Solving the puzzle of what makes immunotherapies work

Abstract

The rapid adoption of immune checkpoint blockade (ICB) therapies has led to a need to understand the mechanistic drivers of efficacy and the identification of novel biomarkers that enrich for patients who benefit from ICB therapy. Here, we provide a perspective on emerging biomarker candidates, their underlying biological mechanisms, and how they may fit into the current landscape of ICB biomarkers. We discuss new frameworks to identify and evaluate biomarker candidates and review the opportunities and challenges of utilizing biomarker-derived models to facilitate the development of new immunotherapies.

Keywords: biomarker; immune checkpoint blockade; immunotherapy; tumor immunology.

Figure 1.. Individual investigation without broad vision leads to suboptimal understanding.

When there is insufficiently broad examination of an entity or a process, or a failure to integrate data that leads to a complete picture, flawed interpretations can result. (A) Blindfolded observers examining only single parts of an elephant can develop incomplete (and wrong) impressions of the nature of the elephant. (B) Blindfolded scientists examining the process of anti-tumor immunity may develop biomarkers that fail to capture the entirety of the process. Single biomarkers may not be sufficient for complex processes such as anti-tumor immunity. Instead, successful integration of information from diverse viewpoints can lead to a better interpretation and understanding of anti-tumor immunity. Abbreviations: DC, dendritic cell; NK, natural killer.

Figure 2.. Framework for biomarker selection, model building, feedback, and improvement.

Biomarkers are analyzed in a multivariable network model to determine which ones can provide non-redundant information. Then, the candidate factors are used to build deep learning models with additional optimization of the prediction power. Factors used need to be cost effective and clinically feasible. The result can be adapted for us as nomograms or weighted scores based on the most important variables.