Toripalimab Plus Bevacizumab and Chemotherapy as Neoadjuvant Therapy in Advanced MSI-H or dMMR Colorectal Cancer

Inclusion Criteria:

1. Histologically confirmed colorectal adenocarcinoma meeting any of the following criterion: a) T3-4 resectable rectal cancer; b) T1-2 rectal cancer located within 12 cm from the anal verge and refusing direct surgery or radiation therapy; c) T4a-b resectable colon cancer.
2. Microsatellite instability-high (MSI-H) or DNA mismatch repair-deficient (dMMR).
3. Measurable disease according to the Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria and haven't received any local treatment.
4. Eastern Cooperative Oncology Group (ECOG) 0-1.
5. Fully aware of this study and having signed informed consent.
6. Age 18 to 75 years old without gender limitation.
7. Good compliance.
8. Absolute neutrophil count ≥1500/mm3, platelet ≥100,000/mm3, Hb ≥10g/dl, serum creatinine ≤1.5 times ULN, creatinine clearance rate ≥50mL/min, ALT and AST ≤2.5 times ULN, INR or aPTT ≤1.5 times ULN (INR ≤2 times ULN and aPTT in normal range for patients who are on prophylactic anticoagulant therapy within 14 days before study treatment), total bilirubin level ≤2 times ULN (within 7 days before study treatment).
9. Women of childbearing age should confirm that serum pregnancy test is negative and agree to use effective contraceptive methods during study treatment and the following 60 days.

Exclusion Criteria:

1. Previously received anti-PD1 or anti-PDL1 or anti-PDL2 or anti-CTLA4.
2. Uncontrolled active bleeding from the primary tumor or intestinal obstruction.
3. Contraindications of bevacizumab or irinotecan.
4. Hypersensitivity to other monoclonal antibodies.
5. Any active, known or suspected autoimmune disease.
6. Uncontrolled pleural effusion, pericardial effusion, or ascites to a moderate or greater extent.
7. History of one of the following dieases: idiopathic pulmonary fibrosis, organized pneumonia (eg. bronchiolitis obliterans), drug-induced pneumonia, idiopathic pneumonia and interstitial pneumonia, or evidence of active pneumonia through enhanced chest CT screening.
8. Major surgery within 4 weeks before enrollment and haven't fully recovered from the previous surgery.
9. Active bleeding or abnormal coagulation (aPTT \>43s or INR \>1.5 times ULN), or having a tendency to bleed or receiving thrombolytic or anticoagulant therapy.
10. Previously received allogeneic stem cell or parenchymal organ transplantation.
11. Any significant clinical or laboratory abnormality that the investigator considers to influence the safety assessment, eg. uncontrolled active infection, uncontrolled diabetes, hypertension that cannot be reduced to normal range with monotherapy, grade II or above peripheral neuropathy, congestive heart failure, heart disease (class II or higher) as defined by the New York College of Cardiology, myocardial infarction within 3 months prior to enrollment, unstable arrhythmias, unstable angina pectinis, chronic kidney disease, abnormal thyroid function and previous or co-existing malignancies.
12. History of uncorrected serum electrolyte disturbances such as potassium, calcium and magnesium.
13. HIV infection.
14. Active hepatitis B or hepatitis C.
15. Pregnancy or lactation period, or unwilling to use contraception during the trial.
16. With other malignancy within 5 year, except cervical carcinoma in situ, basal or squamous skin cancer, local prostatic carcinoma and ductal carcinoma in situ.
17. Use corticosteroids (dose of prednisone or similar drugs\> 10mg/day) or other immunosuppressive agents within 14 days before enrollment.
18. Patients with active tuberculosis (TB) who are receiving anti-TB treatment or have received anti-TB treatment within 1 year.
19. Active infection, or treatment with oral or intravenous antibiotics within the first 2 weeks prior to neoadjuvant therapy, except prophylactic administration.
20. Anti-infective vaccine (eg. influenza vaccine, varicella vaccine, etc.) injection within 4 weeks before neoadjuvant therapy.
21. Previous participation in other clinical trials within 4 weeks before neoadjuvant therapy.
22. Any other disease, metabolic disorder, abnormal physical examination or abnormal laboratory results that may contrainn the use of trial drug, or affect the reliability of study results, or lead to high risk of treatment complications, or affect patient compliance.