Addressing Recent Failures in Immuno-Oncology Trials to Guide Novel Immunotherapeutic Treatment Strategies

The incorporation of checkpoint inhibitors into the treatment armamentarium of oncologic therapeutics has revolutionized the course of disease in many cancers. This has spurred the evaluation of other novel immunotherapy agents in clinical trials with varying levels of success. This review explores possible explanations for differences in efficacy in clinical outcomes among currently US FDA-approved immunotherapy agents, lessons learned from clinical trial failures of investigational immunotherapies, and methods to improve success in the future. An inherent challenge of early phase immunotherapy trials is identifying the maximum tolerated dose and improving understanding of the pharmacokinetics/pharmacodynamics of immunotherapies as they exert their effects indirectly via T cells rather than directly via dose-dependent cytotoxic activity. The wide heterogeneity of the immune system among patients and within an individual patient over time largely affects the results of optimal dose- and toxicity-finding studies as well as the effectiveness of immunotherapy. Therefore, optimization of phase I/II study design is crucial for clinical trial success. These differences may also help elucidate the lack of immunotherapy benefit in certain disease subtypes despite the presence of specific biomarkers. Broader investigation of the tumor microenvironment and its dynamic nature can help in the identification of alternative pathways for targeted therapies, mechanisms of immunotherapy resistance, and more correlative biomarkers. Finally, manipulation of the tumor microenvironment via a single agonist or antagonist may be inadequate, so combination therapies and sequencing of agents must be further assessed while balancing cumulative toxicity risk.