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

Publisher: Taylor & Francis Country of Publication: United States NLM ID: 9007422 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1029-2403 (Electronic) Linking ISSN: 10268022 NLM ISO Abbreviation: Leuk Lymphoma Subsets: MEDLINE

Publication: [Philadelphia, PA] : Taylor & Francis
Original Publication: Chur ; New York : London, UK : Harwood Academic Publishers ; Distributed by STBS, 1989-

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

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.

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P30 CA016672 United States CA NCI NIH HHS; P50 CA100632 United States CA NCI NIH HHS

Keywords: Checkpoint inhibitors; acute myeloid leukemia; immunotherapy; myelodysplastic syndrome

0 (Antineoplastic Agents, Immunological)
0 (Costimulatory and Inhibitory T-Cell Receptors)

Date Created: 20170707 Date Completed: 20190125 Latest Revision: 20190401

20240104

PMC5872841

10.1080/10428194.2017.1344905

28679300