The aim of this study is to evaluate the effect of a probiotic supplement containing Bifidobacterium animalis lactis BL-04 on the clinical effectiveness of immunotherapy in patients diagnosed with metastatic non-small cell lung cancer who are receiving immunotherapy.

Despite modern treatments, lung cancer remains a leading cause of high mortality worldwide. Over the past decade, significant improvements in patient survival have been achieved with immune checkpoint inhibitors, which enhance the T cell-mediated immune response to eradicate cancer cells. However, therapeutic resistance, drug side effects, and heterogeneous treatment responses limit their effectiveness. Recent studies have established a clear relationship between gut microbiota and cancer immunotherapy. The intestinal microbiota has been shown to stimulate the anti-tumor immune response by modulating immune system cells. Evidence from preclinical and clinical studies indicates that gut microbiota plays a crucial role in the efficacy of immunotherapy and the modulation of drug toxicity. Identifying the microbiota as a potential biomarker could facilitate personalized treatment protocols. Genetic, epigenetic, and microbiota modulation factors are essential for optimizing cancer immunotherapy outcomes. Consequently, research is increasingly focusing on personalized treatment protocols for microbiota modulation, including diet regulation, fecal microbiota transfer, prebiotics, and probiotics. There has been a significant rise in studies demonstrating the clinical benefits of microbial therapy products as complementary treatments.

The functional role of microbiota in modulating the systemic immune response has prompted investigations into its impact on cancer immunotherapy, particularly with agents targeting immunological checkpoints like PD-1. Recent studies have identified both positive and negative regulatory bacteria that influence immunotherapy effectiveness. However, sociocultural and dietary lifestyle differences affect gut microbiota composition, leading to variations between populations. Therefore, studies are needed to identify the unique microbiome composition of each population to develop microbiota biological indicators for cancer immunotherapy. No research has been conducted in this area in Türkiye. This study aims to identify bacterial species that may serve as biomarkers for the microbiota specific to Turkish cancer patients receiving immunotherapy and use them for prognostic purposes.

Understanding the significant role of probiotics in modulating intestinal microbiota has increased the demand for these food supplements. Studies show that anti-tumor efficacy is specific to the bacterial strain. For instance, Bifidobacteriums have been reported to enhance the effectiveness of PD-1 blockers in experimental rat models. In another study, B. lactis BL-04 reduced immunotherapy-induced colitis in animals.

This study will investigate the effect of a probiotic supplement containing Bifidobacterium animalis lactis BL-04 on clinical objective response, clinical benefit rates, and intestinal microbiota in patients with metastatic non-small cell lung cancer (mNSCLC) receiving nivolumab. The results may facilitate the development of specific probiotic supplements as a complementary therapy for mNSCLC treatment.

Inclusion Criteria:

• Volunteering to participate in the study.
• Histologically confirmed diagnosis of Non-Small Cell Lung Cancer (NSCLC).
• Patients must be in an advanced stage (incurable with surgery or radiotherapy) or have metastatic disease (Stage IV).
• Male or female patients aged >18 years.
• Eastern Cooperative Oncology Group (ECOG) Performance Status less than 2.
• Laboratory findings must confirm adequate bone marrow function, indicated by:

White Blood Cell (WBC) count > 2,000/mm³, Neutrophil count > 1,500/mm³,Platelet count > 100,000/mm³

Exclusion Criteria:

• Previously received treatment with any of the following antibody blockers: anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4.
• Currently taking probiotic supplements or consuming probiotic bacteria-supported yogurt and similar food supplements.
• Antibiotic utilization within the past month
• Active interstitial lung disease or a history of interstitial lung disease requiring systemic steroid treatment.
• A condition requiring systemic corticosteroids (greater than 10 mg of prednisone daily or equivalent) or who have received immunosuppressive treatment within 14 days prior to the first dose of the study.
• Presence of uncontrolled adrenal insufficiency.
• Pregnancy or breastfeeding.
• Severe congestive heart failure (Class III or higher according to the New York Heart Association Functional Classification) or a history of myocarditis.
• Uncontrolled cardiac arrhythmia that developed within six months prior to the start of the study.