Immune checkpoint-based therapy in myeloid malignancies: a promise yet to be fulfilled

ABSTRACT

Introduction: Immune system evasion is essential for tumor cell survival and is mediated by the immunosuppressive tumor microenvironment and the activation of inhibitory immune checkpoints. While immune checkpoint-based therapy yielded impressive results in several advanced solid malignancies such as melanoma and non-small cell lung cancer, its role in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) is still evolving.

Areas covered: Here we review the immunology in the tumor microenvironment in the bone marrow and discuss the current preclinical and clinical data for immune checkpoint-based therapy in myeloid neoplasms.

Expert commentary: Clinical trials of immune checkpoint inhibitors (ICI) in AML and MDS are still in early stages and reported results so far have been modest especially for monotherapy use in the refractory settings. However, there are preliminary data for synergistic effects for combination of multiple ICI with hypomethylating agents and conventional chemotherapy. ICI might also be effective in eradicating minimal residual disease and to prevent relapse following induction chemotherapy or hematopoietic stem cell transplant. Additional trials to provide insight into the efficacy and safety profile of immune checkpoint-based therapy, its optimal timing and potential combination with other types of therapy as well as identification of predictive biomarkers are needed.

KEYWORDS:

• Acute myeloid leukemia
• immune checkpoint blockade
• PD-1
• CTLA-4
• combination therapy
• tumor immunology
• T-cells

Article highlights

• Immune system evasion is essential for tumor cell survival in both solid malignancies and in myeloid neoplasms and is mediated by the activation of inhibitory immune checkpoints such as cytotoxic T-lymphocyte-associated-protein 4 (CTLA-4) and programmed cell-death protein 1 (PD-1), T-cell immunoglobulin mucin-3 (TIM-3), and lymphocyte activation gene-3 (LAG-3).

• Immune checkpoint therapy has the potential to reverse the immune system evasion of myeloid malignancies. While monotherapy with immune checkpoint inhibitors has only yielded modest results, combination with hypomethylating agents, intensive chemotherapy, and multiple immune checkpoint inhibitors as shown promising results.

• Further research to identify predictive biomarkers, optimize timing, combination partners, and treatment settings is warranted.

Declaration of interest

A.M.Z. received research funding (institutional) from Celgene, Acceleron, Abbvie, Otsuka, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Trovagene, Incyte, Takeda, and ADC Therapeutics. A.M.Z had a consultancy with and received honoraria from AbbVie, Otsuka, Pfizer, Celgene, Ariad, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Seattle Genetics, BeyondSpring, and Takeda. None of these relationships were related to the development of this manuscript.

Reviewer disclosures

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

Additional information

Funding

Amer Zeidan is a Leukemia and Lymphoma Society Scholar in Clinical Research and is also supported by a NCI’s Cancer Clinical Investigator Team Leadership Award (CCITLA). Research reported in this publication was in part supported by the National Cancer Institute of the National Institutes of Health under Award Number P30 CA016359. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.