Personalized Tumor Neoantigen mRNA Therapy for Advanced Hepatocellular Carcinoma

Clinical Study to Evaluate the Safety and Efficacy of Personalized Tumor Neoantigen mRNA Therapy Combined With PD-1 Monoclonal Antibody and TACE for Advanced Hepatocellular Carcinoma

This study is to evaluate the feasibility and safety of personalized tumor neoantigen mRNA therapy iNeo-Vac-R01 combined with PD-1 monoclonal antibody, anti-VEGFR monoclonal antibody and TACE regimen for the treatment of patients with advanced hepatocellular carcinoma.

Inclusion Criteria:

• (1) Subjects who meet all the following inclusion criteria will enter the pre-screening stage of this study and undergo the lesion puncture process:

  1. Voluntarily sign the informed consent form;

  2. Aged ≥18 years and ≤75 years, regardless of gender;

  3. Strictly meet the 2018 American Association for Clinical Diagnosis of Liver Diseases (AASLD) clinical diagnostic criteria for HCC, and imaging assessment is unresectable/metastatic hepatocellular carcinoma (HCC), CNLC stage Ib to IIIb;

  4. Have not received systemic or local treatment for HCC in the past.

  5. According to the solid tumor efficacy evaluation criteria (RECIST 1.1), the investigators assess the presence of measurable lesions.

  6. Child-Pugh score within 7 points (including 7 points)

  7. Eastern Cooperative Oncology Group (ECOG) performance status score is 0 or 1;

  8. Adequate fresh tumor tissue samples can be obtained for exome and transcriptome sequencing analysis;

  9. The main organ functions of the heart, liver and kidney are normal:

     1. QTc (corrected QT interval) in the electrocardiogram: ≤450 milliseconds for men, or ≤470 milliseconds for women;
     2. Coagulation function: international normalized ratio (INR) ≤1.5×ULN; activated partial thromboplastin time (APTT) ≤1.5 times ULN;
     3. Hematological indicators: white blood cells ≥3.5×109/L; absolute neutrophil count (ANC) ≥1.5×109/L; hemoglobin (HGB) ≥10 g/dL; platelet count (PLT) ≥80×109/L;
     4. Biochemical indicators: serum total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times ULN (ALT or AST ≤ 5 times ULN is allowed for patients with liver metastasis and liver cancer); serum creatinine and urea nitrogen ≤ 1.5 times ULN;

  10. Male patients with fertility and female patients of childbearing age agree to take effective contraceptive measures from the signing of the informed consent form to 6 months after the last administration of the trial drug; women of childbearing age include premenopausal women and women within 2 years after menopause;

  11. Able to follow the study protocol and follow-up process.

  (2) Subjects who meet all the following inclusion criteria will enter the formal screening phase of this study and enter the study medication process:

  1. Voluntarily sign the informed consent form;

  2. Aged ≥18 years and ≤75 years, regardless of gender;

  3. Primary hepatocellular carcinoma confirmed by pathology (histology or cytology);

  4. Have not received any systemic treatment.

  5. According to the solid tumor efficacy evaluation criteria (RECIST 1.1), the researcher assesses the presence of measurable lesions.

  6. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1;

  7. Normal function of the heart, liver and kidney:

     1. QTc (corrected QT interval) in the electrocardiogram: ≤450 milliseconds for men, or ≤470 milliseconds for women;
     2. Coagulation function: international normalized ratio (INR) ≤1.5×ULN; activated partial thromboplastin time (APTT) ≤1.5 times ULN;
     3. Hematological indicators: white blood cells ≥3.5×109/L; absolute neutrophil count (ANC) ≥1.5×109/L; hemoglobin (HGB) ≥10 g/dL; platelet count (PLT) ≥80×109/L;
     4. Biochemical indicators: serum total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times ULN (ALT or AST ≤ 5 times ULN is allowed for patients with liver metastasis and liver cancer); serum creatinine and urea nitrogen ≤ 1.5 times ULN;

  8. Male patients with fertility and female patients of childbearing age agree to take effective contraceptive measures from the signing of the informed consent form to 6 months after the last administration of the trial drug; women of childbearing age include premenopausal women and women within 2 years after menopause;

  9. Able to follow the study protocol and follow-up process.

     Exclusion Criteria:

• 1) Diffuse HCC. 2) Known fibrolamellar HCC, cholangiocarcinoma, and mixed HCC. 3) Concomitant tumor thrombus in the main portal vein or contralateral portal vein, superior mesenteric vein, or vena cava.

  4) History of meningeal disease; presence of central nervous system metastases or meningeal metastases.

  5) History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonia, or idiopathic pneumonia, or evidence of active pneumonia on screening chest CT.

  6) Patients with other malignant tumors at the same time, but basal cell carcinoma, thyroid cancer, cervical atypical hyperplasia, etc. that have been cured, have been in a disease-free state for more than 5 years or are considered by researchers to be less likely to relapse; 7) Patients with a history of bone marrow transplantation, allogeneic organ transplantation, or allogeneic hematopoietic stem cell transplantation; 8) Patients with immunosuppressants, that is, those who need to take immunosuppressants regularly 4 weeks before the screening period and during the clinical study, including but not limited to the following: those with severe asthma, autoimmune diseases or immunodeficiency, those who are treated with immunosuppressive drugs, and those with a known history of primary immunodeficiency; but excluding type 1 diabetes, autoimmune-related hypothyroidism requiring hormone treatment, and vitiligo and psoriasis that do not require systemic treatment; 9) Active bacterial or fungal infection confirmed by clinical diagnosis; active tuberculosis or history of tuberculosis; 10) Those with positive human immunodeficiency virus (HIV) antibody test, positive Treponema pallidum (TP) antibody test, active hepatitis C (positive hepatitis C virus (HCV) antibody and HCV RNA result is positive), active hepatitis B; 11) Herpes virus infection (except for those with scabs for more than 4 weeks); respiratory virus infection (except for those who have recovered for more than 4 weeks); 12) Uncontrolled complications include but are not limited to active infection, symptomatic congestive heart failure, unstable angina, arrhythmia; severe coronary artery disease or cerebrovascular disease, or other diseases that the investigators believe are not suitable for inclusion; 13) History of drug abuse, clinical, psychological or social factors that affect informed consent or research implementation; history of mental illness; 14) History of food, drug or vaccine allergy, or other potential immunotherapy allergies considered by the investigator.

  15) Pregnant or lactating women; 16) Those who the investigators believe are not suitable for inclusion or may not be able to complete this trial for other reasons.