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      Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients

      1 , 2 , 3 , 4 , 1 , 1 , 5 , 6 , 7 , 8 , 4 , 9 , 10 , 8 , 8 , 8 , 1 , 1 , 11 , 1 , 1 , 1 , 12 , 4 , 8 , 13 , 10 , 10 , 14 , 15 , 14 , 4 , 8 , 1 , 4 , 14 , 16 , 10 , 1 , 2 , 17 , 4 , 18 , 19
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      American Association for the Advancement of Science (AAAS)

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          Abstract

          The gut microbiome has been shown to influence the response of tumors to anti-PD-1 immunotherapy in pre-clinical mouse models and observational patient cohorts. However, modulation of gut microbiota in cancer patients has not been investigated in clinical trials. Here we performed a phase I clinical trial to assess the safety and feasibility of fecal microbiota transplantation (FMT) and re-induction of anti-PD-1 immunotherapy in ten patients with anti-PD-1-refractory metastatic melanoma. We observed clinical responses in three patients, including two partial responses and one complete response. Notably, treatment with FMT was associated with favorable changes in immune cell infiltrates and gene expression profiles in both the gut lamina propria and the tumor microenvironment. Together, these early findings have important implications for modulating the gut microbiota in cancer treatment.

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          Most cited references63

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          Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

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            Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2

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              New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).

              Assessment of the change in tumour burden is an important feature of the clinical evaluation of cancer therapeutics: both tumour shrinkage (objective response) and disease progression are useful endpoints in clinical trials. Since RECIST was published in 2000, many investigators, cooperative groups, industry and government authorities have adopted these criteria in the assessment of treatment outcomes. However, a number of questions and issues have arisen which have led to the development of a revised RECIST guideline (version 1.1). Evidence for changes, summarised in separate papers in this special issue, has come from assessment of a large data warehouse (>6500 patients), simulation studies and literature reviews. HIGHLIGHTS OF REVISED RECIST 1.1: Major changes include: Number of lesions to be assessed: based on evidence from numerous trial databases merged into a data warehouse for analysis purposes, the number of lesions required to assess tumour burden for response determination has been reduced from a maximum of 10 to a maximum of five total (and from five to two per organ, maximum). Assessment of pathological lymph nodes is now incorporated: nodes with a short axis of 15 mm are considered measurable and assessable as target lesions. The short axis measurement should be included in the sum of lesions in calculation of tumour response. Nodes that shrink to <10mm short axis are considered normal. Confirmation of response is required for trials with response primary endpoint but is no longer required in randomised studies since the control arm serves as appropriate means of interpretation of data. Disease progression is clarified in several aspects: in addition to the previous definition of progression in target disease of 20% increase in sum, a 5mm absolute increase is now required as well to guard against over calling PD when the total sum is very small. Furthermore, there is guidance offered on what constitutes 'unequivocal progression' of non-measurable/non-target disease, a source of confusion in the original RECIST guideline. Finally, a section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included. Imaging guidance: the revised RECIST includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions. A key question considered by the RECIST Working Group in developing RECIST 1.1 was whether it was appropriate to move from anatomic unidimensional assessment of tumour burden to either volumetric anatomical assessment or to functional assessment with PET or MRI. It was concluded that, at present, there is not sufficient standardisation or evidence to abandon anatomical assessment of tumour burden. The only exception to this is in the use of FDG-PET imaging as an adjunct to determination of progression. As is detailed in the final paper in this special issue, the use of these promising newer approaches requires appropriate clinical validation studies.
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                Journal
                Science
                Science
                American Association for the Advancement of Science (AAAS)
                0036-8075
                1095-9203
                December 10 2020
                : eabb5920
                Affiliations
                [1 ]The Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center, Tel-HaShomer, Israel.
                [2 ]Department of Clinical Immunology and Microbiology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
                [3 ]Pediatric Division and the Microbiome Research Center, Shamir (Assaf Harofeh) Medical Center, Be’er Ya’akov, Israel.
                [4 ]School of Medicine, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
                [5 ]Department of Gastroenterology, Sheba Medical Center, Tel HaShomer, Israel.
                [6 ]Department of Gastroenterology, Hadassah Medical Center, Jerusalem, Israel.
                [7 ]Department of Mathematics, Bar Ilan University, Ramat Gan, Israel.
                [8 ]Institute of Pathology, Sheba Medical Center, Tel-HaShomer, Israel.
                [9 ]Radiological Institute, Sheba Medical Center, Tel HaShomer, Israel.
                [10 ]Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel.
                [11 ]Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, PA, USA.
                [12 ]Infectious Diseases Unit, Assuta Ashdod University Hospital, Ashdod, Israel.
                [13 ]Department of Nuclear Medicine, Sheba Medical Center, Tel HaShomer, Israel.
                [14 ]Program for Innovative Microbiome and Translational Research, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
                [15 ]Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
                [16 ]Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
                [17 ]Talpiot Medical Leadership Program, Sheba Medical Center, Tel HaShomer, Israel.
                [18 ]Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA, USA.
                [19 ]Department of Oncology, Sheba Medical Center, Tel HaShomer, Israel.
                Article
                10.1126/science.abb5920
                33303685
                b9dc49ca-c740-4090-8cff-9fe3204f7ed1
                © 2020
                History

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