The Efficacy and Safety of Neoadjuvant Therapy With Iparomlimab and Tuvonralimab in Locally Advanced MSI-H/dMMR Colorectal Cancer: An Prospective, Single-Arm Study (Neo-IT)

Inclusion criteria

• Patients willing to receive neoadjuvant therapy.
• Age ≥18 years.
• Histologically confirmed primary colorectal adenocarcinoma (without squamous or sarcomatoid components).
• Radiologically assessed (contrast-enhanced CT or MRI) as surgically resectable stage IIB-III (limited to cT4 or cN+ per AJCC 8th edition).
• Confirmed dMMR or MSI-H status by immunohistochemistry or MSI genetic testing.
• Lesions diagnosed by investigators as amenable to radical resection (R0 resection) without requiring multi-organ resection prior to neoadjuvant therapy.
• Voluntary participation with signed informed consent.
• ECOG performance status score of 0-1.
• No prior antitumor or immunotherapy before enrollment.
• Adequate organ and bone marrow function defined as:

• Hematology: Absolute Neutrophil Count (ANC) ≥1.5×10⁹/L; Platelets (PLT) ≥100×10⁹/L; Hemoglobin (HGB) ≥7.0 g/dL.
• Liver function: Total Bilirubin (TBIL) ≤1.5×ULN; Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST) ≤3×ULN; Serum Albumin (ALB) ≥28 g/L.
• Renal function: Serum creatinine ≤1.5×ULN or creatinine clearance ≥50 mL/min; Urine dipstick shows protein <2+; for subjects with baseline urine dipstick protein ≥2+, a 24-hour urine collection must demonstrate protein <1 g.
• Coagulation: International Normalized Ratio (INR) ≤1.5 and Activated Partial Thromboplastin Time (APTT) ≤1.5×ULN.
• No severe comorbidities jeopardizing survival (life expectancy <5 years).
• Fertile female subjects or male subjects with fertile partners must use effective contraception during and for 6 months after treatment. Postmenopausal status or negative urine/serum pregnancy test for premenopausal females.

Exclusion criteria

• 1.Prior antitumor therapy for the disease under investigation, including surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy, etc.

2.Previous treatment with anti-PD-1, anti-PD-L1, anti-programmed death ligand 2 (PD-L2), or anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) agents, or any other drugs targeting T-cell co-stimulation or immune checkpoint pathways (e.g., OX40, CD137), as well as adoptive cell immunotherapy.

3.Concurrent participation in another interventional clinical study. 4.Treatment with any investigational drug or device within 4 weeks prior to the first dose of the study drug.

5.Within 7 days before screening laboratory tests: receipt of blood transfusion, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), erythropoietin (EPO), thrombopoietin (TPO), or IL-11 therapy.

6.Use of immunosuppressive drugs within 4 weeks before the first dose of the study drug, excluding: intranasal/inhaled topical steroids or local steroid injections (e.g., intra-articular); systemic corticosteroids at doses ≤10 mg/day prednisone or equivalent; corticosteroids as premedication for allergic reactions (e.g., CT scan premedication).

7.Use of Chinese herbal medicine with antitumor indications or immunomodulatory drugs (including thymosin, interferon, interleukin, etc.) within 1 week before the first dose of the study drug.

8.Receipt of live or attenuated vaccines within 4 weeks before the first dose or anticipated during the study.

9.Major surgery (e.g., craniotomy, thoracotomy, or laparotomy) within 4 weeks before the first dose, anticipated need for major surgery during the study (except protocol-defined radical resection for colon cancer), or presence of unhealed wounds, ulcers, or fractures.