The emerging role of immune checkpoint based approaches in AML and MDS.

Abstract

The development of immune checkpoint inhibitors represents a major breakthrough in the field of cancer therapeutics. Pursuant to their success in melanoma and numerous solid tumor malignancies, these agents are being investigated in hematological malignancies including acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS). Although AML/MDS have traditionally been considered to be less immunogenic than solid tumor malignancies, recent pre-clinical models suggest a therapeutic role for immune checkpoint inhibition in these diseases. CTLA-4 inhibition may be especially effective in treating late post-allogeneic stem cell transplant relapse of AML in patients with limited or no graft versus host disease. Immune checkpoint inhibition, specifically PD-1 inhibition, demonstrated limited single agent efficacy in patients with relapsed AML and with MDS post-hypomethylating therapy. Rationally designed combinations of PD-1 inhibitors with standard anti-leukemic therapy are needed. Hypomethylating agents such as azacitidine, up-regulate PD-1, PD-L1, and PD-L2 in patients with AML/MDS and up-regulation of these genes was associated with the emergence of resistance. The combination of azacitidine and PD-1/PD-L1 inhibition may be a potential mechanism to prevent or overcome resistance to 5-azacitidine. A number of such combinations are being evaluated in clinical trials with early encouraging results. Immune checkpoint inhibition is also an attractive option to improve relapse-free survival or eliminate minimal residual disease post induction and consolidation by enhancing T-cell surveillance in patients with high-risk AML. The ongoing clinical trials with checkpoint inhibitors in AML/MDS will improve our understanding of the immunobiology of these diseases and guide us to the most appropriate application of these agents in the therapy of AML/MDS.

• Authors: Prajwal Boddu, Hagop Kantarjian, Guillermo Garcia-Manero, James Allison, Padmanee Sharma, Naval Daver
• Journal: Leukemia & lymphoma (Leuk Lymphoma) Vol. 59 Issue 4 Pg. 790-802 (04 2018) ISSN: 1029-2403 [Electronic] United States
• PMID: 28679300 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Review)

Chemical References

• Antineoplastic Agents, Immunological
• Costimulatory and Inhibitory T-Cell Receptors

Topics

• Antineoplastic Agents, Immunological (pharmacology, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Clinical Trials as Topic
• Costimulatory and Inhibitory T-Cell Receptors (antagonists & inhibitors, immunology, metabolism)
• DNA Methylation (drug effects)
• Drug Resistance, Neoplasm (immunology)
• Humans
• Leukemia, Myeloid, Acute (drug therapy, immunology, pathology)
• Myelodysplastic Syndromes (drug therapy, immunology, pathology)
• T-Lymphocytes (drug effects, immunology, metabolism)
• Treatment Outcome
• Up-Regulation