• Rates of treatment-related surgery delay [ Time Frame: 1 year ]
  Treatment-related surgery delay was defined as the interval between the last dose of PD-1 inhibitor (Toripalimab) and surgery is more than 28 days.
• Frequency of 3/4 grade adverse events as assessed by CTCAE v5.0 [ Time Frame: 1 year ]
  Frequency of 3/4 grade adverse events occurring up to 90 days after the last dose of Toripalimab or 30 days after surgery (whichever is longer).

• Pathological complete response (pCR) rates [ Time Frame: 1 year ]
  Proportion of patients experiencing a pCR to perioperative PD-1 antibody.
• Major pathological response rates [ Time Frame: 1 year ]
  The proportion of patients experiencing a major pathological response to perioperative PD-1 antibody.
• Disease-free survival (DFS) [ Time Frame: 3 years ]
  Defined as the time from randomization to relapse, metastasis or death from any cause.
• Overall survival (OS) [ Time Frame: 5 years ]
  Defined as the time from randomization to death from any cause.
• R0 resection rates [ Time Frame: 1 years ]
  The proportion of patients achieved a complete resection with negative margin.
• Safety [ Time Frame: 1 year ]
  Assessed by evaluation of treatment-related adverse events
• Feasibility [ Time Frame: 1 year ]
  Any treatment-related delays in the planned surgery of no more than 28 days after the last preoperative toripalimab dose

• Down-staging of primary tumors [ Time Frame: 1 year ]
  Down-staging of the resected tumour as measured by histopathological tumour diameter and stage according to the TNM staging system of AJCC (7th version).
• Proportion of patients experiencing pathologic response to neoadjuvant treatment [ Time Frame: 1 year ]
  The proportion of patients experiencing pathologic response will be computed with associated 95% confidence interval for each treatment arm
• Disease-free survival (DFS) [ Time Frame: 3 years ]
  Defined as the time from randomization to relapse, metastasis or death from any cause.
• Overall survival (OS) [ Time Frame: 5 years ]
  Defined as the time from randomization to death from any cause.

Colorectal cancer of Mismatch Repair-deficient (dMMR)/ Microsatellite Instability-high (MSI-H) accounts for approximately 15% of all colorectal cancer patients, with a higher proportion in right colon cancer. Previous studies have found that colon cancer patients with dMMR/MSI-H cannot benefit from 5-fluorouracil (5-FU) adjuvant chemotherapy. Once patients have distant metastases, they are not sensitive to traditional palliative chemotherapy, and the prognosis is significantly worse than that of mismatch repair-proficient (pMMR)/microsatellite stability (MSS). A phase II clinical study of anti-PD-1 immunotherapy based on mismatch repair (MMR) status published in 《N Engl J Med》 showed that the objective response rate (ORR) of advanced colorectal cancer patients with dMMR received anti-PD-1 is 40%, and a longer response time can be obtained compared to conventional chemotherapy.

Anti-PD-1 neoadjuvant therapy has proven to be safe and feasible in lung cancer, bladder cancer and malignant melanoma, and can achieve more than 40% of major pathological response. However, there are no reports of anti-PD-1 neoadjuvant therapy for the dMMR/MSI-H colorectal cancer. Therefore, the aim of this study was to find the best multidisciplinary treatment for resectable colorectal cancer patient with the dMMR/MSI-H phenotype and to explore whether cyclooxygenase (COX) inhibitors combined with anti-PD-1 monoclonal antibody (mAb) could further improve efficacy.

• Colorectal Cancer
• Mismatch Repair-deficient (dMMR)
• Microsatellite Instability-high (MSI-H)
• Neoadjuvant Therapy

• Drug: Neoadjuvant therapy with PD-1 inhibitor plus COX inhibitor
  Toripalimab (IV given over 30 min at a dose of 3mg/m2 on day 1, every 2 weeks for 6 cycles) and Celecoxib (oral 200mg twice daily for 12 weeks) followed by colectomy
  Other Names:

  • Toripalimab
  • Celecoxib
• Drug: Neoadjuvant therapy with PD-1 inhibitor
  Toripalimab (IV given over 30 min at a dose of 3mg/m2 on day 1, every 2 weeks for 6 cycles) followed by colectomy
  Other Name: Toripalimab

• Experimental: PD-1 inhibitor plus COX inhibitor
  Neoadjuvant therapy with PD-1 inhibitor (Toripalimab) plus COX inhibitor (Celecoxib)
  Intervention: Drug: Neoadjuvant therapy with PD-1 inhibitor plus COX inhibitor
• Experimental: PD-1 inhibitor
  Neoadjuvant therapy with PD-1 inhibitor (Toripalimab)
  Intervention: Drug: Neoadjuvant therapy with PD-1 inhibitor

Inclusion Criteria:

1. Willing and able to provide written informed consent.
2. Histological or cytological documentation of adenocarcinoma of the colon or rectum.
3. Tumor tissues were identified as mismatch repair-deficient (dMMR) by immunohistochemistry (IHC) method or microsatellite instability-high (MSI-H) by polymerase chain reaction (PCR).
4. Male or female subjects > 18 years < 70 of age.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6. Determined CT or MRI scans (done within 14 days of registration) of the chest, abdomen and pelvis: locally advanced (cT3-4 or cN1-2 [with the definition of a clinically positive lymph node being any node ≥ 1.0 cm]).
7. Non complicated primary tumor (obstruction, perforation, bleeding).
8. No previous any systemic anticancer therapy for colorectal cancer disease or radiologic evaluation of tumor regression < 20% or unacceptable toxic effects during neoadjuvant chemotherapy.
9. Adequate bone marrow, hepatic and renal function as assessed by the following laboratory requirements conducted within 7 days of starting study treatment.

Exclusion Criteria:

1. Previous or concurrent cancer that is distinct in primary site or histology from colon cancer within 5 years prior to randomization.
2. Significant cardiovascular disease including unstable angina or myocardial infarction within 6 months before initiating study treatment.
3. Heart failure grade III/IV (NYHA-classification).
4. Unresolved toxicity higher than CTCAE v.4.0 Grade 1 attributed to any prior therapy/procedure.
5. Subjects with known allergy to the study drugs or to any of its excipients.
6. Current or recent (within 4 weeks prior to starting study treatment) treatment of another investigational drug or participation in another investigational study.
7. Breast- feeding or pregnant women
8. Lack of effective contraception.
9. Previously received anti-programmed death-1 (PD-1) or its ligand (PD-L1) antibody, anti-cytotoxic T lymphocyte-associated antigen 4 (cytotoxic T-lymphocyte-associated Protein 4, CTLA-4) antibody or other drug/antibody that acts on T cell costimulation or checkpoint pathways.
10. With any distant metastasis.