Conversion of unresponsiveness to immune checkpoint inhibition by fecal microbiota transplantation in patients with metastatic melanoma: study protocol for a randomized phase Ib/IIa trial

BMC Cancer

Study Protocol

J. G. E. Henderickx¹  M. van Dijk²  R. Kessels³  M. E. van Leerdam⁴  C. M. Korse⁵  J. S. W. Borgers⁶  J. B. A. G. Haanen⁶  F. H. Burgers⁶  C. U. Blank⁶  C. C. Flohil⁷  T. N. Schumacher⁸  E. J. Kuijper⁹  E. M. Terveer⁹  H. W. Verspaget^1,10  J. J. Keller^1,11 

[1] Center for Microbiome Analyses and Therapeutics at Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands;Clinical Trial Service Unit, Antoni Van Leeuwenhoek, The Netherlands Cancer Institute, Amsterdam, The Netherlands;Department of Biometrics, Antoni Van Leeuwenhoek, The Netherlands Cancer Institute, Amsterdam, The Netherlands;Department of Gastrointestinal Oncology, Antoni Van Leeuwenhoek, The Netherlands Cancer Institute, Amsterdam, The Netherlands;Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands;Department of Laboratory Medicine, Antoni Van Leeuwenhoek, The Netherlands Cancer Institute, Amsterdam, The Netherlands;Department of Medical Oncology, Antoni Van Leeuwenhoek, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands;Department of Pathology, Antoni Van Leeuwenhoek, The Netherlands Cancer Institute, Amsterdam, The Netherlands;Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands;Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands;Netherlands Donor Feces Bank, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands;Center for Microbiome Analyses and Therapeutics at Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands;Netherlands Donor Feces Bank, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands;Department of Biobanking, Leiden University Medical Center, Leiden, The Netherlands;Netherlands Donor Feces Bank, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands;Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands;Department of Gastroenterology, Haaglanden Medical Center, Den Haag, The Netherlands;

关键词: FMT;    Gut microbiome;    Immunotherapy;    Anti-PD-1;    Melanoma;   

DOI  :  10.1186/s12885-022-10457-y

 received in 2022-07-22, accepted in 2022-12-16,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundThe gut microbiome plays an important role in immune modulation. Specifically, presence or absence of certain gut bacterial taxa has been associated with better antitumor immune responses. Furthermore, in trials using fecal microbiota transplantation (FMT) to treat melanoma patients unresponsive to immune checkpoint inhibitors (ICI), complete responses (CR), partial responses (PR), and durable stable disease (SD) have been observed. However, the underlying mechanism determining which patients will or will not respond and what the optimal FMT composition is, has not been fully elucidated, and a discrepancy in microbial taxa associated with clinical response has been observed between studies. Furthermore, it is unknown whether a change in the microbiome itself, irrespective of its origin, or FMT from ICI responding donors, is required for reversion of ICI-unresponsiveness. To address this, we will transfer microbiota of either ICI responder or nonresponder metastatic melanoma patients via FMT.MethodsIn this randomized, double-blinded phase Ib/IIa trial, 24 anti-PD1-refractory patients with advanced stage cutaneous melanoma will receive an FMT from either an ICI responding or nonresponding donor, while continuing anti-PD-1 treatment. Donors will be selected from patients with metastatic melanoma treated with anti-PD-1 therapy. Two patients with a good response (≥ 30% decrease according to RECIST 1.1 within the past 24 months) and two patients with progression (≥ 20% increase according to RECIST 1.1 within the past 3 months) will be selected as ICI responding or nonresponding donors, respectively. The primary endpoint is clinical benefit (SD, PR or CR) at 12 weeks, confirmed on a CT scan at 16 weeks. The secondary endpoint is safety, defined as the occurrence of grade ≥ 3 toxicity. Exploratory endpoints are progression-free survival and changes in the gut microbiome, metabolome, and immune cells.DiscussionTransplanting fecal microbiota to restore the patients’ perturbed microbiome has proven successful in several indications. However, less is known about the potential role of FMT to improve antitumor immune response. In this trial, we aim to investigate whether administration of FMT can reverse resistance to anti-PD-1 treatment in patients with advanced stage melanoma, and whether the ICI-responsiveness of the feces donor is associated with its effectiveness.Trial registrationClinicalTrials.gov: NCT05251389 (registered 22-Feb-2022). Protocol V4.0 (08–02-2022).

【 授权许可】

CC BY   
© The Author(s) 2022