# Immune Checkpoint Blockade in Hematological Malignancies: Current Status and Future Directions

## TL;DR

This paper reviews the use of immune checkpoint inhibitors in treating blood cancers, highlighting their effectiveness in certain lymphomas and future research directions.

## Contribution

The paper provides a comprehensive review of immune checkpoint inhibitors in hematological malignancies and suggests future therapeutic strategies.

## Key findings

- Immune checkpoint inhibitors show variable efficacy in different hematological malignancies, with highest effectiveness in classical Hodgkin lymphoma and NK/T-cell lymphomas.
- Combining immune checkpoint inhibitors with chemotherapy and other therapies may improve treatment outcomes.
- Efficacy of immune checkpoint inhibitors remains uncertain in myeloid malignancies and multiple myeloma.

## Abstract

Immune checkpoint inhibitors (ICI) are important options in the treatment of cancers. In hematological malignancies, classical Hodgkin lymphoma, primary mediastinal B-cell lymphoma, NK/T-cell lymphoma, immune-privileged site large B-cell lymphoma, and cutaneous T-cell lymphomas have been shown to be sensitive to ICI in variable proportions. The combination of ICI with conventional chemotherapy and other targeting molecules holds promise in further increasing efficacy and extending the disease spectrum in the management of hematological malignancies.

Immune checkpoint proteins including PD-1, CTLA-4, LAG-3, TIM-3, and TIGIT regulate T-cell functions, which are essential for anti-tumor immunity. Over-expression of these immune checkpoint proteins leads to T-cell exhaustion and a significant impairment of anti-tumor immunity. Rejuvenation of effector T-cell function with immune checkpoint inhibitors (ICI) restores anti-tumor immunity, which translates into clinical efficacy in the frontline and salvage treatment of various hematological malignancies. Efficacy of ICIs is highest in classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, and NK/T-cell lymphomas, and modest in immune-privileged-site lymphomas and cutaneous T-cell lymphoma. However, in myeloid malignancies and multiple myeloma, the efficacy of ICIs remains doubtful. In addition to being used as single agents, ICIs have also been combined with other ICIs; as well as chemotherapy, antibody drug conjugates, and epigenetic agents (histone deacetylase inhibitors and hypomethylating agents). More innovative strategies include the use of ICIs in the context of allogeneic haematopoietic stem cell transplantation and chimeric antigen receptor T-cell therapy. This review synthesizes current evidence for the use of ICI in different haematological malignancies, and highlights future directions toward biomarker-driven, rationally designed therapeutic combinations.