Testing Immunotherapy for Patients With Liver Cancer and Moderately Altered Liver Functions

Inclusion Criteria:

1. Age ≥18 years old

2. Patient presenting with histologically-proven Hepatocellular Carcinoma (HCC), or HCCdefined by typical imaging findings (EASL criteria), if no biopsy could be performedsafely

3. Pretreated or not by tyrosine kinase inhibitors (e.g., sorafenib, lenvatinib,regorafenib, cabozantinib)

4. Child-Pugh B cirrhosis

5. ALBI (Albumin-Bilirubin) grade 1 or 2

6. BCLC (Barcelona Clinic Liver Cancer Group) B or C

7. Availability of biopsy specimen at study enrolment (taken within 3 months ofenrolment with the exception of cases where biopsy could not be performed safely)

8. ECOG Performance status ≤2

9. Adequate organ function as indicated by the following laboratory values:

10. Patients must not have required a blood transfusion or growth factor support ≤14 days before sample collection at screening for the following:

• Absolute neutrophil count (ANC) ≥1.5 x 10⁹/L
• Platelets ≥75 x 10⁹/L
• Hemoglobin ≥90 g/L

2. Serum creatinine ≤1.5 x upper limit of normal (ULN) or estimated GlomerularFiltration Rate ≥60 mL/min/1.73 m²

3. Serum total bilirubin ≤3 mg/dL

4. Liver function: ASAT and ALAT ≤5 ULN, albumin >2.0 g/dL

5. Presence of measurable and evaluable disease according to RECIST v1.1

6. Women of childbearing potential must be willing to use a highly effective method ofbirth control for the duration of the study, and ≥120 days after the last dose oftislelizumab, and have a negative urine or serum pregnancy test ≤7 days of firstdose of study drug. In case of a urine pregnancy test, it must be a highly sensitiveurine pregnancy test

7. Non-sterile males must be willing to use a highly effective method of birth controlfor the duration of the study and for ≥120 days after the last dose of tislelizumab.A sterile male is defined as one for whom azoospermia has been previouslydemonstrated in a semen sample examination as definitive evidence of infertility.Males with known "low sperm counts" (consistent with "sub-fertility") are not to beconsidered sterile for purposes of this study

8. Patients must have provided consent for the study by signing and dating a writteninformed consent form prior to any study specific procedures, sampling, or analyses.When the patient is physically unable to give their written consent, a trustedperson of their choice, independent from the investigator or the sponsor, canconfirm in writing the patient's consent

9. Patient consent to the use of their collected tumour specimen, as well as bloodsamples as detailed in the protocol for future scientific research which includesbut not limited to DNA, RNA, and proteinbased biomarker detection

10. Patient affiliated to a social security regimen

11. Men and women patients must consent to not donate or bank sperm or ova duringtreatment and for 120 days after treatment stop

Exclusion Criteria:

1. More than 50% of the liver is affected by the HCC (according to investigatorsevaluation)

2. Fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC

3. Previous treatment with immunotherapy (anti-PD-1, anti-PD-L1, or anti-CTLA-4 agents)

4. History of active autoimmune disease. Note: Patients with the following diseases arenot excluded and may proceed to further screening:

5. Type I diabetes

6. Hypothyroidism (provided it is managed with hormone replacement therapy only)

7. Controlled celiac disease

8. Skin diseases not requiring systemic treatment (e.g., vitiligo, psoriasis,alopecia)

9. Any other disease that is not expected to recur in the absence of externaltriggering factors

10. History of interstitial lung disease, non-infectious pneumonitis or uncontrolleddiseases including pulmonary fibrosis, acute lung diseases

11. Any of the following cardiovascular risk factors:

12. Cardiac chest pain, defined as moderate pain that limits instrumentalactivities of daily living, ≤28 days before first dose of study drug

13. Pulmonary embolism ≤28 days before first dose of study drug

14. Any history of acute myocardial infarction ≤6 months before first dose of studydrug

15. Any history of heart failure meeting New York Heart Association (NYHA)Classification III or IV ≤6 months before first dose of study drug

16. Any event of ventricular arrhythmia ≥ Grade 2 in severity ≤6 months beforefirst dose of study drug

17. Any history of cerebrovascular accident ≤ 6 months before first dose of studydrug

18. Uncontrolled hypertension: systolic pressure ≥160 mmHg or diastolic pressure ≥100 mmHg despite anti-hypertension medications before first dose of drug

19. Any episode of syncope or seizure before first dose of study drug

20. Patients with untreated chronic hepatitis B or chronic hepatitis B virus (HBV)carriers whose HBV DNA is >500 IU/mL or patients with active hepatitis C virus (HCV)should be excluded. Note: Inactive hepatitis B surface antigen (HBsAg) carriers,treated and stable hepatitis B (HBV DNA <500 IU/mL), and cured hepatitis C patientscan be enrolled

21. Known primary immunodeficiency or active HIV

22. Immunosuppression, including subjects with a condition requiring systemic treatmentwith either corticosteroids (>10 mg/day prednisone equivalent) ≤14 days beforeinclusion. Note: Patients who are currently or have previously been on any of thefollowing steroid regimens are not excluded:

23. Adrenal replacement steroid (dose ≤10 mg daily of prednisone or equivalent)

24. Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid withminimal systemic absorption

25. Short course (≤7 days) of corticosteroid prescribed prophylactically (e.g., forcontrast dye allergy) or for the treatment of a non-autoimmune condition (e.g.,delayed-type hypersensitivity reaction caused by contact allergen)

26. Live vaccine within 4 weeks of first dose of study drug. Note: Seasonal vaccines forinfluenza are generally inactivated vaccines and Covid vaccination with non-livevaccine are allowed. Intranasal vaccines are live vaccines, and are not allowed

27. Transplanted liver, or patient with intent for transplantation

28. Received locoregional therapy to the liver (TACE, transcatheter embolization,hepatic arterial infusion, radiation, radioembolization or ablation) in the 4 weeksbefore inclusion

29. Prior malignancy active within the previous 3 years of inclusion except for locallycurable cancers considered cured or successfully resected, such as basal or squamouscell skin cancers, superficial bladder cancer, or gastric cancers, or carcinoma insitu of the prostate, cervix, or breast carcinomas. Any oncological concomitanttreatment are not allowed during the treatment period

30. Has received any herbal medicine used to control cancer with immunostimulantproperties that may interfere with liver function within 14 days of the first studydrug administration

31. Pregnant woman or breast-feeding women or patient with no adequate contraception

32. Participation in another therapeutic trial within the 30 days prior to studyinclusion

33. Patients deprived of their liberty or under protective custody or guardianship

34. Patients unable to adhere to the protocol for geographical, social, or psychologicalreasons

35. Patients eligible for treatment by TACE or SIRT are not allowed