Proofs of concepts of the impact of the gut microbiome in cancer immunotherapy are based on four lines of evidence. These include:
- Antibiotics: beta-lactams, fluoroquinolones, tetracyclines, and macrolides
- Gut OncoMicrobiome Signatures: Mg-based fingerprints
- Avatar mice: human feces into murine intestines
- Pilot studies: fecal microbiota transplantation from responding to nonresponding patients
Previous studies have shown that the antitumor efficacy of anticancer immunotherapy requires gut bacteria. In mice and patients, T cell responses specific for B. thetaiotaomicron or B. fragilis are associated with the efficacy of CTLA-4 blockade. Additionally, primary resistance to immune checkpoint inhibitors can be attributed to abnormal gut microbiome composition. In a study led by Dr. DeRosa,2 they examined patients with advanced RCC and non-small-cell lung cancer treated with anti-PD-L1 mAb monotherapy or combination. Those receiving antibiotics within 30 days of beginning immune checkpoint inhibitors were compared with those who did not. Sixteen of 121 (13%) RCC patients received antibiotics, the most common were β-lactam or quinolones for pneumonia or urinary tract infections. In RCC patients, antibiotics compared with no antibiotics was associated with increased risk of primary progressive disease (75% versus 22%, P < 0.01), shorter progression-free survival (median 1.9 versus 7.4 months, HR 3.1, 95% CI 1.4-6.9, p < 0.01), and shorter overall survival (median 17.3 versus 30.6 months, HR 3.5, 95% CI 1.1-10.8, p = 0.03).
Dr. DeRosa also recently published in European Urology,3 evaluating the predictive value of stool bacteria composition for immune checkpoint blockade efficacy among 69 advanced RCC patients. Recent antibiotic use (n = 11; 16%) reduced objective response rates from 28% to 9% (p < 0.03) and markedly affected the composition of the microbiota, facilitating the dominance of distinct species such as Clostridium hathewayi, which were also preferentially over-represented in stools from RCC patients compared with healthy volunteers.
In mice, there is also proof of concept of the efficacy of the microbiota-centered therapeutic interventions. In their European Urology paper, DeRosa et al.3 found that non-responding-fecal microbiota transplantation mice were successfully compensated with either fecal microbiota transplantation from responding RCC patients or beneficial commensals identified by whole-genome sequencing of the gut microbiome (Akkermansia muciniphila and Bacteroides salyersiae).
Pilot studies have shown that in humans, there is proof of concept of the efficacy of the microbiota-centered therapeutic intervention based on fecal transplant from responding to non-responding melanoma patients. A phase 1 clinical trial assessed the safety and feasibility of fecal microbiota transplantation and reinduction of anti-PD-1 immunotherapy in 10 patients with anti-PD-1-refractory metastatic melanoma. There were clinical responses in three patients, including two partial responses and one complete response, along with a favorable change in the immune cell infiltrate.
There are ways to modulate the gut microbiome, with the possibility of microbiota-centered therapeutic intervention:
For example, based on mouse models, a ketogenic diet (very low carbohydrate, high fat diet) can induce an immunogenic fecal composition and mediate tumor growth retardation.
To conclude, Dr. DeRosa suggested the following next steps regarding gut microbiome modulation as a novel therapeutic strategy:
Presented by: Lisa DeRosa, Department of Immunotherapy, Gustave Roussy Cancer Center, Villejuif, France
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md, during the 2021 European International Kidney Cancer Symposium (EIKCS), April 23-24, 2021
- Sepiche-Poore GD, Zitovgel L, Straussman R, et al. The microbiome and human cancer. Science. 2021 Mar 26;371(6536):eabc4552.
- DeRosa L, Hellmann MD, Spaziano M, et al. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer. Ann Oncol. 2018 Jun 1;29(6):1437-1444.
- DeRosa L, Routy B, Fidelle M, et al. Gut Bacteria Composition Drives Primary Resistance to Cancer Immunotherapy in Renal Cell Carcinoma Patients. Eur Urol. 2020 Aug;78(2):195-206.