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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.

Simple Summary: The introduction of immunotherapy into the treatment options for Hodgkin's lymphoma has improved survival in patients with recurrence of their cancer. These agents help the body's immune system respond and clear cancer cells. Currently, these agents are only approved in patients who have had their cancer return multiple times or have progressed through multiple therapies. However, the evaluation of these agents as part of therapy in the upfront setting or second line setting has been conducted. This study will review these clinical studies and provide insights into the future directions of immunotherapy use by physicians in treatment of patients with Hodgkin's lymphoma. Classical Hodgkin's lymphoma is a highly curable disease, but 10–25% of patients with higher-risk disease relapse. The introduction of checkpoint inhibitors (CPIs) targeting PD-1 have changed the landscape of treatment for patients with relapsed/refractory disease to multiple lines of therapy. The depth of response to CPI as a monotherapy is highest in the first relapse as salvage therapy based on outcomes reported in several phase II studies. With earlier use of CPI and brentuximab vedotin, the optimal sequencing of therapy is evolving. In this review, we will summarize clinical investigation of anti-PD-1 mAb in earlier line settings to provide insights on utilizing these agents as chemotherapy- and radiation-sparing approaches, increasing depth of response, and as part of combination regimens. [ABSTRACT FROM AUTHOR]