Triple Combination Targeting Methyltransferase, BCL-2, and PD-1 Facilitates Antileukemia Responses in Acute Myeloid Leukemia

Authors

Zhihong Zeng
Abhishek Maiti
Shelley Herbrich
Tianyu Cai
Antonio Cavazos
Taylor Manzella
Helen Ma
Kala Hayes
Jairo Matthews
Courtney D DiNardo
Naval G Daver
Marina Y Konopleva

Publication Date

2-15-2023

Journal

Cancer

Abstract

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.

Keywords

Humans, Aged, Methyltransferases, Programmed Cell Death 1 Receptor, Antineoplastic Agents, Leukemia, Myeloid, Acute, DNA Modification Methylases, Proto-Oncogene Proteins c-bcl-2, DNA, Antineoplastic Combined Chemotherapy Protocols, BCL-2, T-cell immunity, acute myeloid leukemia therapy, co-targeting methyltransferase, immunomodulation, programmed cell death protein 1 (PD-1), programmed cell death protein 1

DOI

10.1002/cncr.34566

PMID

36477735

PMCID

PMC11884106

PubMedCentral® Posted Date

3-6-2025

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes