Clinical Study of Personalized mRNA Vaccine Encoding Neoantigen in Subjects With Resected Digestive System Neoplasms

This is a single-center, open-label, single-arm clinical study of personalized mRNA vaccine iNeo-Vac-R01 in combination with standard adjuvant therapy in subjects with surgically resected digestive system neoplasms.

Inclusion criteria

• Male or female, >/= 18 years old and </= 75 years old, with the ability to understand and provide signed and witnessed informed consent, and agree and are able to comply with protocol requirements.
• Subjects must have one of the histologically- or cytologically-confirmed advanced (locally advanced or metastatic) digestive system neoplasms listed below that can be radical resected. Subjects must be able to receive at least 4 cycles of standard adjuvant therapy according to CSCO clinical guidelines after surgery. The toxic effects of previous anti-tumor treatments have returned to </= grade 1 defined by NCI-CTCAE v5.0 or to the level specified by the inclusion/exclusion criteria.

Subjects with any of the following digestive system neoplasms:

a. Cholangiocarcinoma b. Pancreatic cancer c. Hepatocellular carcinoma d. Gastric cancer e. Colorectal carcinoma

• Expected survival >/= 6 months.
• ECOG performance status score of 0 ~ 1.
• Sufficient tumor tissue samples can be obtained from subjects for genetic analysis, with at least 0.5cm*0.5cm of tissue required for surgical samples.
• Echocardiographic evaluation: left ventricular ejection fraction (LVEF) >/= 50%.
• The organ function level must meet the following requirements: absolute neutrophil count (ANC) >/= 1.5 × 10^9/L, platelet count (PLT) >/= 80 × 10^9/L, hemoglobin (Hb) >/= 90 g/L; serum total bilirubin (TBIL) </= 1.5 × ULN, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) </= 2.5 × ULN (if there is liver metastasis, TBIL </= 3 × ULN, AST, ALT </= 5 ×ULN are allowed), serum albumin >/= 28g/L, serum creatinine </= 1.5 × BUN, Glomerular filtration rate >/= 50mL/min, prothrombin time (PT) and activated partial thromboplastin time (APTT) and international standardized ratio (INR) </= 1.5 × ULN (without anticoagulant therapy) .
• For women of childbearing potential: having a negative serum or urine pregnancy test within 7 days prior to study initiation, agreement to remain abstinent or use contraceptive measures during the treatment period.
• For men: agreement to remain abstinent or use contraceptive measures during the treatment period.

Exclusion criteria

• Subjects with cancer requiring anti-tumor treatment within the 5 years prior to enrollment in the study (except stage I prostate cancer, cervical cancer in situ, breast cancer in situ, papillary thyroid cancer and non-melanoma skin cancer that have been treated).
• Subjects who received major surgery, or had obvious traumatic injury or long-term untreated wounds or fractures within 2 weeks prior to the first dose of iNeo-Vac-R01.
• Subjects whose sequencing data was found that there are no new antigens available for individualized immunotherapy after analysis.
• Subjects who prepare to undergo or have previously received bone marrow transplantation, allogeneic organ transplantation, or allogeneic hematopoietic stem cell transplantation. Subjects who receive other anti-tumor treatments within 2 weeks prior to the first dose of iNeo-Vac-R01, including surgical treatment, chemotherapy, radiation therapy, targeted therapy, endocrine therapy, immunotherapy, biological therapy, interventional therapy, or other clinical trial related treatments.
• Subjects who need to use immunosuppressants, or systemic or absorbable local glucocorticoids therapy to achieve immunosuppressive effects and continue to use them within 7 days before the first administration (excluding those with daily doses of glucocorticoids less than 10mg of prednisone or doses of other therapeutic glucocorticoids equal to 10mg of prednisone).
• Subjects who received other vaccines within 4 weeks before the first dose of iNeo-Vac-R01, and are expected to receive other vaccines during treatment period of the study or within 60 days after the last dose of iNeo-Vac-R01.
• Subjects who have an active infection or uncontrollable infection requiring systemic treatment, including fungi, bacteria, viruses, or other infections; subjects with active tuberculosis;
• Subjects with positive hepatitis B surface antigen (HBsAg) and/or positive hepatitis B core antibody (HBcAb) and positive hepatitis B virus DNA titer detection greater than normal range; positive hepatitis C virus (HCV) antibody and HCV RNA detection greater than normal range; positive human immunodeficiency virus antibody; positive treponema pallidum-specific antibody.
• Subjects with autoimmune diseases or immune deficiencies treated with immunosuppressive drugs, except vitiligo, type 1 diabetes, autoimmune hypothyroidism requiring hormone treatment and psoriasis not requiring systemic treatment; known history of primary immunodeficiency.
• Subjects with cardiocerebrovascular events: previously or currently heart valve disease >/= grade 3, heart failure within 8 weeks before the first dose of iNeo-Vac-R01 (New York Heart Association [NYHA] cardiac function >/= grade II, myocardial infarction, unstable angina, stroke, transient ischemic attack, cardiac surgery (including coronary artery bypass grafting or percutaneous coronary intervention) within 8 weeks before the first dose of iNeo-Vac-R01, concomitant severe electrocardiogram abnormalities (such as ventricular flutter, ventricular fibrillation, multiform ventricular tachycardia, sick sinus syndrome, third degree atrioventricular block without pacemaker treatment, QTc >/= 480ms, and other conditions evaluated by the investigators as severe abnormalities), hypertension with poor drug control (systolic blood pressure >/= 160mmHg and/or diastolic blood pressure >/= 100mmHg), or other cardiocerebrovascular diseases that have been evaluated by the investigators as unsuitable for participation in this trial.
• Subjects with respiratory disease: previously or currently pulmonary fibrosis, interstitial lung disease, pneumoconiosis, radiation pneumonia, drug-related pneumonia, severe asthma, pulmonary hypertension or severe impairment of lung function, etc.
• Subjects with moderate to severe ascites with clinical symptoms; uncontrolled or moderate to equal amounts of pleural effusion and pericardial effusion.
• Subjects with drug abuse; clinical or psychological or social factors that affect informed consent or research implementation.
• Subjects with a history of allergies to immunotherapy or vaccines, or other potential immunotherapy allergies identified by the investigators.
• Subjects identified that it is not suitable for enrollment or may not be able to complete this experiment for other reasons by the investigators.
• Vulnerable groups, including individuals with mental illness, cognitive impairment, critical patients, minors, pregnant or lactating women, etc.