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. 2023 Dec 21;16(1):47.
doi: 10.3390/cancers16010047.

Association of Clostridium butyricum Therapy Using the Live Bacterial Product CBM588 with the Survival of Patients with Lung Cancer Receiving Chemoimmunotherapy Combinations

Yusuke Tomita  1 , Shinya Sakata  1 , Kosuke Imamura  1 , Shinji Iyama  1 , Takayuki Jodai  1 , Koichi Saruwatari  1 , Shohei Hamada  1 , Kimitaka Akaike  1 , Moriyasu Anai  1 , Kazuaki Fukusima  1 , Akira Takaki  1 , Hirotake Tsukamoto  2 , Yoshihiko Goto  1   3 , Chihiro Motozono  3 , Kenji Sugata  4 , Yorifumi Satou  4 , Takamasa Ueno  3 , Tokunori Ikeda  5 , Takuro Sakagami  1
Affiliations

Association of Clostridium butyricum Therapy Using the Live Bacterial Product CBM588 with the Survival of Patients with Lung Cancer Receiving Chemoimmunotherapy Combinations

Yusuke Tomita et al. Cancers (Basel). .

Abstract

The gut microbiota has emerged as a key regulator of immune checkpoint inhibitor (ICI) efficacy. Therapeutic approaches aimed at manipulating the microbiota through targeted reconstitution to enhance cancer treatment outcomes have garnered considerable attention. A single live microbial biotherapeutic bacterium, Clostridium butyricum MIYAIRI 588 strain (CBM588), has been shown to enhance the effects of ICI monotherapy in patients with advanced lung cancer. However, whether CBM588 affects the outcomes of chemoimmunotherapy combinations in lung cancer remains unknown. We hypothesized that CBM588 augments the effect of chemoimmunotherapy combinations and restores diminished effectiveness in patients with non-small cell lung cancer (NSCLC) receiving dysbiosis-inducing drugs. To validate this hypothesis, we retrospectively analyzed 106 patients with stage IV or recurrent metastatic NSCLC consecutively treated with chemoimmunotherapy combinations. A survival analysis was performed employing univariate and multivariate Cox proportional hazard models with inverse probability of treatment weighting (IPTW) using propensity scores. Forty-five percent of patients received Clostridium butyricum therapy. CBM588 significantly extended overall survival in patients with NSCLC receiving chemoimmunotherapy. The favorable impact of CBM588 on the efficacy of chemoimmunotherapy combinations varied based on tumor-programmed cell death ligand 1 (PD-L1) expression. The survival benefit of CBM588 in the PD-L1 <1% cohort was higher than that in the PD-L1 1-49% and PD-L1 ≥ 50% cohorts. Furthermore, CBM588 was associated with improved overall survival in patients receiving proton pump inhibitors and/or antibiotics. CBM588-induced manipulation of the commensal microbiota holds the potential to enhance the efficacy of chemoimmunotherapy combinations, warranting further exploration of the synergy between CBM588 and immunotherapy.

Keywords: CBM588; Clostridium butyricum; antibiotics; dysbiosis; gut microbiome; immune checkpoint inhibitor; lung cancer; proton pump inhibitors.

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Conflict of interest statement

Takuro Sakagami received research funding from Miyarisan Pharmaceutical Co., Ltd. The funder, Miyarisan Pharmaceutical Co., Ltd., was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication. All authors declare no other competing interest.

Figures

Figure 1
Figure 1
Association between Clostridium butyricum therapy using CBM588 and overall survival (OS) in patients with advanced non-small cell lung cancer treated with chemoimmunotherapy combinations. The figure illustrates the overall survival of patients, stratified by CBM588 administration.
Figure 2
Figure 2
Subgroup analysis of overall survival among all patients. The dashed vertical line represents the hazard ratio. Factors considered include Eastern Cooperative Oncology Group performance status (ECOG PS), tumor proportion score (TPS), and proton pump inhibitors (PPIs).
Figure 3
Figure 3
Kaplan–Meier estimates of a survival outcome in patients with advanced non-small cell lung cancer treated with chemoimmunotherapy combinations. The figure displays overall survival stratified by CBM588 administration. Kaplan–Meier curves depicting the impact of CBM588 based on tumor-programmed cell death ligand 1 (PD-L1) expression.
Figure 4
Figure 4
Kaplan–Meier estimates of a survival outcome in patients with non-small cell lung cancer (NSCLC) receiving proton pump inhibitors (PPIs) and those who did not receive PPIs within the 60-day window. (A) PPI user: overall survival (OS) in patients with NSCLC who received PPIs, stratified by CBM588 administration. (B) PPI non-user: OS of patients with NSCLC who did not receive PPIs, stratified by CBM588 administration.
Figure 5
Figure 5
Kaplan–Meier estimates of survival outcome in patients with non-small cell lung cancer (NSCLC) who received antibiotics and those who did not receive antibiotics within the 60-day window. (A) Antibiotic exposure: overall survival (OS) in patients with NSCLC who received antibiotics, categorized by CBM588 administration. (B) No antibiotic exposure: OS of patients with NSCLC who did not receive antibiotics, stratified by CBM588 administration.
Figure 5
Figure 5
Kaplan–Meier estimates of survival outcome in patients with non-small cell lung cancer (NSCLC) who received antibiotics and those who did not receive antibiotics within the 60-day window. (A) Antibiotic exposure: overall survival (OS) in patients with NSCLC who received antibiotics, categorized by CBM588 administration. (B) No antibiotic exposure: OS of patients with NSCLC who did not receive antibiotics, stratified by CBM588 administration.
Figure 6
Figure 6
Kaplan–Meier estimate of overall survival (OS) in patients with non-small cell lung cancer (NSCLC) who received both PPIs and antibiotics within the 60-day window. The figure depicts the OS of patients with NSCLC treated with chemoimmunotherapy combinations, categorized by CBM588 administration.
Figure 7
Figure 7
Overall schema of this study.
See this image and copyright information in PMC

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