In the past decade, ICI immunotherapy has significantly advanced traditional cancer treatment and has led to breakthroughs in the management of metastatic malignancies[14]−[17]. This is particularly true for lung cancer, including both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), where immunotherapy has shown substantial benefits. As the use of immune checkpoint inhibitors (ICIs) in cancer treatment has become more widespread, researchers have been working tirelessly to identify factors that may influence their effectiveness [18]. One such factor that has gained increasing recognition is the human gut microbiota. Mounting evidence supports the role of the gut microbiota in the ICI response in preclinical and clinical studies[19]− [24]. Probiotics, which are live microorganisms that provide health benefits when administered in sufficient quantities, have emerged as a potential adjunct therapy to enhance the efficacy of ICIs and mitigate treatment-related adverse effects [8]. Given the potential role of oral probiotic supplements in enhancing immune responses and improving the outcomes of ICI treatments by modulating the composition of the gut microbiota, it is worthwhile to explore this topic further.
To the best of our knowledge, this is the first study to report on the impact of oral probiotic supplements on the efficacy of immune checkpoint inhibitors (ICIs) in the treatment of small cell lung cancer (SCLC). Currently, the combination of ICIs (such as pembrolizumab, durvalumab, or atezolizumab) with platinum-based chemotherapy has been shown to improve overall survival in extensive-stage SCLC and is recommended as the preferred first-line therapy (Rudin et al., 2020; Paz-Ares et al., 2019; Horn et al., 2018) [25]−[27]. Our results demonstrate that the addition of oral probiotic supplements to ICIs significantly prolongs progression-free survival in patients with advanced small cell lung cancer, and may also improve the response rate. These findings suggest a synergistic effect between oral probiotic supplements and ICIs, enhancing the immune response against cancer cells clinically. The mechanisms underlying the beneficial effects of oral probiotic supplements in combination with ICIs remain to be elucidated. It is possible that probiotic supplements enhance the composition of the gut microbiota, leading to a more favorable immune microenvironment and increased efficacy of ICIs. Previous studies have shown that the gut microbiome can interact with innate and adaptive immune cells, enhancing the anti-tumor effects of innate immune cells, promoting the anti-tumor effects of adaptive immune cells, and increasing the immunogenicity of tumor cells, which in turn modify the tumor microenvironment and improve ICI responses (Lu et al., 2022) [28]. Further research is needed to explore the specific mechanisms involved.
Previous prospective clinical studies have demonstrated that the combination of immune checkpoint inhibitors (ICI) and platinum-based chemotherapy has resulted in a median progression-free survival (mPFS) of up to 5.4 months (95% CI 4·8–6·2) for small cell lung cancer (SCLC) [26]. In our study, SCLC in Group C showed an mPFS of approximately 7.0 months(95% CI: 5.0–9.0), which is slightly higher than the previously reported data. The reason for this difference may be attributed to the fact that our study did not solely focus on the combination of chemotherapy and immunotherapy. Instead, it also included patients who received chemoradiotherapy in conjunction with immunotherapy, as well as chemoradiotherapy combined with immunotherapy and anti-vascular endothelial growth factor medications. In our study, the ORR in group C was similar to the previous study [25], while the ORR and mPFS of the OPS group were significantly prolonged. These findings suggest that probiotic combination therapy may be more suitable for SCLC.
Previous retrospective studies have suggested that probiotics could enhance the efficacy of ICIs in patients with non-small cell lung cancer. Tomita et al. conducted a retrospective evaluation of 118 patients with advanced NSCLC who underwent ICI treatment and found that probiotic CBT (clostridium butyricum therapy) significantly prolonged progression-free survival (PFS) (median, 250 vs. 111 days; HR, 0.37; p = 0.001, 95% CI: 0.21–0.65) and overall survival (OS) (median, not reported vs. 361 days; HR, 0.2; p < 0.001; 95% CI: 0.07–0.44) compared to those not receiving probiotic CBT[29]. A meta-analysis was conducted to assess the association between probiotic use and PFS using data from five studies. The results indicated that NSCLC patients treated with ICIs in combination with probiotics achieved significantly longer PFS (HR: 0.532, 95% CI: 0.354–0.798, p = 0.002) and OS (HR: 0.528, 95% CI: 0.306–0.912, p = 0.022)[29]−[32]. In the current study, we observed a trend towards a higher median PFS in patients with NSCLC who received oral probiotic supplements (16.5 months vs. 12.3 months). However, this difference was not statistically significant. Several factors may have contributed to these findings. Firstly, the variety of commercially available probiotic supplements and their varying compositions make it difficult to observe specific effects of individual microbial strains. Secondly, the sample size in this real-world study might have been inadequate to detect subtle differences in treatment outcomes. Thirdly, there may have been inherent differences in the concurrent treatments received by the probiotic and control groups, which could have influenced the outcomes. Additionally, in order to maintain the study sample size as much as possible, we did not perform propensity score matching (PSM), which may introduce confounding bias. Interestingly, another study by Takada et al. found no significant differences in PFS and overall survival (OS) between patients who did and did not receive probiotics before applying inverse probability of treatment weighting (IPTW). However, after IPTW, they observed a significant difference in PFS between the groups in a multicenter and retrospective study (Takada et al., 2021) [32]. In order to obtain more robust evidence, future prospective randomized controlled trials should be conducted. These studies should aim to address the limitations identified in this real-world study, including the use of specific probiotic strains, larger sample sizes, and standardized treatment protocols. Conducting such studies will provide more powerful evidence regarding the efficacy of oral probiotics in the context of immune checkpoint inhibitors (ICIs) for the treatment of advanced lung cancer.
In addition, limitations should be considered. Firstly, the study was designed as a real-world observational research, which could not strictly limit the intervening measure, confounding factors might interfere the analysis. Secondly, the sample size was not as large as expected when the study was designed. The insufficient case may make the significance to be a trend. Besides, the study relied on self-reporting of probiotics supplement usage, which may introduce recall bias and inaccuracies in the reporting. Additionally, the specific strains and dosages of the probiotic supplements were not assessed because of the complex kinds and different components. A further prospective randomized control study is warranted.