Intestinal microbiome characterization in immune checkpoint inhibition (ICI) resistant disease.
Authors: Spiliopoulou Pavlina , Rooney Ashley , Genta Sofia , Kulikova Maria , Wang Ben X , Tsao Ming Sound , Felicen Sam , Speers Vanessa , Patrick Theresa , Nguyen Alisa , Butler Marcus O. , Eng Lawson , Hansen Aaron Richard , Saibil Sam , Bedard Philippe L. , Pugh Trevor John , Siu Lillian L. , Coburn Bryan , Spreafico Anna 
Published: June 2023

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Background: The gut microbiome modifies response to ICI treatment. Despite durable response rates seen with ICI, most pts do not benefit from treatment (primary resistance) or have only a period of disease control (acquired resistance). The Immune Resistance Interrogation Study (IRIS, NCT03702309) is a prospective pan-cancer study that aims at characterizing ICI-resistant disease through multiomic and gut microbial composition profiling. Herein we compare the gut microbial diversity of pts with PR vs AR to PD-1/PD-L1 based treatment as part of the wider IRIS framework. Methods: Patients who progressed after anti-PD1/PD-L1-based ICI were classified into 2 groups. Acquired resistance (AR): complete response (CR), partial response (PR) or stable disease (SD) for ≥6 months (m) with subsequent (PD) or PD after ≥3m from last dose of adjuvant ICI; or primary resistance (PR): PD at first imaging, SD but progressed ≤6m or progression ≤3m from last dose of adjuvant ICI. Stool samples were collected at time of PD and underwent DNA extraction and metagenomic sequencing. Species-level Shannon diversity indices were calculated and compared using unpaired Wilcoxon test. Principal component analysis (PCA) of Bray-Curtis dissimilarity indices was performed to assess differences in taxonomic composition. Results: Stool samples from 62 pts (PR n=38; AR n=24) were evaluated. Tumor types were melanoma n=37 (60%), head and neck n=17/62 (27%), gastrointestinal n=3/62 (5%), gynaecological n=2/62 (3%) and other n=3/61 (5%). Most pts n=59/62 (95%) were treated with palliative intent, and n= 3/62 (5%) with adjuvant therapy. Anti-PD-1/PD-L1 monotherapy was received by 32/62 (52%) pts and n=30/62 (48%) received combination anti-PD-1/PD-L1 with either anti-CTLA-4 inhibition, experimental immunotherapy, chemotherapy, or targeted treatment. The median Shannon diversity index was similar between pts with PR (median: 3.5; range: 2.5 - 4.3) vs AR (median: 3.4; range: 0.9 – 3.9; p = 0.7). There were no differences in composition by group by PCA of Bray-Curtis dissimilarity indices. Abundance testing did not reveal any differentially abundant species between pts with AR vs PR while controlling for antibiotic use within 1m of sampling and type of treatment. No taxa were significantly different between AR and PR; top taxa per group are shown. Conclusions: Primary analysis showed no significant differences in gut microbial composition between primary vs acquired resistance to ICI. Comparative analysis between ICI-resistance samples and ICI-naïve samples from historical patient cohorts is underway. These results will be collated with other analyses from IRIS to create a multi-modal characterisation of ICI resistance. Clinical trial information: NCT03702309 . [Table: see text]