Interaction between gut microbiome and immune checkpoint inhibitor treatment in lymphoma patients: Final results of the MICRO‐LINF study

Abstract

Introduction: Over the last decades, a revolution has occurred in oncology with the development of immune checkpoint inhibitors (ICIs). Following tremendous successes in solid tumors, interest has risen to explore these inhibitors also in hematologic malignancies, especially lymphomas. Biomarkers for ICIs response and resistance include PD-L1 expression and other environmental factors, among which the gut microbiome (GM) is gaining increasing interest. Several studies have demonstrated a connection between GM compositional and functional patterns and ICIs efficacy in solid tumors, but no data in lymphomas have yet been published. We hypothesize that GM dynamics in lymphoma patients during ICIs therapy correlate with treatment response and toxicities. Methods: We enrolled 20 patients (15 with classical Hodgkin lymphoma [cHL] and 5 with primary mediastinal B-cell lymphoma [PMBCL]) treated with ICIs due to relapsed/refractory (R/R) disease. Feces were collected at baseline, before each therapy cycle and at response assessment, and profiled through Illumina sequencing. Sequencing data were processed using a bioinformatics pipeline combining PANDASEQ and QIIME 2. At each time point, patients compiled a 7-day weighted food intake record that was analyzed by MètaDieta (METEDA). All statistical analysis was performed in R (4.4.2). Results: The two groups of patients did not differ for baseline characteristics, thus both clinical outcomes and GM results are reported as pooled. Nineteen patients were refractory to last therapy, with a median of previous treatments of 3 (range 2–8). The median number of ICIs cycles was 14 (1–39). The overall response rate (ORR) was 30.5%, with a median progression-free survival of 11 months and a median disease survival not reached, at a median follow-up of 28.9 months. No association was found between clinical characteristics and response/survival outcomes. Three patients developed 6 hematological toxicities and 18 patients developed 58 extra-hematological toxicities; 4 patients had SAE, of which 2 were judged as drug related. As for GM (Figure 1), responding patients showed a peculiar enrichment of Lachnospira at baseline (p = 0.013). The relative abundance of this taxon negatively correlated with dietary intake of Omega-6 (p = 0.038). On the other hand, non-responders showed higher basal levels of Enterobacteriaceae (p = 0.041). These features were also maintained at the end of the treatment, even if only as trends (p < 0.1). Keywords: Diagnostic and Prognostic Biomarkers, Immunotherapy No conflicts of interests pertinent to the abstract.