Method of predicting for benefit from immune checkpoint inhibition therapy
An immune checkpoint and therapy technology, applied in immunoglobulins, chemical instruments and methods, biochemical equipment and methods, etc., which can solve problems such as insufficient description of negative predictive biomarkers
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Embodiment 1
[0148] Example 1: Alternative Promoter Utilization in Metastatic Gastric Cancer
[0149] The first cohort consisted of 24 patients with metastatic gastric cancer treated with nivolumab and pembrolizumab (initially included 29 individuals from whom 24 tumor samples passed quality control to obtain sufficient tissue for Nanostring analysis). A custom Nanostring panel was used to measure transcripts associated with canonical or alternative promoters. A differentially expressed alternative promoter was defined as a promoter site whose expression level showed a 4-fold change (for acquired somatic promoter). Using this algorithm, one third of tumors (8 / 24) were found to show high alternative promoter utilization in more than 10% of sites (>8 / 80). The group is defined as AP high , while the rest are defined as AP low ( Figure 2A ).
[0150] The measurement of cytolytic T cell activity has been previously described by studying the expression of CD8A (CD8+ tumor infiltrating lym...
Embodiment 2
[0151] Example 2: Alternative Promoter Utilization as a Predictor of Pembrolizumab Treatment Response and Survival
[0152] For the second cohort, transcriptome data from an earlier described phase II study were used. Transcriptomic data and matched clinical data from pre-treatment biopsy samples were available for 37 individuals and used for analysis. Median age was 57 years, 73% were male (N=27), 4 (11%) were EBV positive, 4 were MSI (11%), and the rest were defined as CIN or GS TCGA subtype. A complete or partial response to treatment was observed in 11 subjects (30%). Using 2732 somatic alternative promoter sites previously identified in gastric cancer [10], the definition of differentially expressed alternative promoters was similar to the first cohort (4-fold change). Notably, good agreement between the RNAseq platform and the Nanostring platform for assessing alternative promoter utilization has been previously shown. The sum of differentially expressed sites in each...
Embodiment 3
[0162] Example 3: Alternative Promoter Utilization Evolution After Pembrolizumab Treatment
[0163] Paired biopsy samples were available for a second cohort of 8 individuals, which provided the opportunity to monitor tumor evolution resulting from the stress of ICI therapy. Post-treatment biopsies were taken from primary gastric tumors at the point of pembrolizumab progression. Of these 8 individuals, two had a partial response (PR) with a duration of response of 211 and 491 days (both AP low ), one in stable disease (SD) with a duration of response of 167 days (AP low ), 5 with progressive disease (PD) (AP high N=3; AP low N=2) as the best response. Interestingly, remarkably consistent changes were observed in the directionality of alternative promoter utilization based on clinical response. Specifically, tumors with PR and SD exhibited a 1.5-fold or greater increase in alternative promoter utilization scores in post-treatment biopsy samples compared with pre-treatment...
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