Deep Mechanistic profiling of immune oncology drug combinations in cancer patients with CIVO intratumoral micro-dosing and NanoString's GeoMx® Digital Spatial Profiler

With an introduction by Sarah Warren, the Senior Director of Translational Science, this webinar will open by providing a brief technology overview of NanoString Technologies. Dr. Warren will give an overview of the NanoString digital spatial profiling platform, GeoMx® DSP, along with curated gene expression panels that focus on all aspects of the biomarker and drug development continuums. Following the introduction will be speaker Jason Frazier from Presage Biosciences. Despite over four thousand clinical trials designed to investigate combinations of various anti-cancer agents with PD1/PD-L1 targeting checkpoint inhibitors (CPI), few have demonstrated significant clinical improvement over CPI alone.  This suggests the need for far greater mechanistic understanding of tumor cell and microenvironment response to drug exposure to guide development of complex (≥ 3 drug) combination treatments.  Here, we show how an approach based on two technologies, the Presage Comparative In Vivo Oncology (CIVO) Platform and the Nanostring GeoMx Digital Spatial Profiler (GeoMx DSP), can provide information on the activity of drugs in vivo at the cellular level, delineate the cellular targets and mechanisms of action, and provide a path to rapid identification of effective drug combinations, all in the most authentic and relevant context, the human cancer patient. The CIVO platform enables trackable multiplexed intratumoral delivery of spatially restricted micro-dosed drugs, either as single agents or in combinations, allowing simultaneous evaluation of the localized tumor response to multiple different drugs and drug combinations in the native tumor microenvironment (TME).  By combining GeoMx digital spatial profiling with multiplex CIVO micro-dosing in human sarcomas, we evaluated over 1800 gene transcripts per site of drug exposure and measured drug-, cell-, and region-specific transcriptional responses in individual patient tumors.  We showed T-cell specific activation following exposure to localized combination of aldesleukin (recombinant IL-2) and nivolumab (anti-PD1).  Importantly, we show how such events indicating T-cell activation may be dampened by feedback loops involving immune suppressive responses such as elevation of IDO-1 in the non T-cell compartment of the TME. Ultimately, the capability to perform high-plex spatial analysis across multiplex micro-dosed patient tumors will allow us to better understand the mechanism of action of drugs and responses in different compartments of the TME and evaluate the inter-individual variation in the responses to many different IO drugs and drug candidates.

Learning Objectives:

1. Understand some key bulk gene expression tools available for oncology biomarker and drug development research

2. Understand the concept of spatially resolved transcriptomics- Nature’s 2020 Method of the Year

3. Understand how two synergistic platforms were used to profile IO drug combinations in a real world setting at a biotech company