Novel strategy to seek and destroy leukemia stem cells

Discovery using lab and animal models could provide an alternative for older, sicker patients who do not qualify for stem cell transplants.

Scientists at City of Hope, one of the largest cancer research and treatment organizations in the United States, have devised an innovative approach to target and destroy hard-to-kill leukemia stem cells. The journal Blood published the preclinical findings today.

By overcoming challenges, such as drug resistance and treatment relapse common to patients with acute myeloid leukemia (AML), the therapy method could provide a less toxic and more effective approach for older and sicker patients who don’t quality for stem cell transplants — currently the only cure for AML available.

Type II interferon (IFNy), a substance produced by immune cells, disrupts the leukemia stem cells’ ability to divide and spread cancer. However, IFNy also stimulates CD38, a protein that suppresses the immune cells’ ability to mount a response against infection.

To overcome this challenge, the researchers designed a T cell engager antibody called CD38-BIONIC that creates a bridge between the T cells and the leukemia stem cells expressing CD38, enabling the immune system to kill off the cancer cells. Equally important, the approach did not damage healthy early blood stem cells or immune cells in human tissue or AML mouse models.

SIGNIFICANCE
When leukemia invades the bone marrow, it produces abnormal early blood cells called blasts that are CD38-positive. These divide rapidly and are easy to target. In contrast, the leukemia stem cells that form cancer stubbornly resist treatment and are CD38-negative.

“CD38 has successfully been exploited as a therapeutic target in multiple myeloma and other forms of leukemia,” said Flavia Pichiorri, Ph.D., M.S., who co-led the study with fellow investigators John Williams, Ph.D., and Guido Marcucci, M.D. — all professors at City of Hope. “Because AML stem cells are mainly CD38-negative, however, scientists have not prioritized CD38 as a therapeutic target for relapsed acute myeloid leukemia.”

In the current study, CD38-BIONIC binds to the CD38-positive blasts. This triggers the T cells to release IFNy, which converts the immature leukemia stem cells from CD38-negative to CD38-positive. In one stroke, the engineered antibody unmasks all the leukemia cells, exposing them to treatment.

“We believe that the compact format of BIONIC leads to an efficient immune system connection point with the CD38-positive blast, which drives IFNy production,” said Williams. “The leukemia stem cells react to the IFNy, painting themselves with CD38, which in turn allows them to be targeted by the CD38-CD3 BIONIC.”

Marcucci added, “This novel mechanism and the targeting by City of Hope’s homegrown approach will allow us to eliminate otherwise dormant leukemia stem cells. Our hope and goal is that eradication of leukemia stem cells will decrease and even eliminate the risk of disease relapse in patients with AML, but much more research needs to be done to translate our preclinical research into human treatment.”

BACKGROUND
Despite recent Food and Drug Administration-approved therapies, only 30% of adult patients with AML survive five years past diagnosis. More than half of patients relapse after treatment, and treatment resistance remains a major challenge. Patients often must remain hospitalized because their blood and immune systems are compromised by the cancer and its therapies.

While stem cell transplants from a bone marrow donor can prolong life, many older patients do not qualify due to their compromised health or the inability to find a matched donor. The majority of patients with AML urgently need less toxic and more effective treatments.

FUNDING
The research was partly supported by grants from the National Institutes of Health (R01-CA238429, R50-CA252135, P30CA033572), National Cancer Institute, Nason-Hollingsworth Project for Multiple Myeloma project and City of Hope’s Integrated Drug Development Venture program.

DISCLOSURE OF CONFLICT OF INTEREST
Co-authors Mariam Murtadha, Miso Park, Guido Marcucci, John C. Williams and Flavia Pichiorri are among the co-inventors on patent applications that cover certain inventions that are disclosed in this work. City of Hope is working to commercialize the technologies disclosed and claimed in these patent applications.

About City of Hope
City of Hope’s mission is to make hope a reality for all touched by cancer and diabetes. Founded in 1913, City of Hope has grown into one of the largest cancer research and treatment organizations in the U.S. and one of the leading research centers for diabetes and other life-threatening illnesses. City of Hope research has been the basis for numerous breakthrough cancer medicines, as well as human synthetic insulin and monoclonal antibodies. With an independent, National Cancer Institute-designated comprehensive cancer center at its core, City of Hope brings a uniquely integrated model to patients spanning cancer care, research and development, academics and training, and innovation initiatives. City of Hope’s growing national system includes its Los Angeles campus, a network of clinical care locations across Southern California, a new cancer center in Orange County, California, and treatment facilities in Atlanta, Chicago and Phoenix. City of Hope’s affiliated group of organizations includes Translational Genomics Research Institute and AccessHope^TM. For more information about City of Hope, follow us on Facebook, X, YouTube, Instagram and LinkedIn.

Journal: Blood
Method of Research: Experimental study
Subject of Research: Cells
Article Title: CD38-directed, single-chain T cell-engager targets leukemia stem cells through IFNγ-induced CD38 expression
Article Publication Date: 26-Feb-2024
COI Statement: Co-authors Mariam Murtadha, Miso Park, Guido Marcucci, John C. Williams and Flavia Pichiorri are among the co-inventors on patent applications that cover certain inventions that are disclosed in this work. City of Hope is working to commercialize the technologies disclosed and claimed in these patent applications.

Media Contact

Zen Logsdon
City of Hope
zlogsdon@coh.org
Cell: 626-409-9367