1040P - Chemotherapy remodels the tumor immune microenvironment to increase the pCR rate of anti-PD-1 neoadjuvant therapy in MSS/pMMR locally advanced colon cancer: A prospective clinical trial and translational study

Background

The recurrence rate of locally advanced colon cancer (T3-4 or N+, M0) after surgery is significantly high. We have designed a prospective trial to investigate whether the anti-PD-1 in combination with chemotherapy constitutes a safe and beneficial treatment approach for locally advanced colon cancer.

Methods

Inclusion Criteria: Patients diagnosed with locally advanced colon cancer (T3-4 or N+, M0). The neoadjuvant chemoimmunotherapy group (NACI) receives mFOLFOX 6 (bi-weekly) and the anti-PD-1 monoclonal antibody Toripalimab (3mg/kg, bi-weekly), while the neoadjuvant chemotherapy group (NAC) is administered only mFOLFOX 6 for a total of 12 cycles, comprising 6 cycles pre-surgery and 6 cycles post-surgery. The primary endpoint is the pathological complete response (pCR) rate. Simultaneously, the study explored the remodeling effects of chemotherapy on the tumor microenvironment.

Results

From 2019 to 2023, 30 patients were enrolled in the study. In the NACI group, more than 30% (5/16) of patients achieved pCR, while in the NAC group, only one patient (1/14) achieved pCR. Among the pCR patients, one was classified as MSI-H/dMMR, two as MSS/pMMR, and three were classified with an unknown status. Tumor regression grade (TRG) levels showed that all patients in the NACI group scored below grade 2, significantly outperforming the NAC group (P < 0.05). Adverse reactions showed no significant differences. Chemotherapy activates the STING pathway and upregulates the levels of immunogenic cell death (ICD) and type I interferon responses. This process further promotes dendritic cell (DC) activation, thus recruiting and augmenting the infiltration of CD8+ T cells.

Conclusions

Chemotherapy activates the adaptive immune response through the STING-related pathway, thereby reshaping the immune microenvironment of colon cancer. This process synergistically enhances immunotherapy and is associated with tolerable adverse reactions. Therefore, combining immunotherapy with chemotherapy may represent a new treatment option for locally advanced colon cancer, particularly for patients with the MSS/pMMR molecular type.

Clinical trial identification

NCT03985891.

Editorial acknowledgement

Legal entity responsible for the study

S. Zeng.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.