Safety and Feasibility of Akkermansia Probiotics Combined with Anti-PD-1 Monoclonal Antibody in MSS/pMMR Advanced Colorectal Cancer The investigators propose to conduct a single-center, single-arm, Phase I clinical study to explore the safety and efficacy of Akkermansia probiotics combined with anti-PD-1 monoclonal antibody in patients with MSS/pMMR advanced colorectal cancer, as well as its impact on gut microbiota and the immune microenvironment.
Inclusion Criteria:
- Age 18-75 years
- ECOG performance status score of 0-2
- Histopathologically confirmed colorectal cancer; tumor tissue immunohistochemistry or genetic testing showing pMMR or MSS/MSI-L type
- Metastatic colorectal adenocarcinoma that has failed standard treatments (including irinotecan, oxaliplatin, fluorouracil, bevacizumab, cetuximab, etc.)
- No prior use of immunotherapy (such as immune checkpoint inhibitors, adoptive cell immunotherapy, etc.)
- At least one evaluable lesion according to RECIST version 1.1 criteria
- No intestinal obstruction and good oral compliance
- Adequate bone marrow, liver, and kidney function to receive treatment
- Signed informed consent
Exclusion Criteria:
- History of allergic diseases, severe drug allergies, or known allergies to probiotic drugs
- Use of antibiotics or probiotic drugs/health products within the last 3 months
- History of other malignancies with a disease-free interval of less than 5 years (except for cured basal cell carcinoma of the skin, cured cervical carcinoma in situ, and gastrointestinal tumors cured by endoscopic mucosal resection)
- Presence of any active autoimmune disease or history of autoimmune disease
- Current use of immunosuppressants or hormone therapy, continued within 2 weeks prior to enrollment
- Concurrent severe infections
- Congenital or acquired immune deficiency, or active hepatitis
- Concurrent severe complications
Intervention Strategy:
According to the inclusion and exclusion criteria, 22 patients will be recruited. After enrollment, patients will receive anti-PD-1 monoclonal antibody + Tyrosine kinase inhibitor (TKI, e.g., regorafenib, fruquintinib) treatment or anti-PD-1 monoclonal antibody ± chemotherapy (etc., CAPEOX [oxaliplatin+capecitabine ], XELIRI [irinotecan+capecitabine ]) ± Bevacizumab treatment (anti-PD-1 monoclonal antibody, chemotherapy, and bevacizumab every 3 weeks, TKI every 4 weeks), along with daily continuous administration of Akkermansia probiotics (Songke, dose: 1 capsule/day, taken with breakfast), until disease progression, intolerable toxicity, or patient withdrawal from the study.
Primary Observation Indicators:
Gastrointestinal adverse reactions, including nausea, vomiting, diarrhea, abdominal pain, etc., and quality of life assessment.
Secondary Indicators:
- Objective Response Rate (ORR): The proportion of patients with a measurable reduction in tumor burden (defined by standardized criteria such as RECIST 1.1) who achieve either a complete response (CR) or a partial response (PR) during the course of treatment.
- Progression-Free Survival (PFS) ：The length of time during and after treatment that a patient lives with the disease without it getting worse. It is typically measured from the start of treatment (or randomization in a clinical trial) until the date of disease progression or death from any cause, whichever occurs first.
- Overall Survival (OS): The duration from the start of treatment (or randomization in a clinical trial) until death from any cause.
Exploratory Indicators:
Changes in the immune microenvironment such as proportions of common immune cells in peripheral blood (CD3+, CD4+, CD8+ T cells, macrophages, dendritic cells, MDSC, etc.), fetal Akkermansia abundance, gut microbiota, and metabolomics.
- Evaluation of the Safety and Efficacy of Combined Treatment (Incomplete) Quality of life of enrolled patients will be assessed using the EORTC QLQ-C30 scale. Baseline and every 3 weeks, hematological tests (blood routine, liver and kidney function, electrolytes, myocardial markers, thyroid function, etc.) will be conducted to assess bone marrow, liver, and kidney function for adverse reactions. Baseline and every 2 months, imaging (chest and abdominal enhanced CT) will be performed to evaluate tumor efficacy. Patients will be followed up every 2 weeks after enrollment, with follow-up content including treatment tolerance, adverse reactions, survival status, etc.
- Exploration of the Impact of Akkermansia on Gut Microbiota and the Immune Microenvironment in Colorectal Cancer Patients Treated with Anti-PD-1 Monoclonal Antibody (Incomplete) Baseline and every 3 weeks after enrollment, stool and peripheral blood samples will be collected to detect changes in fecal Akkermansia abundance and gut microbiota, as well as changes in the immune microenvironment such as proportions of common immune cells in peripheral blood (CD3+, CD4+, CD8+ T cells, macrophages, dendritic cells, MDSC, etc.).