Abstract CT042: Fecal microbiota transplantation (FMT) and re-induction of anti-PD-1 therapy in refractory metastatic melanoma patients - preliminary results from a phase I clinical trial (NCT03353402)

Abstract

Background: The majority of metastatic melanoma patients treated with Programed cell Death (PD)-1 blockade fail to achieve durable response. The gut microbiota profoundly affects host immunity, and fecal microbiota transplantations (FMT), which transfers the entire gut microbiota from one host to another, has been shown to enhance anti-PD-1 effectiveness in murine models. We report initial safety and efficacy results from the first three patients treated on a Phase I study of FMT and re-induction anti-PD-1 therapy in anti-PD-1 refractory metastatic melanoma. Methods: FMT donors were two metastatic melanoma patients who achieved a durable complete response. FMT Recipients were metastatic melanoma patients who failed at least one anti-PD-1 line of treatment. FMT was conducted by both colonoscopy and oral ingestion of stool capsules, followed by anti-PD-1 re-treatment (Nivolumab, BMS). Each recipient underwent pre- and post-treatment stool sampling, tissue biopsy of both gut and tumor, and total body imaging. Results: Recipients #1 and #3 received fecal implants from Donor #1, while Recipient #2 receive implants from Donor #2. No FMT-related or immunotherapy-related adverse events were observed. To assess engraftment of the new microbiota, recipients were paired with their respective donors and stool 16S rDNA gene sequence analysis performed. Ideal engraftment from a single donor would result in identical microbiota composition between that donor and recipients. In the case of two donors, ideal engraftment would result in two distinctive recipient-donor compositions. Sequencing results demonstrated post-FMT compositional dissimilarity (Unweighted UniFrac, p=0.04, FDR q=0.22) between the two recipient-donor groups. Immunohistochemical stains of biopsies demonstrated an increased post-FMT infiltration of antigen presenting cells (CD68+) in the gut (paired T test, p=0.008) and in the tumor (p=0.076). Post-treatment intra-tumoral CD8+ T-cells infiltration was also increased (p=0.096), especially in recipients #1, #3. Recipient #1 and Recipient #3 demonstrated clinical and radiological benefit from treatment. Conclusion: FMT in metastatic melanoma patients seemed to be safe and may alter recipient gut microbiota to resemble that of a responder donor. This alteration may result in intra-tumoral T-cell activity, which was translated to a clinical and radiological benefit in two recipients. Citation Format: Erez N. Baruch, Ilan Youngster, Rona Ortenberg, Guy Ben-Betzalel, Lior H. Katz, Adi Lahat, Iris Barshack, Daniela Dick-Necula, Ronac Mamtani, Naamah Bloch, Bella Ungar, Daniel Rotin, Camila Avivi, Liat Anafi, Yael Steinberg-Silman, Nethanel Asher, Ronnie Shapira-Frommer, Tal Brosh-Nissimov, Yael Eshet, Stephen Raskin, Hagit Harati, Jenny Melnichenko, Jacob Schachter, Omry Koren, Gal Markel, Ben Boursi. Fecal microbiota transplantation (FMT) and re-induction of anti-PD-1 therapy in refractory metastatic melanoma patients - preliminary results from a phase I clinical trial (NCT03353402) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT042.

The Cancer-Immune Set Point in Oesophageal Cancer

“…In NSCLC and melanoma, faecal microbiota transplant (FMT) from human ICI responders improved response to ICI in mice, raising a possibility of a microbiome based therapeutic intervention (91, 92). A pilot study that subjected three ICIrefractory melanoma patients to FMT from ICI-responders has reported preliminary results (103). FMT increased intratumoural CD8 + TILs in recipients, and this translated into a clinical and radiological response in two of three patients.…”

Defined microbiota transplant restores Th17/RORγt+ regulatory T cell balance in mice colonized with inflammatory bowel disease microbiotas

“…FMT is effective for treating recurrent Clostridioides difficile infection (rCDI) (van Nood et al 2013), but is also under investigation for the treatment of ulcerative colitis (UC), Crohn's disease (CD), liver diseases, obesity and metabolic disease, food allergy, graft-versus-host disease, check point colitis and to improve the efficacy of cancer immunotherapy (Ooijevaar et al 2019;Wang et al 2018;Baruch et al 2019). Clinical trials of FMT in UC have suggested some potential for using microbiota-targeted therapy in this setting (Paramsothy et al 2017;Moayyedi et al 2015;Rossen et al 2015;Costello et al 2019), but evidence for efficacy in other indications is currently extremely limited and there is currently little or no scientific basis for the adoption of FMT as a mainstream therapeutic option outside of rCDI.…”

Defined microbiota transplant restores Th17/RORγt+regulatory T cell balance in mice colonized with inflammatory bowel disease microbiotas

“…FMT is effective for treating recurrent Clostridioides difficile infection (rCDI) (5), but is also under investigation for the treatment of ulcerative colitis (UC), Crohn's disease (CD), liver diseases, obesity and metabolic disease, food allergy, graft-versushost disease, checkpoint colitis, and to improve the efficacy of cancer immunotherapy (6)(7)(8). Clinical trials of FMT in UC have suggested some potential for using microbiota-targeted therapy in…”

“…FMT is effective for treating recurrent Clostridioides difficile infection (rCDI) ( 5 ), but is also under investigation for the treatment of ulcerative colitis (UC), Crohn’s disease (CD), liver diseases, obesity and metabolic disease, food allergy, graft-versus-host disease, checkpoint colitis, and to improve the efficacy of cancer immunotherapy ( 6 – 8 ). Clinical trials of FMT in UC have suggested some potential for using microbiota-targeted therapy in this setting ( 9 – 12 ), but evidence for efficacy in other indications is currently extremely limited, and there is currently little or no scientific basis for the adoption of FMT as a mainstream therapeutic option outside of rCDI.…”