Human kidney cross section on scientific background
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Metastatic kidney cancer patients who took a proprietary live bacterial supplement showed signs that it could improve their outcomes in a Phase I trial of cabozantinib and nivolumab, according to researchers at City of Hope. The microbiome supplement, Clostridium butyricum MIYAIRI 588 (CBM588), produces butyric acid, which is critical for intestinal health and is an established immunomodulator. Patients receiving CBM588 showed an increase in gut microbes linked to improved clinical outcomes with immune checkpoint inhibitors. 

Their study was published in Nature Medicine. The lead author is  Hedyeh Ebrahimi, MD, PhD, City of Hope postdoctoral medical oncology fellow. 

“We at City of Hope are the first to demonstrate a live bacterial product’s ability to improve clinical outcomes for patients with kidney cancer treated with immunotherapy. CBM588 could be exciting in cancer treatment because of its potential to enhance the efficacy of immune checkpoint inhibitor-based treatment, improve patient outcomes and modulate the gut microbiota in beneficial ways,” said Pal, a City of Hope medical oncologist and corresponding author of the new study. 

Gut microorganisms help modulate the immune system. One estimate suggests 44% of U.S. patients with cancer in 2018 were eligible for checkpoint inhibitor drugs. However, only 20% to 40% of patients respond to immunotherapy. Previous studies on lung cancer, melanoma, metastatic kidney cancer, and more, have shown that the composition of the gut microbiome could affect immunotherapy outcomes for patients with cancer. 

In this single-center, phase I trial, 30 people with metastatic kidney cancer were randomized to receive kinase inhibitor cabozantinib and checkpoint inhibitor nivolumab, with or without CBM588 as first-line treatment. Participants’ gut microbiomes were analyzed via stool samples in the beginning for a baseline and then 13 weeks into treatment. 

Patients receiving CBM588 showed an increase in unclassified Ruminococcaceae genera, which has been linked with improved clinical outcomes with immune checkpoint inhibitors. The primary endpoint of the study was not met, but the objective response rate (ORR) was significantly higher in participants treated with CBM588. 

According to Pal, City of Hope researchers are now in discussions with the global SWOG Cancer Research Network to design a phase II/III trial to assess the use of CBM588 and microbiome modulation in people with advanced cancer. Pal is slated to be co-leader of the potential phase II/III SWOG trial.

Current guidelines for metastatic renal cell carcinoma (kidney cancer) recommend that newly diagnosed patients receive either dual checkpoint inhibitor therapy or a combination of immunotherapy and tyrosine kinase inhibitor, but most patients eventually experience disease progression while on treatment. Positive patient outcomes usually do not last, and subsequent treatments are largely palliative rather than curative. So, physician scientists are looking to combine current strategies with new treatments that do not introduce toxic side effects, such as through microbiome modulation.

“While not yet part of standard cancer treatment protocols, microbiome modulation is a promising area of research with the potential to enhance the efficacy of cancer therapies, particularly immunotherapies,” said Ibrahimi.

City of Hope has granted an exclusive worldwide license to Osel for intellectual property on the novel use of CBM588 to enhance the efficacy of checkpoint inhibitors used to treat cancer, including metastatic renal cell carcinoma. Scientists from Osel and Miyarisan Pharmaceutical Co. Ltd, the manufacturer of CBM588, collaborated on the study.

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