一项toripalimab联合nadunolimab治疗化疗难治性转移性微卫星稳定型（MSS）结直肠癌（CRC）的1b/2期研究

Background: MSS CRC accounts for more than 90% of all metastatic CRC cases. For these patients, there are few systemic therapeutic options beyond chemotherapy, most of which have response rates under 10% despite significant toxicities. Conventional immunotherapy with PD-1 blockade and CTLA-4 blockade has shown minimal activity against MSS CRC, especially those with liver metastases. Single-cell profiling of CRC tumors has revealed a profoundly immunosuppressive tumor microenvironment (TME) dominated by macrophages/monocytes and regulatory T (Treg) cells. Our group identified the stromal-myeloid axis as the key driver of immunosuppression in liver metastases in preclinical mouse models. Targeting IL1RAP, the shared component of IL-1 and IL-33 receptor, disrupts the stromal-myeloid axis and restores sensitivity to immunotherapy. Based on these findings, we initiated a phase 1/2 clinical trial evaluating nadunolimab (anti-IL1RAP) plus toripalimab (anti-PD1) in patients with chemotherapy-refractory MSS CRC. Methods: This is an investigator-initiated phase 1b/2 trial to assess the safety and efficacy of nadunolimab plus toripalimab in patients with metastatic MSS CRC (NCT07281716). Eligible patients must have biopsy-proven MSS CRC (non-MSI-H or Mismatch Repair-proficient) whose disease has progressed after 5-FU, oxaliplatin and/or irinotecan-based chemotherapy. Patients will receive nadunolimab 5mg/kg and toripalimab 240mg every 3 weeks for up to 1 year or until disease progression. Patients enrolled will undergo core needle biopsy and serial blood collection prior to and during treatment. Two patients (10%) have been enrolled as of January 12 th , 2026. The study includes a phase 1b lead-in of 3+3 patients, and the primary endpoint is the occurrence of dose-limiting toxicities (DLT). For phase 2, the primary endpoint is the overall response rate, and the secondary endpoints include disease control rate, progression free survival, overall survival, and duration of response. To avoid futility, the study follows a two-stage minimax design (12+ 9 patients). The operating characteristics for 21 patients will test a null hypothesis of poor ORR of 5% or less versus an alternative hypothesis of a promising ORR of 20% or more at a 10% one-sided significance level and 80% power. For exploratory analyses, we will conduct comprehensive genomic, transcriptomic, proteomic, and digital pathology analyses of biopsies and blood samples to characterize the dynamic immune responses to IL1RAP blockade, identify biomarkers of responses, and define the mechanisms of resistance.