Project 1: Targeting Neutrophils to Enhance ICI Efficacy in NSCLC

Project Summary/Abstract – Project 1 Our group has discovered that approximately 30% of non-small cell lung cancers (NSCLC) display evidence of myeloid lineage cell infiltration, which includes an abundance of neutrophils. We have termed such tumors Myeloid to distinguish them from Active tumors, which frequently respond to immune checkpoint inhibitor therapy. We have generated data in pre-clinical mouse models showing that inhibiting or depleting neutrophils synergizes with ICI treatment to reduce tumor burden. Here, we will develop an Immune Phenotype Classifier to reliably identify Myeloid lung cancers and perform a Phase 2 clinical trial combining the novel CXCR1/2 inhibitor SX-682 with atezolizumab for NSCLC patients in the 2nd line designed to rescue ICI treatment failure in Myeloid cancers. The Classifier will be designed to be translational relevant and transportable. Most sophisticated predictors of immune response rely on platforms, such as single cell sequencing, RNA seq, and multi-omic approaches, that are not easy to translate. We will develop a multiplexed-immunohistochemistry (M- IHC) panel that only requires one FFPE slide as input, something that is universally available even at rural hospitals. We will also test the utility of adding a ~20 gene transcriptional panel of the Nanostring platform, that may or may not improve the performance. This Classifier will be tested on clinical trial specimens of patients receiving a myeloid antagonist in combination with an anti-PDL1 antibody (atezolizumab). This will allow us to test the concept that Myeloid immune subtype patients will demonstrate favorable treatment outcomes upon the addition of the CXCR1/2 inhibitor. All performance metrics will compared head-to-head with PDL1 tumor proportion score (TPS), the accepted gold-standard companion diagnostic at this time.