Development of a Novel Plasma Based Microsatellite Instability Diagnostic for Guiding Immunotherapy

Abstract Immune checkpoint inhibitors have recently emerged as a revolution in cancer care providing the potential for durable response and improved survival for numerous cancer patients across multiple cancer types However only of patients who are treated with checkpoint inhibitors have responded in most cancer types necessitating biomarker assays that can reliably and accurately identify those patients likely to respond Recent compelling evidence supports the clinical utility of microsatellite instability MSI as a predictive marker of immunotherapy response reaching overall survival rates of andgt versus in microsatellite stable MSS tumors MSI high tumors are histopathologically distinct from their MSS counterparts displaying a marked influx of tumor infiltrating lymphocytes and express high levels of immune checkpoint inhibitors including PD This unique immune microenvironment supports the hypothesis that MSI high tumors more susceptible to immunotherapies and has been proposed as a biomarker for stratifying patient populations Supporting this notion The FDA just granted priority review for a supplemental application of Keytruda a PD inhibitor in previously treated MSI H tumors on the basis of open label Phase I II trials across multiple tumor types Current MSI screening is conducted on tumor biopsies using variable non standardized PCR based and IHC laboratory developed tests LDTs creating the need for a standardized accurate non invasive assay that may be decentralized to inform the clinical management of patients for treatment with immunotherapies Cell free tumor specific genetic alterations or circulating tumor DNA ctDNA are detectable in the plasma of of cancer patients with metastatic disease Reliable detection of tumor specific alterations in plasma can aid in the stratification of patients for targeted therapies and overcome the need for tumor tissue by traditional molecular approaches The goal of this proposal is to develop a stand alone molecular diagnostic assay to determine MSI status from plasma in cancer patients known as CancerPRO MSI to guide immunotherapy for multiple indications Relevance of Research to Public Health The recent advances in the field of immunotherapy are considered breakthrough treatment approaches for a variety of different cancers However predicting the efficacy of such therapies including immune checkpoint inhibitors remains ambiguous in certain patient populations Clinical studies have demonstrated the significant influence of microsatellite instability MSI status of tumors on the clinical benefit of an immune checkpoint inhibitor anti PD where the response to treatment in patients regardless of cancer type with and without MSI is vs respectively Because the clinical evidence supporting MSI as a highly predictive pan cancer biomarker for response to checkpoint inhibitors is rapidly accumulating there is an urgent need for molecular tests that can identify patients with MSI tumors across cancer types in an accurate fast cost effective manner This research proposes to develop a novel stand alone molecular diagnostic assay to determine MSI status from plasma in cancer patients known as CancerPRO MSI to guide immunotherapy for multiple indications