Pan-tumor genomic biomarkers for PD-1 checkpoint blockade–based immunotherapy

Abstract

INTRODUCTION: Immunotherapy targeting the programmed cell death protein–1 (PD-1) axis elicits durable antitumor responses in multiple cancer types. However, clinical responses vary, and biomarkers predictive of response may help to identify patients who will derive the greatest therapeutic benefit. Clinically validated biomarkers predictive of response to the anti–PD-1 monoclonal antibody pembrolizumab include PD-1 ligand 1 (PD-L1) expression in specific cancers and high microsatellite instability (MSI-H) regardless of tumor type. Tumor mutational burden (TMB) and T cell–inflamed gene expression profile (GEP) are emerging predictive biomarkers for pembrolizumab. Both PD-L1 and GEP are inflammatory biomarkers indicative of a T cell–inflamed tumor microenvironment (TME), whereas TMB and MSI-H are indirect measures of tumor antigenicity generated by somatic tumor mutations. However, the relationship between these two categories of biomarkers is not well characterized. RATIONALE: This study assessed the potential for TMB and a T cell–inflamed GEP to jointly predict clinical response to pembrolizumab in >300 patient samples with advanced solid tumors and melanoma across 22 tumor types from four KEYNOTE clinical trials. To assess the individual and joint clinical utility of TMB and GEP, patients were stratified in four biomarker–defined clinical response groups [GEP low and TMB low (GEPlo TMBlo), GEP low and TMB high (GEPlo TMBhi), GEPhi TMBlo, and GEPhi TMBhi] based on predefined cutoffs for TMB and GEP. These patient–defined biomarker groups were further used to guide transcriptome and exome analyses of tumors in a large molecular database [The Cancer Genome Atlas (TCGA)] (n = 6384 tumors) to identify targetable patterns of biology that may modulate response and resistance. RESULTS: TMB and GEP exhibited only modest correlation and were independently predictive of response across the KEYNOTE clinical datasets. We found that objective response rates were strongest in patients with GEPhi TMBhi (37 to 57%), moderate in those with GEPhi TMBlo (12 to 35%) and GEPlo TMBhi (11 to 42%), and reduced or absent in those with GEPlo TMBlo (0 to 9%) (see the figure). Additionally, longer progression–free survival times were seen in patients with higher levels of both TMB and GEP. Findings were comparable when TMB and PD-L1 expression were jointly assessed. Within TCGA database, GEP and TMB again had a low correlation, demonstrating the potential to jointly stratify transcriptomic and genomic features across cancer types. Specific gene expression patterns reflective of TME biology showed significant associations with TMB, GEP, or both. In particular, gene set enrichment analysis identified proliferative and stromal, myeloid, and vascular biology corresponding to specific TMB-defined subgroups within GEPhi tumors. In TMBhi tumors, indication-dependent somatic DNA alterations in key cancer driver genes showed a strong negative association with GEP. CONCLUSION: This analysis shows that TMB and inflammatory biomarkers (T cell–in...

4‐1BB Delineates Distinct Activation Status of Exhausted Tumor‐Infiltrating CD8+ T Cells in Hepatocellular Carcinoma

“…This suggests that the higher degree of T‐cell activation associated with 4‐1BB expression may reflect a robust antitumor response that leads to improved survival outcomes in HCC patients. Furthermore, HCCs with higher 4‐1BB signature expression showed enrichment of the T‐cell–inflamed gene signature, suggesting that 4‐1BB–related T‐cell activation directs active IFN‐γ and cytotoxic antitumor T‐cell responses, which are also associated with anti–PD‐1 response . This gene set will be an important resource for mining additional key genes and pathways involved in T‐cell activation against HCC.…”

Tumor mutational burden standardization initiatives: Recommendations for consistent tumor mutational burden assessment in clinical samples to guide immunotherapy treatment decisions

“…Therefore, multiomic analyses may provide a more complete patient biomarker profile for guiding treatment decisions. Indeed, other biomarkers commonly investigated alongside TMB include PD‐L1, microsatellite instability (MSI) or deficient mismatch repair, and immune signatures …”

Immunotherapy with checkpoint inhibitors in patients with ovarian cancer: Still promising?

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