Emerging immunotherapies in the Hodgkin lymphoma armamentarium

ABSTRACT

Introduction

Brentuximab vedotin and PD-1 inhibitors have improved outcomes for classic Hodgkin lymphoma (cHL), but better therapies are needed for patients who relapse after these agents. Based on an improved understanding of cHL biology, there is a robust pipeline of novel therapies in development. In this review, we highlight emerging immunotherapeutic agents and combinations for cHL.

Areas covered

We review clinical trials of novel PD-1/PD-L1 inhibitors beyond FDA-approved agents, checkpoint inhibitors targeting CTLA-4, LAG-3, TIM-3, TIGIT, and CD47/SIRPα, PD-1 inhibitor combinations with immunomodulatory agents and epigenetic modifying therapies, antibody-drug conjugates, bispecific antibodies, and cellular therapies including anti-CD30 CAR-T and allogeneic NK cell therapy. We review the key safety and efficacy data from published phase 1–2 studies and highlight trials in progress, including the first phase 3 trial for PD-1 inhibitor-refractory cHL.

Expert opinion

Many novel immunotherapies hold great promise in cHL. Rational combinations with existing agents and next-generation antibody and CAR-T constructs may improve response rates and durability. Identifying biomarkers of response to these immunotherapies and using more sensitive tools to assess response, such as circulating tumor DNA, may further inform treatment decisions and enable a precision medicine approach in the future.

KEYWORDS:

• Hodgkin lymphoma
• immunotherapy
• checkpoint inhibitor
• antibody–drug conjugate
• bispecific antibody
• chimeric antigen receptor T-cell therapy

Article highlights

• Hodgkin and Reed-Sternberg cells evade the immune system through multiple mechanisms including overexpression of PD-1 ligands, loss of MHC class I/II, and an immunosuppressive tumor microenvironment.

• Brentuximab vedotin and PD-1 inhibitors have improved outcomes for Hodgkin lymphoma, but better therapies are needed for patients who relapse after these agents.

• Ongoing trials are combining PD-1 inhibitors with other checkpoint inhibitors, immunomodulatory agents, or epigenetic modifying therapies to enhance antitumor immune responses.

• There is a robust pipeline of novel immunotherapies in development including antibody-drug conjugates, bispecific antibodies, and cellular therapies.

• Innate immune effectors including macrophages and natural killer cells can be recruited, activated, or engineered to target Hodgkin and Reed-Sternberg cells.

• Identifying biomarkers of response and incorporating ultrasensitive tools for response assessment, such as circulating tumor DNA, may further inform treatment decisions in the future.

List of abbreviations

Table

Declaration of interests

M.A. Spinner has done consulting for Gilead and served on an advisory board for ADC Therapeutics. R. H. Advani has received research funding from Gilead, Merck, Seattle Genetics, Bristol Myers Squibb, ADC Therapeutics, Millennium, Beigene, Roche/Genentech, and served on an advisory board for Merck, Roche/Genentech, ADC Therapeutics, Daiichi Sanyo, and Beigene. 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.

Reviewer disclosures

Peer reviewers in this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.