Triple combination targeting methyltransferase, BCL‐2, and PD‐1 facilitates antileukemia responses in acute myeloid leukemia

• Published in: Cancer Vol. 129; no. 4; pp. 531 - 540
• Main Authors: Zeng, Zhihong, Maiti, Abhishek, Herbrich, Shelley, Cai, Tianyu, Cavazos, Antonio, Manzella, Taylor, Ma, Helen, Hayes, Kala, Matthews, Jairo, DiNardo, Courtney D., Daver, Naval G., Konopleva, Marina Y.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 15.02.2023
• Subjects: 5-aza-2'-deoxycytidine; Acute myeloid leukemia; acute myeloid leukemia therapy; Aged; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Apoptosis; BCL‐2; CD4 antigen; CD8 antigen; Cell death; Clinical trials; co‐targeting methyltransferase; DNA - therapeutic use; DNA methyltransferase; DNA Modification Methylases; Flow cytometry; Humans; Immune checkpoint; Immunological memory; Immunomodulation; Inhibitors; Leukemia; Leukemia, Myeloid, Acute; Lymphocytes; Lymphocytes T; Memory cells; Methyltransferases; Oncology; PD-1 protein; Progenitor cells; Programmed Cell Death 1 Receptor - therapeutic use; programmed cell death protein 1 (PD‐1); programmed cell death protein 1 inhibition; Proto-Oncogene Proteins c-bcl-2 - genetics; Stem cells; Therapy; T‐cell immunity; acute myeloid leukemia therapy; BCL-2; immunomodulation; T-cell immunity; programmed cell death protein 1 inhibition; co-targeting methyltransferase; programmed cell death protein 1 (PD-1)
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.34566

Background A recent breakthrough therapy combining the BCL‐2 inhibitor venetoclax with hypomethylating agents (HMAs) targeting DNA methyltransferase has improved outcomes for patients with acute myeloid leukemia (AML), but the responses and long‐term survival in older/unfit patients and in patients with relapsed/refractory AML remain suboptimal. Recent studies showed that inhibition of BCL‐2 or DNA methyltransferase modulates AML T‐cell immunity. Methods By using flow cytometry and time‐of‐flight mass cytometry, the authors examined the effects of the HMA decitabine combined with the BCL‐2 inhibitor venetoclax (DAC/VEN therapy) on leukemia cells and T cells in patients with AML who received DAC/VEN therapy in a clinical trial. The authors investigated the response of programmed cell death protein 1 (PD‐1) inhibition in the DAC/VEN–treated samples in vitro and investigated the triple combination of PD‐1 inhibition with HMA/venetoclax in the trial patients who had AML. Results DAC/VEN therapy effectively targeted leukemia cells and upregulated the expression of the immune checkpoint‐inhibitory receptor PD‐1 in T cells while preserving CD4‐positive and CD8‐positive memory T cells in a subset of patients with AML who were tested. In vitro PD‐1 inhibition potentiated the antileukemia response in DAC/VEN–treated AML samples. The combined use of azacitidine, venetoclax, and nivolumab eliminated circulating blasts and leukemia stem cells/progenitor cells and expanded the percentage of CD8‐positive memory T cells in an illustrative patient with relapsed AML who responded to the regimen in an ongoing clinical trial. Conclusions Immunomodulation by targeting PD‐1 enhances the therapeutic effect of combining an HMA and venetoclax in patients with AML. Combining a hypomethylating agent with venetoclax modulates acute myeloid leukemia T‐cell immunity. Co‐targeting programmed cell death protein 1 enhances antileukemia efficacy.