follow-up phase of an investigational study may participate so long as it has been at least 3 months since the last dose of the previous investigational agent. 16. Has a systemic infection or other serious infection requiring systemic treatment within 30 days prior to Screening. 17. Has a history of hypersensitivity to EXL01 and/or any excipients, which are listed in the IB, and/or to soybean or soy-containing products 18. Has a history of hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies 19. Active inflammatory intestinal disease (Crohn disease, Hemorrhagic recto-colitis, coeliac disease) or any serious chronic intestinal disease with uncontrolled diarrhea, or other inflammatory disease requiring anti-inflammatory medications 20. Current probiotics administration, or planned probiotics administration during treatment course. 21. Specific contra-indication to the continuation of the standard-of-care approved first-line immunotherapy : 21.1: for atezolizumab-bevacizumab: * Thromboembolic events in the 3 months prior to inclusion * Prior bleeding event due to untreated or incompletely treated esophageal and / or gastric varices within 6 months' prior inclusion * Has a history of hypersensitivity to the atezolizumab or to any of the excipients listed in section 6.1 of the SmPC of atezolizumab * Has a history of hypersensitivity to bevacizumab or to any of the excipients listed in section 6.1 of the SmPC of bevacizumab * Uncontrolled hypertension * Clinically significant cardiovascular disease such as pre-existing coronary artery disease, or congestive heart failure * Proteinuria 21.2: for durvalumab: * Has a history of hypersensitivity to the durvalumab or to any of the excipients listed in section 6.1 of the SmPC of durvalumab.