Investigational PD-1 inhibitors in HL and NHL and biomarkers for predictors of response and outcome

ABSTRACT

Introduction: Inhibitors against the PD-1/PD-L1 pathway are revolutionizing the treatment and management of malignancies.

Areas covered: We summarize our current understanding of the function of PD-1, its role in immune evasion, the clinical data available that support the use of PD-1 antagonist in Hodgkin and non-Hodgkin lymphomas, and potential predictors of response.

Expert opinion: We anticipate that in the next 10 years, agents that modulate the immune system such as PD-1 antagonists will be increasingly used in favor over traditional cytotoxic chemotherapeutic agents. PD-1 antagonists will be combined with future immunotherapies or used as adjuncts to cellular therapy to boost tumor-specific immune responses.

KEYWORDS:

• PD-1
• PD-L1
• non-Hodgkin lymphoma
• Hodgkin lymphoma
• immunotherapy
• PD-1 inhibitor

Article highlights

• PD-1 is a surface receptor on T-cells. Binding to its ligands, PD-L1 or PD-L2, leads to a cascade of interactions that dampens the immune response and thus preventing overactivation of the immune system.

• Several lymphomas overexpress PD-1 ligands as a method for immune evasion. These include classical Hodgkin lymphoma, primary mediastinal B-cell lymphoma, T-cell lymphomas, and those associated with infections like EBV. In some cases, overexpression of PD-1 ligands are due to alterations in chromosome 9p24.1, which contains the genetic loci for PD-L1, PD-L2, and Jak2.

• PD-1 inhibitors, pembrolizumab and nivolumab, are FDA-approved for use in many tumors including relapsed classical Hodgkin lymphoma.

• Many studies are underway to assess the role of inhibitors of the PD-1/PD-L1 pathway in the treatment of lymphomas, including some with very promising results.

• We foresee that PD1/PD-L1 inhibitors may be used alongside curative therapies, as immune adjuncts, or as single agents for those who cannot tolerate conventional therapy. They will likely provide alternative options forsalvage therapy in the treatment of relapsed disease.

• Further studies are needed to understand the complexity of immune regulation in the setting of malignancy to optimize outcome and minimize treatment-related adverse events.

This box summarizes key points contained in the article.

Declaration of Interest

C. R. Flowers receives research grants from Celgene and other research funding from Abbvie, Acerta, Gilead, Janssen, Millenium, Infinity, Pharmacyclics, TG Therapeutics and personal fees from Bayer and Celgene outside of the submitted work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the Winship Cancer Institute at Emory University Neil W. and William S. Elkin Fellowship to A. Chang, and the NIH T32 training grant (4T32CA160040-04) for which A. Chang. is an awardee.