First in human study with GSK3359609 [GSK609], inducible T cell co-stimulator (ICOS) receptor agonist in patients [Pts] with advanced, solid tumors: Preliminary results from INDUCE-1

Abstract

Here we analyzed gene expression profiles (GEPs) associated with A2AR agonism to characterize a "signature" of adenosine exposure in human immune cells and correlated this with GEPs in tumor biopsies from patients with renal cell cancer (RCC) treated with CPI-444. Methods: Human PBMCs were stimulated with NECA (a stable adenosine analog) or an A2AR specific agonist (CGS21680). Purified RNA was analyzed using the NanoString PanCancer Immune Panel in conjunction with RNASeq. Select analytes were validated in culture supernatant by ELISA. RCC tumor biopsies collected from 64 pts treated with CPI-444 (100 mg BID) either as a single agent (n ¼ 32) or in combination with atezolizumab (n ¼ 32) were analyzed using NanoString. Results: In vitro A2AR stimulation resulted in dose-dependent increases in CXCR2 ligands (CXCL1,2,3,5,8) and key mediators of neutrophil/MDSC biology (CSF3, IL-23). Increases in monocyte/macrophage inflammatory mediators such as IL-1b and CCL2,3,7,8, 20 were also observed, as were increases in SERPINB2, S100A8, PTGS2, THBS1. Expression of CXCL10 and GZMB were decreased, consistent with a suppressed IFNg response. CPI-444 inhibited these changes at the transcript and protein level. Preliminary biomarker analysis suggests CPI-444 anti-tumor activity in RCC was associated with increased expression of these adenosine responsive genes in pretreat-ment biopsies. A second module of genes, which included CX3CL1 and complement inhibition, was associated with tumor progression. Conclusions: A2AR agonists induce a specific gene signature dominated by immuno-suppressive mediators of MDSC and monocyte/macrophage biology. Inhibition of these GEPs by CPI-444 are observed in vitro and in vivo in tumor biopsies from treated patients. These gene signatures may be used as biomarkers for patient selection. Background: ICOS, a member of CD28/B7 superfamily, is expressed on T cells (TC) after TC receptor engagement with cognate antigen. ICOS provides a costimulatory signal augmenting TC expansion, function and survival. GSK609 is a humanized, IgG4 antibody engineered to reduce Fc-mediated depleting effects yet retain cross-linking for potent agonist activity against human ICOS. GSK609's unique profile as a pure TC agonist void of TC depleting effects offers antitumor potential as monotherapy and in rational combinations with agents that modulate key immune pathways.