With Georges Mjaess, MD, at University Clinics of Brussels, Erasme Hospital
By Sarah DiGiulio
In a recent commentary article in the journal Cancer, researchers noted that there is some very preliminary evidence that the bacteria in the gut may affect immune checkpoint inhibitor therapy efficacy in people with melanoma—and furthermore, that fecal microbiota transplant may help improve response to the drugs in people who would otherwise not do well (2022; https://doi.org/10.1002/cncr.33893). The group investigates how it may be time to explore the potential for a similar approach in urological cancers. Georges Mjaess, MD, the paper's lead author and a researcher in the Department of Urology at University Clinics of Brussels, Erasme Hospital in Belgium, shared more on this research with Oncology Times.
1. What promise does fecal transplant hold for urological cancers?
“Immune checkpoint inhibitors are often considered as the last strong weapon in treating cancer until now, and [they] have a better safety profile compared to other systemic treatments, providing a good quality-of-life to our patients. In urological tumors, they are recently proposed in the adjuvant, as well as in the neoadjuvant settings, in urothelial carcinoma and are the backbone of first-line treatment of metastatic renal cell carcinoma. However, in many situations, we find unfortunately that some patients are resistant to immune checkpoint inhibitors, and until now we do not know exactly why.
“An important goal to reach is to try to understand why some patients are non-responders, and to overcome this resistance in a way that helps patients benefit from this type of treatment that has a good safety profile, provides a good quality-of-life, and prolongs survival.
“In the last decade, there is a boom in discoveries and research about the human microbiota, and it has been demonstrated that it plays an important role in immunological, metabolic, and structural landscapes of the human body. Cancer is not an exception, and it has been proven to be in one way or another related to certain patterns of microbiota. More precisely, as the tumor development is dependent on the immune system, and given that immunity is modulated by the gut microbiota, any disruption in this microbiota could result in tumor progression. In the same way, the gut microbiota has been proven to be a potential modulator of response to immune checkpoint inhibitors.
“Regarding urological tumors, the human microbiome was shown to be linked to bladder cancer, prostate cancer, and renal cell carcinoma, both in the progression and treatment response of these malignancies. Moreover, antibiotics, which are a key modulator of the gut microbiome, were linked to worse oncological outcomes in urological tumors.
“Fecal microbiota transplantation is also an important modulator of human microbiome, commonly used in the treatment of refractory C. difficile infection, inflammatory bowel diseases, metabolic disorders, and liver cirrhosis. As the fecal transplant concept is to 'refresh' the status of the gut microbiota, it was interesting in the last years [to test] fecal transplant from responders to non-responders to immune checkpoint inhibitors to see if this can reverse the non-response to the drugs, and this was confirmed in two studies on melanoma. Since immune checkpoint inhibitors are a vital treatment in urological tumors, fecal transplant could be also applied in the field of genitourinary cancers."
2. What research most aptly demonstrates the potential of this approach?
“The most important studies that were recently published are two proof-of-concept studies published on melanoma by Davar, et al (Science 2021; doi: 10.1126/science.abf3363) and Baruch, et al (Science 2021; doi: 10.1126/science.abb5920). In the study by Davar, et al, fecal microbiota transplant was demonstrated to overcome resistance to anti-PD1 immunotherapy, offering a clinical benefit in six out of the 15 included patients (40%) with a median overall survival and progression-free survival of 14 months. In the Baruch, et al, study, three patients out of 10 (30%) have shown clinical responses, including one complete and two partial responses. Fecal microbiota transplant was demonstrated, therefore, to indeed 'reset the dial' in patients whose melanoma is not responding to immune checkpoint inhibitors.
“Until now, there is no published clinical trials on urological tumors and publications are restraint to melanoma patients. However, there are numerous trials ongoing in urological tumors, such as the TACITO trial, a randomized controlled trial assessing fecal microbiota transplant in advanced renal cell carcinoma patients, and the PERFORM trial whose aim is to evaluate the safety of a combination of immune checkpoint inhibitors and fecal microbiota transplant in intermediate/poor risk advanced renal cell carcinoma. On the other hand, fecal microbiota transplant still holds limitations that need to be considered, such as the gut microbiota's large heterogeneity among donors and/or receivers, high cost, and low evidence of the studies published until now. For these reasons, fecal transplant cannot be considered until now in the treatment of immunotherapy-resistant urological tumors."
3. What should cancer care providers know about your work?
“Microbiota modulating strategies, such as fecal transplant for gut microbiota, and the encouraging results recently published with anti-PD1 immunotherapy in melanoma, promote more trials and investigations aiming to test these strategies in urological tumors.
“A clear message from our work is that we cannot nowadays deny the prominent role of the human microbiota in cancer. Polymorphic microbiomes—including gut, skin, vaginal, lung, and oral microbiomes, but also tumoral, and recently urinary microbiota—constitute distinct promoting characteristics that enable the acquisition of hallmark capabilities and modulation of tumor phenotypes.
“We have seen the emergence of targeted therapy whose aim is to target many hallmarks of cancer development. We think that we should now focus more on targeting the human microbiota in cancer treatment, since it is now well-known to be an essential hallmark of cancer, and fecal transplant is a promising modulating strategy that could be one of the new standards in the next decade."