Programming the immune checkpoint to treat hematologic malignancies

ABSTRACT

Introduction: Hematologic malignancies manipulate the immune suppressive pathways involving CTLA-4, PD-1, and others to promote immune tolerance of cancer. New monoclonal antibodies targeting immune checkpoints are showing meaningful responses in the treatment of relapsed and refractory Hodgkin lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, and chronic lymphocytic leukemia. The basis for success of anti-PD-1 therapy appears to be expression of PD-L1 on tumor cells and cells of the tumor microenvironment (TME). While adverse events associated with immune checkpoint inhibitors are capable of generating auto-immune phenomena, in general these therapies are well tolerated.

Areas covered: In this review, the authors discuss the development of immune checkpoint inhibitors and activators which hold promise as useful therapies in malignancies of hematologic origin, since many exploit endogenous pathways to induce tolerance. By programming the immune response to attack hematologic malignancies, unique regimens can be developed to optimally treat patients with curative potential.

Expert opinion: The utilization of immune checkpoint targeting agents to boost the innate and acquired immune systems to eradicate human malignancies represents a unique opportunity to develop novel therapies with increased clinical efficacy. Side effects of these therapies come with the price of auto-immune phenomena that require appropriate management.

KEYWORDS:

• Hematologic malignancy
• immune checkpoint inhibitors and activators
• PD-1
• PD-L1
• CTLA-4
• leukemia
• lymphoma
• myelodysplastic syndromes
• multiple myeloma
• immune related adverse events

Article highlights

• Immune checkpoint therapies represent a novel and continually growing list of anti-cancer therapies. Their success in targeting advanced solid tumors have recently stoked enthusiasm in the treatment of hematologic malignancies.

• Immune checkpoint inhibitors and activators represents a central axis of immunotherapy with investigational trials evaluating the safety and efficacy guided by novel biologic insights for lymphoma and leukemia.

• Blockade of PD-1 in Hodgkin lymphoma represents a major step forward for treatment of refractory cases, however results are promising with follicular lymphoma, certain subtypes of diffuse large B-cell lymphoma and Richter’s syndrome.

• Immune checkpoint modulators are overall well tolerated but may lead to a variety of autoimmune phenomena that require careful monitoring and treatment to prevent serious adverse events.

• Future analysis will likely demonstrate broad clinical utility for these agents, while others will be tumor specific, requiring pre-treatment screening for meaningful outcomes in patient care.

• Predictive biomarkers to immune checkpoint therapies and combination therapies including chemotherapy, radiation therapy (‘Abscopal’ effect) and targeted approaches has the potential to revolutionize therapies for hematologic malignancies.

This box summarizes key points contained in the article.

Declaration of interest

The authors are supported by the South West Oncology Group (SWOG). D Mahadevan is also the recipient of a Hope Foundation Impact Award (2016-2018) while E Vick is the recipient of a University of Tennessee Health Sciences Centre Medical Student Research Award. 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.