Dynamic Exosome Analysis to Predict Response to the Combination of SABR and Immunotherapy in Oligoprogressive Disease

Abstract

Up to 80% of metastatic patients face resistance to immune checkpoint inhibitors (ICI). Combined SABR and ICI (I-SABR) can unleash antitumor immune cascades to overcome resistance and improve response with minimal toxicity. This synergy is particularly interesting in the oligoprogressive setting to extend the clinical benefit (CB) of ICI. However, there are no current biomarkers for patient selection. We hypothesize that differential expression of exosomal RNA in liquid biopsy may predict response to I-SABR. Ongoing prospective multicenter study in two cohorts. Cohort A consists of metastatic patients in oligoprogression to ICI (1-5 extracranial sites) but maintaining the same ICI due to CB and who receive concomitant SABR (35 Gy in 5 fractions, fx) to oligoprogressive sites. Cohort B is a comparative group of oligometastatic patients receiving only SABR in ablative doses. Blood samples are extracted before SABR (T1), after the first (T2) and last (T3) fx, two months post-SABR (T4) and at further progression (TP). Response is evaluated by iRECIST and defined by the objective response rate (ORR) in all lesions (in and out-of-field)- complete and partial responses. For exosome analysis, we perform RNA isolation and small RNA sequencing from plasma. We use Cutadapt, Bowtie and featureCounts to quantify the number of reads of miRNA, small nuclear RNA (snRNA) and small nucleolar RNA (snoRNA). Pairwise differences in expression in responders and non-responders are examined by DESeq2 differential expression analysis. Differentially expressed transcripts are consulted in Ingenuity Pathway Analysis (IPA). Of 22 patients recruited, we present preliminary results of the first 10 (8 from cohort A and 2 from B) that had undergone re-evaluation after SABR. Most frequent cancer types were lung (60%) and renal cell (20%). Seventy percent were polymetastatic (>5 lesions) and 90% had a single progressing site. Pembrolizumab (40%) and Nivolumab (30%) were the most frequent ICI. Most lesions for SABR were lung (45%). With a median follow-up of 7.1 months (95% CI, 3.7-10.6) ORR at two months was 60% (6 partial responses, 1 stable disease and 3 progressions). Median progression-free survival was 10.3 months (95% CI, 3.7-not reached) and median overall survival was not reached. Seven patients in cohort A were available for small RNA analysis. We identified 3 miRNA, 24 snRNA and 9 snoRNA that were significantly differentially expressed at T1. Hsa-miR-493, marker of tumor progression, was upregulated in non-responders. RN7SK inhibits LAS1L (a known inductor of metastasis in lung cancer) and was upregulated in responders. SNORD71, which is inhibited by ILF3 (promotor of progression), was also upregulated in responders. I-SABR is an effective approach for extending CB of ICI in oligoprogressive patients. Exosomal RNA expression analysis in liquid biopsy is a novel and non-invasive technique that may predict response to this combination and aid in patient selection.