Microbiome alteration via fecal microbiota transplantation is effective for refractory immune checkpoint inhibitor-induced colitis

• Published in: Science translational medicine 2023-06, Vol.15 (700), p.eabq4006-eabq4006
• Main Authors: Halsey, Taylor M, Thomas, Anusha S, Hayase, Tomo, Ma, Weijie, Abu-Sbeih, Hamzah, Sun, Baohua, Parra, Edwin Roger, Jiang, Zhi-Dong, DuPont, Herbert L, Sanchez, Christopher, El-Himri, Rawan, Brown, Alexandria, Flores, Ivonne, McDaniel, Lauren, Ortega Turrubiates, Miriam, Hensel, Matthew, Pham, Dung, Watowich, Stephanie S, Hayase, Eiko, Chang, Chia-Chi, Jenq, Robert R, Wang, Yinghong
• Format: Article
• Language: English
• Subjects: Aged; CD8 antigen; Colitis; Colitis - chemically induced; Colitis - therapy; Corticosteroids; Diarrhea; Donors; Fecal Microbiota Transplantation - methods; Fecal microflora; Feces; Feces - microbiology; Female; Humans; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - adverse effects; Immunosuppression; Inflammatory bowel disease; Infliximab; Lymphocytes T; Male; Malignancy; Microbiomes; Microbiota; Middle Aged; Monoclonal antibodies; Patients; Remission; RNA, Ribosomal, 16S - genetics; rRNA 16S; Transplantation; Tumor necrosis factor-α
• ISSN: 1946-6234; 1946-6242; 1946-3242
• DOI: 10.1126/scitranslmed.abq4006

Immune checkpoint inhibitors (ICIs) target advanced malignancies with high efficacy but also predispose patients to immune-related adverse events like immune-mediated colitis (IMC). Given the association between gut bacteria with response to ICI therapy and subsequent IMC, fecal microbiota transplantation (FMT) represents a feasible way to manipulate microbial composition in patients, with a potential benefit for IMC. Here, we present a large case series of 12 patients with refractory IMC who underwent FMT from healthy donors as salvage therapy. All 12 patients had grade 3 or 4 ICI-related diarrhea or colitis that failed to respond to standard first-line (corticosteroids) and second-line immunosuppression (infliximab or vedolizumab). Ten patients (83%) achieved symptom improvement after FMT, and three patients (25%) required repeat FMT, two of whom had no subsequent response. At the end of the study, 92% achieved IMC clinical remission. 16 rRNA sequencing of patient stool samples revealed that compositional differences between FMT donors and patients with IMC before FMT were associated with a complete response after FMT. Comparison of pre- and post-FMT stool samples in patients with complete responses showed significant increases in alpha diversity and increases in the abundances of and , which were depleted in FMT responders before FMT. Histologically evaluable complete response patients also had decreases in select immune cells , including CD8 T cells, in the colon after FMT when compared with non-complete response patients ( = 4). This study validates FMT as an effective treatment strategy for IMC and gives insights into the microbial signatures that may play a critical role in FMT response.