Status of Immune Oncology: Challenges and Opportunities

Abstract

This volume is intended to review the methods used to identify biomarkers predictive of cancer responsiveness to immunotherapy. The successful development of clinically actionable biomarkers depends upon three features: (a) their biological role with respect to malignant transformation and tumor progression; (b) the ability to detect them with robust, reliable, and clinically applicable assays; and (c) their prognostic or predictive value, as validated in clinical trials.Identifying biomarkers that have predictive value for patient selection based on the likelihood of benefiting from anticancer immunotherapy is a lengthy and complex process. To date, few predictive biomarkers for anticancer immunotherapy have been robustly analytically and clinically validated (i.e., PD-L1 expression as measured by IHC assays and microsatellite instability (MSI)/dMMR as measured by PCR or IHC, respectively).This introductory chapter to this book focuses on scientific and technical aspects relevant to the identification and validation of predictive biomarkers for immunotherapy. We emphasize that methods should address both the biology of the tumor and the tumor microenvironment. Moreover, the identification of biomarkers requires highly sensitive, multiplexed, comprehensive techniques, especially for application in clinical care. Thus, in this chapter, we will define the outstanding questions related to the immune biology of cancer as a base for development of the biomarkers and assays using diverse methodologies. These biomarkers will likely be identified through research that integrates conventional immunological approaches along with high-throughput genomic and proteomic screening and the host immune response of individual patients that relates to individual tumor biology and immune drugs' mechanism of action.Checkpoint inhibitor therapy (CIT) is by now an accepted modality of cancer treatment. However, immune resistance is common, and most patients do not benefit from the treatment. The reasons for resistance are diverse, and approaches to circumvent it need to consider genetic, biologic, and environmental factors that affect anticancer immune response. Here, we propose to systematically address fundamental concepts based on the premise that malignant cells orchestrate their surroundings by interacting with innate and adaptive immune sensors. This principle applies to most cancers and governs their evolution in the immune-competent host. Understanding the basic requirement(s) for this evolutionary process will guide biomarker discovery and validation and ultimately guide to effective therapeutic choices. This volume will also discuss novel biomarker approaches aimed at informing an effective assay development from a mechanistic point of view, as well as the clinical implementation (i.e., patient enrichment) for immune therapies.

Keywords: Cancer immune resistance; Checkpoint inhibitors; Predictive biomarkers.