January 4, 2024

Potential AML therapy induces leukemic stem cell death

Vanderbilt researchers are studying a potential therapy for acute myeloid leukemia that targets the residual leukemic stem cells in bone marrow after treatment that are responsible for relapses and drug resistance.

A potential therapy for acute myeloid leukemia (AML) targets the residual leukemic stem cells in bone marrow after treatment that are responsible for relapses and drug resistance.

The potential therapy, NC525, is an agonist antibody to the leukocyte-associated immunoglobulin-like receptors (LAIR-1), which have abnormally elevated expression on leukemic cells. NC525 induced death of leukemic stem cells — but not healthy stem cells — while also killing AML blasts in a mouse model study with patient-derived xenografts. The findings by Vanderbilt researchers were published Nov. 15, 2023, in The Journal of Clinical Investigation.

Tae Kon Kim, MD, PhD

“I really hope this can be a game changer,” said Tae Kon Kim, MD, PhD, assistant professor of Medicine, one of the study’s senior authors.

Although AML survival rate has improved significantly over the past 20 years, new therapies are needed because it remains a deadly cancer. AML has a five-year survival rate of 31.7%, according to the National Cancer Institute’s Surveillance, Epidemiology, and End Results program.

The cancer is most prevalent among people between 65 and 74, an age group with patients who may not tolerate intensive treatments, such as stem cell transplants. In 2018, the Food and Drug Administration granted accelerated approval for venetoclax in combination with existing standard of care medications for people 75 and older or who have comorbidities that preclude the use of intensive induction chemotherapies. However, the majority of patients who initially respond to the combination develop resistance within 18 months, and one-third of newly diagnosed patients fail to achieve complete remission, according to a 2020 study published in The New England Journal of Medicine.

Failure of venetoclax in combination with the hypomethylating agents, azacytidine and decitabine, results in highly aggressive refractory AML with a median overall survival of just 2.4 months, according to data published 2021 in Haematologica. Importantly, NC525 kills AML cells that are resistant to the venetoclax combination.

“LAIR1 agonistic antibody, NC525 killed leukemia cells resistant to venetoclax/hypomethylating agents in patient-derived xenografts. We hope this could be one of the most effective salvage therapies in relapsed/refractory AML patients,” Kim said.

NC525 could be a possible therapy for AML in conjunction with a venetoclax combination or as a stand-alone treatment for patients who can’t tolerate the venetoclax combination, the researchers said in the study.

“VEN-based (venetoclax) therapies, like currently available and experimental therapies, are associated with significant severe cytopenias that drive serious and fatal complications, such as neutropenic fever, sepsis, fungal infections and bleeding,” the study stated. “This study shows that NC525 may provide an effective therapeutic intervention in AML with minimal effects on healthy hematopoietic cells or leukocytes. Therapeutically, the effective removal of LSCs (leukemic stem cells) and leukemia-initiating cells may prevent relapses that are extremely common with currently available AML therapies.”

A phase 1 clinical study for patients with relapsed or refractory AML began in February 2023 to determine the safety and tolerability of NC525 that will also assess the clinical benefit in participants with advanced myeloid neoplasms.

The other senior author of the NC525 study published in The Journal of Clinical Investigation is Dallas Flies, PhD. The co-first authors are Rustin Lovewell, PhD, and Junshik Hong MD, PhD. Vanderbilt authors who contributed to the study are Carly Fiedler, MS, Qianni Hu, PhD, Kwang Woon Kim, PhD, Haley Ramsey, PhD, Agnleszka Gorska, MSc, Londa Fuller, Emily Mason, MD, PhD, and Michael Savona, MD.

This work was supported by a grant from the Edward P. Evans Foundation, a Conquer Cancer Foundation of ASCO Career Development Grant (CSDG-18-198-01), an Institutional Research Grant (19-139-59) from the American Cancer Society, the Vanderbilt Center for Immunobiology, Vanderbilt-Ingram Cancer Center, a Cancer Center Support Grant (P30CA068485), Translational Pathology Shared Resource (P30CA068485), Shared Instrumentation Grant (S10 OD023475-O1A1), and the Cooperative Center of Excellence in Hematology (U54DK106829).