Abstract B200: Using “omics” to select immunotherapy and conventional therapy combinations
Authors: Schwartz Sarit , Heaton Robert , Tian Yuan , Sanborn Zack , Sellappan Shankar , Cecchi Fabiola , Benz Steve , Hembrough Todd 
Published: August 2018

Abstract
Background: As only a subset of patients respond to immunotherapies, therapeutic biomarkers are needed to predict which patients will benefit and which should be spared from potentially toxic treatment. Proteins expressed by tumor cells and by the immune microenvironment may predict response to immune checkpoint inhibitors. In noninflamed tumors, chemotherapy and targeted therapy may stimulate an immune response, thereby affecting the relationship between tumor and immune system. Combinations of immunotherapies and conventional therapies are the subject of ongoing clinical trials. We hypothesized that genomic and proteomic evaluation of multiple immune biomarkers in tumor tissue and in lymphocytes would identify a signature that could (a) differentiate between responders and nonresponders to checkpoint inhibitors and (b) identify candidates for combination therapy. Methods: A pathologist marked areas of tumor and tumor-associated lymphocytes on archived tissue sections (N=2) of non-small cell lung cancer (NSCLC) and melanoma. The marked areas were microdissected and solubilized to tryptic peptides. In each liquefied tumor sample, 110 protein biomarkers, including 60 immunomarkers, were quantified with a mass spectrometry-based proteomic assay. The genomic material was analyzed by whole genome sequencing and RNA-seq. Results: Tumor and lymphocytes expressed several immunomarker proteins (eg, PDL1, IDO1, B7H3, B7-2, STAT1, GBP1). The melanoma patient’s tumor and lymphocytes expressed markers for response to immunotherapy (PDL1 and IDO1). Genomic and proteomic analysis suggested sensitivity to BRAF inhibitors and resistance to platinum and taxane. The NSCLC patient’s tumor and lymphocytes expressed IDO1 protein, but genomic analysis suggested a noninflamed tumor. Based on expression levels of ERCC1 and hENT1, one possible regimen for this patient is platinum plus gemcitabine followed by immunotherapy. In the NSCLC patient, comparison of protein expression in tumor-associated lymphocytes versus distal lymphocytes (&gt;1 mm from marked tumor areas) showed variation &lt;10% for 11 proteins and &lt;30% for 14 proteins. Conclusions: Both lymphocytes and tumor expressed immunoproteins that may be used to select patients for approved immunotherapies or clinical trials. Proteomic and genomic profiling also characterized biomarkers that inform selection of targeted therapies and chemotherapies. Ongoing clinical trials of immunotherapy and combination therapies could benefit from precise, quantitative molecular stratification of patients. Protein level cutoffs that correlate with response to immunotherapy are in development.
Citation Format: Sarit Schwartz, Robert Heaton, Yuan Tian, Zack Sanborn, Shankar Sellappan, Fabiola Cecchi, Steve Benz, Todd Hembrough. Using “omics” to select immunotherapy and conventional therapy combinations [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B200.