Personalized Tumor Neoantigen mRNA Therapy for 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:

• Voluntarily sign the informed consent form;
• Aged ≥18 years and ≤75 years, regardless of gender;
• 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;
• Have not received systemic or local treatment for HCC in the past.
• According to the solid tumor efficacy evaluation criteria (RECIST 1.1), the investigators assess the presence of measurable lesions.
• Child-Pugh score within 7 points (including 7 points)
• Eastern Cooperative Oncology Group (ECOG) performance status score is 0 or 1;
• Adequate fresh tumor tissue samples can be obtained for exome and transcriptome sequencing analysis;
• The main organ functions of the heart, liver and kidney are normal:

• QTc (corrected QT interval) in the electrocardiogram: ≤450 milliseconds for men, or ≤470 milliseconds for women;
• Coagulation function: international normalized ratio (INR) ≤1.5×ULN; activated partial thromboplastin time (APTT) ≤1.5 times ULN;
• 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;
• 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;
• 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;
• 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:

• Voluntarily sign the informed consent form;
• Aged ≥18 years and ≤75 years, regardless of gender;
• Primary hepatocellular carcinoma confirmed by pathology (histology or cytology);
• Have not received any systemic treatment.
• According to the solid tumor efficacy evaluation criteria (RECIST 1.1), the researcher assesses the presence of measurable lesions.
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1;
• Normal function of the heart, liver and kidney:

• QTc (corrected QT interval) in the electrocardiogram: ≤450 milliseconds for men, or ≤470 milliseconds for women;
• Coagulation function: international normalized ratio (INR) ≤1.5×ULN; activated partial thromboplastin time (APTT) ≤1.5 times ULN;
• 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;
• 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;
• 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;
• 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.

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

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

• 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.

• 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.