Analysis of Gut Microbiome Did Not Show Significant Differences Relating to Immune Checkpoint Inhibition Resistance

It is known that the gut microbiome modifies the response to immune checkpoint inhibition (ICI) treatment, and specifically that the microbiota composition of responders to ICI vs non-responders differs, explained Pavlina Spiliopoulou, MD, PhD, during a presentation at the American Society of Clinical Oncology (ASCO) 2023 Annual Meeting. Further, prior antibiotic treatment is associated with inferior survival during ICI treatment, which is known to primarily impact the microbiome, according to Spiliopoulou.

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Despite the demonstrated durable response rates with ICI, most patients do not benefit from treatment (primary resistance) or have only a period of disease control (acquired resistance), according to Spiliopoulou. However, fecal microbiota transplant from responders to non-responders was able to rescue ICI use in patients with melanoma, with 40% of those who were ICI resistant showing clinical benefit after administration of this therapy.

In the prospective pan-cancer Immune Resistance Interrogation Study (IRIS, NCT03702309), investigators, including Spiliopoulou, looked to characterize ICI-resistant disease through multiomic and gut microbial composition profiling. Progressive disease (PD) was defined as being stable disease (SD) at first imaging but then PD at 6 months or more, or PD at 3 months or more from last dose of adjuvant ICI. Acquired resistance, on the other hand, is the complete response (CR), partial response (PR), or SD for 6 months or more with subsequent PD or PD after 3 months or more from the last dose of adjuvant ICI.

The investigators classified patients who progressed after anti-PD-1/PD-L1-based ICI into 2 groups. In the acquired resistance (AR) group is CR, PR, or SD for 6 months or more with subsequent PD or PD that progressed after 3 months or more from the last dose of adjuvant ICI; or primary resistance (PR), which includes PD at first imaging, SD progressed at 6 months or more, or progression at 3 months or more from the last dose of adjuvant ICI.

During the trial, investigators collected stool samples at time of PD and conducted DNA extraction and metagenomic sequencing, according to Spiliopoulou. Species-level Shannon diversity indices were calculated and compared using unpaired Wilcoxon test. Further, principal component analysis (PCA) of Bray-Curtis dissimilarity indices was performed to assess differences in taxonomic composition.

Investigators also evaluated stool samples from 62 patients (PR n=38; AR n=24). Tumor types were melanoma n=37 (60%), head and neck n=17/62 (27%), gastrointestinal n=3/62 (5%), gynecological n=2/62 (3%), and other n=3/61 (5%). Fifty-nine out of 62 (95%) patients were treated with palliative intent, and 3 out of 62 (5%) with adjuvant therapy.

Anti-PD-1/PD-L1 monotherapy was also received by 32/62 (52%) months 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 patients with PR (median: 3.5; range: 2.5-4.3) vs AR (median: 3.4; range: 0.9–3.9; p = 0.7).

The primary analysis demonstrated that there were no significant differences in gut microbial composition in patients with primary vs acquired resistance to ICI. Further, comparative analysis between ICI resistance samples and ICI-naive samples from historical patient cohorts is underway. The investigators plan to collate the results with other analyses from IRIS to create a multi-modal characterization of ICI resistance, according to Spiliopoulou.

“The preliminary analysis of the patients’ gut microbiome did not show significant differences in alpha and beta diversity measures between acquired and primary ICI resistance samples. Similarly, analysis of gut microbiome did not show significant differences in alpha and beta diversity measures between ICI-naïve and ICI-resistant samples,” Spiliopoulou said. “Further in-depth taxonomic and functional analysis of the gut microbiome samples is on-going.”

Reference

Spiliopoulou P. Developmental Therapeutics – Immunotherapy. June 2, 2023; Presented at: 2023 ASCO Annual Meeting. Accessed June 2, 2023. https://meetings.asco.org/2023-asco-annual-meeting/15134