Abstract 2676: Associations of peripheral biomarkers to outcomes to anti-PD-L1 immune checkpoint blockade in metastatic urothelial cancer
Authors: Yuen Kobe C. , Gupta Vinita , Li Congfen , Rishipathak Deepali , Kadel Edward E. , Chen Ying-Jiun J. , Goldstein Leonard D. , Modrusan Zora , Mariathasan Sanjeev 
Published: August 2019

Abstract
Introduction Immune checkpoint blockade such as inhibition of programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) has been shown to be effective in metastatic urothelial cancer (mUC) and many other types of cancers. Despite its robust efficacy, a large proportion of patients still fail to show durable responses; therefore, it is important to understand the mechanisms that drive clinical responses, as well as the pathways associated with lack of response. Circulating peripheral biomarkers are particularly useful as readily accessible and minimally invasive markers to enable monitoring both tumor growth and responses to treatment.
Methods Baseline plasma from 337 patients treated with an anti-PD-L1 (atezolizumab) in the mUC Ph2 trial IMvigor210 (NCT02108652) were analyzed using a Myriad-RBM panel. To further characterize the findings, single-cell RNA sequencing (scRNAseq) was performed with PBMC isolated from responders and non-responders (n=5 each) to atezolizumab in the same trial. NanoString gene expression levels of the PBMC isolated from mUC patients in IMvigor210 was used to validate the identified signatures.
Results High levels of CXCL9 (HR: 0.692, CI: 0.529-0.903, p=0.006) and leptin (HR: 0.633, CI: 0.485-0.825, p=0.001) were associated with better overall survival (OS), whereas high levels of pro-inflammatory cytokines IL6 (HR: 2.744, CI: 2.084-3.612, p&lt;0.0001) and CXCL8/IL8 (HR: 2.639, CI: 1.997-3.489, p=0.006) were associated with poor OS. In addition, high levels of angiogenesis and cell adhesion proteins such as TIMP1 (HR: 2.317, CI: 1.773-3.029, p&lt;0.0001), VWF (HR: 1.571, CI: 1.207-2.045, p=0.001), and ICAM1 (HR: 1.349, CI: 1.034-1.76, p=0.026) correlated with poor OS. High plasma IL6 levels and high tumor IL6 expression are significantly enriched in non-responders in the T cell excluded phenotype, further suggesting association of IL6 with stroma/angiogenesis. Results from scRNAseq show response (CR/PR) to checkpoint blockade was associated with adaptive immune signature (GZMM, PSMB8, PSMB9) (FDR&lt;0.0001) in lymphoid PBMC. Lack of response (SD/PD) was associated with complement coagulation (PF4, THBS, TIMP1) (FDR&lt;0.0001) and innate inflammation (IL8, IL1B, IL18) (FDR=&lt;0.0001) signatures in the myeloid cells. We confirmed these outcome-associated signatures with OS modeling with gene expression levels in PBMC.
Conclusion Peripheral biomarker analysis revealed that adaptive immune signatures to be associated better clinical outcome, whereas innate inflammation and angiogenesis signatures to be correlated with worse clinical outcome to anti-PD-L1 immunotherapy. The link between IL6 and angiogenesis in the tumor microenvironment will be further characterized. Understanding the genes and pathways associated with outcomes will shed light on peripheral biomarker development.
Citation Format: Kobe C. Yuen, Vinita Gupta, Congfen Li, Deepali Rishipathak, Edward E. Kadel, Ying-Jiun J. Chen, Leonard D. Goldstein, Zora Modrusan, Sanjeev Mariathasan. Associations of peripheral biomarkers to outcomes to anti-PD-L1 immune checkpoint blockade in metastatic urothelial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2676.