Fecal microbiota transplant boosts cancer immunotherapy in patients

Abstract

A S S O C IA TI O N F O R T H E A D VA N C E M E N T O F S C IE N C E In humans, the gut hosts trillions of bacteria, which are collectively called the gut microbiota. They are incredibly rich and diverse in terms of bacterial species and can exert a signifi cant impact on the overall well-being of the hosts. Their infl uence over the immune system extends far beyond where they reside and often includes responses at distal organs and tissue sites. Reports suggest that changes in the gut microbiota (dysbiosis) are closely associated with the severity of diseases mostly involving organs other than the gut. However, whether and how the gut microbiota can be modulated for therapeutic purposes in the clinic remains an open question, and answers to this question are important in multiple clinical settings, including organ transplantation. Baruch et al. addressed this issue in a phase I clinical trial involving a cohort of metastatic melanoma patients who were refractory to immunotherapy for anti-programmed cell death protein 1 (PD-1). The trial was designed based on the assumption that the gut microbiota are a key determinant of tumor responses to anti–PD-1 therapy in that the gut microbiota from patients who have eliminated the melanoma will restore the anti-tumor responses in those who are refractory. Two donors were selected. Both responded to the anti-PD-1 therapy and completely cleared the metastatic melanoma after treatment. The composition of their gut microbiota was comparable, as assessed by 16S rRNA and metagenomic sequencing of their stool samples. Ten patients were enrolled in this trial, and all showed obvious tumor progression despite anti–PD-1 immunotherapy. Stool samples from each donor were randomly assigned to 5 patients. Patient interventions included “native microbiota depletion,” which involved antibiotic treatment, followed by fecal transplants, with the fi rst dose being introduced via colonoscopy and oral capsules. All patients then received the anti–PD-1 therapy plus fecal oral capsules, and this was repeated for 6 cycles with a 14-day interval in between. Of note, the median time between the initial anti–PD-1 therapy and the re-introduction of anti–PD-1 therapy was 133 days (to avoid residual anti–PD-1 effects from the initial treatments). Patient assessments included objective clinical responses, properties of host gut microbiota, gut biopsies and features of tumor-infi ltrating cells. The authors found that among the 10 patients enrolled, 3 had objective clinical responses and 1 of the 3 showed complete recovery from the metastatic melanoma. Interestingly, those who experienced clinical responses all received fecal microbiota transplants from the same donor (donor #1), whereas the gut microbiota from donor #2 failed to produce any clinical effects after fecal transplants. The stool 16S rRNA sequencing analysis demonstrated that the gut microbiota composition differed signifi cantly for all patients pre and post fecal transplant, with the posttransplant composition more resembling that of the donors, whereas the pretransplant gut microbiota composition of all patients did not show marked differences. One striking feature about the posttransplant composition was a higher relevant abundance of bacterial species favoring immune responses, such as the Veillonellaceae family, and a lower relative abundance of Bifi dobacterium bifi dum, which is known to promote regulatory T cells. However, the question as to why the two fecal donors produced strikingly different clinical responses after fecal transplant remains unresolved. In gut biopsies, the authors found that in patients who received donor #1 gut microbiota and showed clinical responses, increased posttransplant infi ltration of antigen-presenting cells (APCs) was observed in the gut mucosa, which expressed features of APC activation. Moreover, those with activated gut APCs also showed marked intratumoral infi ltration of CD8+ T cells, which was correlated with clinical responses in the control of tumor progression. Those fi ndings establish a clear link between local APC activation in the gut and distal antitumor immunity after fecal transplants. Clearly, this phase I clinical trial re-enforced the concept that the gut microbiota can have a profound impact on the immune system, including cancer immunotherapies, but also raised many questions regarding the mechanisms of such responses (or lack of such responses). Future studies are warranted to uncover the exact identity of bacterial species in mediating robust immunity or immune tolerance, and how they regulate systemic immunity from the gut.