December 8, 2023

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Phase 1 results of First probiotic combined immunotherapy were announced

Phase 1 results of First probiotic combined immunotherapy were announced


Phase 1 results of First probiotic combined immunotherapy were announced.

“Nature Medicine”: Probiotics + immunotherapy, the first victory against cancer! 


Not long ago, Singularity Cake shared with you the results of a Phase 3 clinical trial of a fecal bacteria transplant oral pill , which may become the first approved stool capsule in history this year [1]. At that time, someone asked, the same is to adjust the structure of intestinal bacteria, why not use probiotics?


Don’t worry, probiotics are here, and it’s still a practical exercise in tumor immunotherapy!


A few days ago, an article published in the journal Nature Medicine published the results of a Phase 1 clinical trial, demonstrating for the first time that oral probiotics can improve gut microbiota homeostasis and enhance immunotherapy response in cancer patients [2].


The Phase 1 clinical trials (NCT03829111) were completed by Sumanta K. Pal and colleagues from City of Hope National Medical Center. The results show that when patients with metastatic renal cell carcinoma (mRCC) are treated with nivolumab + ipilimumab, if combined with the probiotic oral drug CBM588, the median progression-free survival can be greatly improved. Period (PFS), the median PFS increased from 2.5 months to 12.7 months, an increase of nearly 400%!


Phase 1 results of First probiotic combined immunotherapy were announced

Screenshot of the paper’s homepage


Since it has been confirmed that enterobacteria do play a decisive role in immunotherapy, the study of the characteristics of enterobacteria in specific populations, which “predominant bacteria” can enhance the efficacy, and how to improve the efficacy by regulating the homeostasis of enterobacteria has become the focus of the field of tumor immunotherapy. hot topic.


At present, studies have shown that the abundance of Akkermansia spp. (Akk bacteria for short) is significantly correlated with the improvement of objective response rate and the prolongation of median PFS in mRCC patients receiving immunotherapy [3]. In vivo experiments in mice have also demonstrated that intestinal transplantation of Akk bacteria can delay tumor growth in mice [4,5].


In this case, we must not properly cultivate the bifidobacteria in the patient’s intestines?


The probiotic drug CBM588 has been proven to inhibit the growth of “bad bacteria” in the intestine, promote the regeneration and repair of intestinal epithelial tissue cells, and restore the homeostasis of “good bacteria” such as Akk bacteria in the intestine due to the presence of Clostridium butyricum. . On this basis, CBM588 seems very suitable to be used to help the immunotherapy of mRCC patients [6].


The purpose of this phase 1 clinical trial is to initially explore the efficacy of the combination of CBM588 + nivolumab (O drug) + ipilimumab (Y drug) in the treatment of mRCC patients . The combination of nivolumab and ipilimumab is currently the first-line immunotherapy regimen for patients with mRCC [7,8].


So let’s take a look at the test data together!


A total of 30 mRCC patients who have not received any treatment were recruited and randomly divided into CBM588 + O drug + Y drug group and O drug + Y drug group according to 2:1 for treatment . The median age of the participants was 66 years (45-90 years), and the majority were male (72%).


The results showed that the median PFS of patients in the O drug + Y drug group was 2.5 months, and 20% achieved partial remission . In contrast, the median PFS of patients in the CBM588 + O drug + Y drug group was significantly improved (P < 0.001), up to 12.7 months, and 58% of the patients achieved partial remission .


After a median follow-up of 12.2 months, the median overall survival was not reached in either group, and no patients achieved complete remission.


Phase 1 results of First probiotic combined immunotherapy were announced

a: PFS; c: Objective response rate


In terms of safety, the O drug + Y drug group and CBM588 + O drug + Y drug group performed similarly , with 50% and 52% of patients having treatment-related grade 3 or 4 adverse events, respectively. Among them, the treatment-related grade 3 or 4 adverse events occurred in the CBM588 + O drug + Y drug group, including fatigue, rash, adrenal insufficiency, pancreatitis, and diarrhea .


From the perspective of intestinal bacterial colonization, the differences in the abundance of Akk bacteria in the intestinal tract of the two groups of patients before and after treatment were not statistically significant .

Only in the CBM588 + O drug + Y drug group, the colonization level of Akk bacteria and “good bacteria” such as Butyricimonas faecalis in the intestines of patients who responded to the treatment was significantly increased, and the “bad bacteria” such as Desulfovibrio ‘ was significantly reduced.


Phase 1 results of First probiotic combined immunotherapy were announced

Responders in the CBM588 + O drug + Y drug treatment group had significantly fewer “bad bacteria” and more “good bacteria” in the gut


Overall, the results of this Phase 1 clinical trial are quite encouraging, initially demonstrating the efficacy of the probiotic drug CBM588 in mRCC immunotherapy, greatly improving mRCC patients treated with nivolumab + ipilimumab The median PFS showed new possibilities for the clinical treatment of mRCC.


In addition, this is the first randomized clinical trial to demonstrate that the use of probiotic drugs can modulate intestinal bacterial homeostasis and enhance immunotherapy response in cancer patients .


It is worth mentioning that another phase 1 clinical trial of CBM588 has also been launched, which will explore the efficacy of CBM588 + nivolumab + cabozantinib in the treatment of patients with advanced or metastatic renal cancer.


Finally, Singularity Cake still has to be reminded that probiotics cannot be eaten by themselves ! Not to mention that probiotics may just go through the motions after entering the stomach, and they are expelled before they are colonized [9]; there are also studies showing that too many “good bacteria” will not work, and probiotics will lead to impaired immunotherapy. [10], the high abundance of Akk bacteria in the gut of patients with non-small cell lung cancer may also be associated with poor prognosis [11].








[1]Feuerstadt P,et al. SER-109, an Oral Microbiome Therapy for Recurrent Clostridioides difficile Infection. N Engl J Med. 2022 Jan 20;386(3):220-229. doi: 10.1056/NEJMoa2106516. PMID: 35045228.


[3]Routy, B. et al. Gut microbiome infuences efcacy of PD-1-based immunotherapy against epithelial tumors. Science 359, 91–97 (2018).

[4]Matson, V. et al. Te commensal microbiome is associated with anti-PD-1 efcacy in metastatic melanoma patients. Science 359, 104–108 (2018).

[5]Sivan, A. et al. Commensal Bifdobacterium promotes antitumor immunity and facilitates anti-PD-L1 efcacy. Science 350, 1084–1089 (2015).

[6]Hagihara M, et al. Clostridium butyricum Modulates the Microbiome to Protect Intestinal Barrier Function in Mice with Antibiotic-Induced Dysbiosis. iScience. 2020 Jan 24;23(1):100772. doi: 10.1016/j.isci.2019.100772. Epub 2019 Dec 13. PMID: 31954979; PMCID: PMC6970176.

[7]Motzer, R. J. et al. NCCN guidelines insights: kidney cancer, version 2.2020. J. Natl Compr. Canc. Netw. 17, 1278–1285 (2019).

[8]Escudier, B. et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 30, 706–720 (2019).

[9]Niv Zmora, et al. Personalized Gut Mucosal Colonization Resistance to Empiric Probiotics Is Associated with Unique Host and Microbiome Features. Cell, 2018; 174 (6): 1388 DOI: 10.1016/j.cell.2018.08.041

[10]Spencer CN, McQuade JL, Gopalakrishnan V, et al. Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response. Science. 2021;374(6575):1632-1640. doi:10.1126/science.aaz7015

[11]Derosa, L., B. Routy, A.M. Thomas, et al., Intestinal Akkermansia muciniphila predicts clinical response to PD-1 blockade in patients with advanced non-small-cell lung cancer. Nat Med. 2022.

Phase 1 results of First probiotic combined immunotherapy were announced

(source:internet, reference only)

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