Application of mRNA Immunotherapy Technology in Hepatitis B Virus-related Refractory Hepatocellular Carcinoma

A Phase I Study of mRNA Vaccine for Patients With HBV-positive Advanced Hepatocellular Carcinoma

The purpose of this study is to evaluate the efficacy and safety of mRNA vaccine for HBV-positive Advanced Hepatocellular Carcinoma.

Hepatocellular carcinoma is a common malignant tumor of the digestive system worldwide and is particularly prevalent in China. More than 80% of hepatocellular carcinoma patients in China have concomitant hepatitis B virus infection. However, there are limited effective treatments for hepatocellular carcinoma that have failed standard treatment, and the prognosis for these patients is poor. About 350 million people worldwide are chronically infected with the hepatitis B virus (HBV), and chronic HBV infection accounts for at least 50% of hepatocellular carcinoma cases worldwide. Therefore, anti-HBV can be a potential target for hepatocellular carcinoma.

The mRNA vaccines are a highly promising novel anti-tumor approach. The applicant team of this project has carried out research on raw materials and preparation process, vaccine stability, quality standard, delivery vector construction, and anti-tumor mechanism of action of mRNA immune formulation in the early stage. Now we have completed the optimized design of mRNA raw materials, and the construction and optimization of the mRNA delivery vector. The tumor therapeutic mRNA immune formulation with high efficiency, safety, scalable preparation, and quality control has been selected and preclinical evaluation has been completed to verify its safety and efficacy. The project has constructed mRNA vaccines, and no similar therapeutic method or product has been reported in the international arena.

This project proposes to conduct a phase I clinical study based on the previous study to include patients with advanced hepatocellular carcinoma who have failed second-line standard treatment or cannot receive standard treatment. A dose-escalation trial will be conducted, and one effective dose will be selected for a fixed-dose trial to explore the safety, tolerability, and efficacy of mRNA immunotherapy technology for clinical application. Project implementation is expected to benefit a wide range of hepatocellular carcinoma patients and improve their prognosis.

Inclusion Criteria:

1. Male or female patients: ≥ 18 years old; ≤ 70 years old;

2. Patients with HBV-positive advanced hepatocellular carcinoma after failure of second-line standard therapy (including PD-1 inhibitor therapy, chemotherapy, and anti-vascular targeted drugs);

3. HBsAg positive, regardless of whether the peripheral blood is positive for HBV DNA.

4. ECOG physical fitness score: 0~1 points;

5. Estimated survival ≥ 3 months;

6. The main organs have good function, that is, the relevant examination indicators within random 14 days meet the following requirements:

   1. Blood routine examination: hemoglobin ≥ 80 g/L (no blood transfusion within 14 days); Neutrophil count> 1.5×109/L; Platelet count≥ 80×109/L;

   2. Biochemical examination: total bilirubin ≤ 1.5× ULN (upper limit of normal); alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 2.5×ULN; If liver metastases are present, ALT or AST ≤ 5×ULN; Endogenous creatinine clearance

      ≥ 60 ml/min (Cockcroft-Gault formula);

   3. Cardiac Doppler ultrasound assessment: left ventricular ejection fraction (LVEF) ≥50%.

7. Sign the informed consent form;

8. Good compliance, family members agree to cooperate with survival follow-up.

Exclusion Criteria:

1. Participated in clinical trials of other drugs within 4 weeks;
2. The patient has a history of other tumors, unless it is cervical cancer in situ, treated cutaneous squamous cell carcinoma or bladder epithelial tumor or other malignant tumors that has received radical treatment (at least 5 years before enrollment)
3. Patients with uncontrolled cardiac clinical symptoms or diseases, such as heart failure above NYHA grade 2, unstable angina, myocardial infarction within 1 year, and clinically significant supraventricular or ventricular arrhythmias requiring treatment or intervention.
4. For female subjects: pregnant or lactating women.
5. The patient has active tuberculosis, bacterial or fungal infection (≥ grade 2 of NCI-CTC, 3rd edition); There is HIV infection with active HBV infection, HCV infection.
6. Those who have a history of psychotropic drug abuse and have mental disorders that cannot be remitted;
7. The subject has any active autoimmune disease or has a history of autoimmune disease (such as, but not limited to uveitis, enteritis, pituitary inflammation, nephritis, hyperthyroidism, hypothyroidism; Participants with vitiligo or who had complete remission of asthma in childhood and did not require any intervention in adulthood could be included; Participants in asthma requiring medical intervention with bronchodilators omitted).
8. According to the judgment of the investigator, there are concomitant diseases that seriously endanger the safety of patients or affect the completion of the patient's research.