Engineering Against the Odds: A New Antibody's Battle with Leukemia

Scientists at City of Hope have developed a new therapy targeting hard-to-kill leukemia stem cells, offering hope for more effective treatment of acute myeloid leukemia
Health & Medicine
February 26, 2024

In a groundbreaking development at City of Hope, one of America's foremost cancer research and treatment institutions, scientists are redefining the battle against acute myeloid leukemia (AML). Their innovative strategy, published in the journal Blood, targets the formidable leukemia stem cells, often the culprits behind treatment relapse and drug resistance in AML patients.

Overcoming Obstacles in AML Therapy

AML, a daunting adversary in cancer treatment, has long evaded effective treatment due to its resistance to conventional therapies. The only known cure, stem cell transplants, is not viable for many patients, especially the elderly or those with severe illness. Enter the novel approach of the City of Hope team, which leverages Type II interferon (IFNγ), a naturally occurring substance in immune cells. While IFNγ disrupts leukemia stem cells' replication, it also activates CD38, a protein that inadvertently suppresses the immune response against infections.

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, City of Hope 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. [John Williams, Ph.D., Lab / City of Hope]

In a stroke of genius, the researchers developed an antibody, dubbed CD38-BIONIC, that acts as a bridge, connecting T cells to leukemia stem cells marked by CD38. This enables the immune system to effectively target and destroy these cancer cells. Remarkably, this method spares healthy early blood stem cells and immune cells in both human tissue and AML mouse models, offering a beacon of hope for a less toxic treatment option. Findings from the new study were published recently in Blood.

A Paradigm Shift in Leukemia Stem Cell Targeting

The crux of this breakthrough lies in the understanding of leukemia's behavior. Leukemia invades the bone marrow, producing abnormal early blood cells or blasts, which are CD38-positive and rapidly dividing, making them easy targets. However, the real challenge lies in CD38-negative leukemia stem cells, known for their stubborn resistance to treatment.

Dr. Flavia Pichiorri, alongside Dr. John Williams and Dr. Guido Marcucci, spearheaded this research at City of Hope. “CD38 has successfully been exploited as a therapeutic target in multiple myeloma and other forms of leukemia,” Pichiorri notes. However, she points out that AML stem cells, being mainly CD38-negative, have been overlooked in CD38-targeted therapies.

BN-CD38 eradicates acute myeloid leukemia (AML) by inducing the expression of its own therapeutic target and by expanding and redirecting autologous T-cells against AML blasts and leukemia stem cells. [Flavia Pichiorri, Ph.D., M.S., Lab / City of Hope]

CD38-BIONIC changes the game. It binds to CD38-positive blasts, stimulating T cells to release IFNγ. This, in turn, converts the CD38-negative immature leukemia stem cells to CD38-positive, unveiling them to therapeutic attacks. Williams elaborates, “The compact format of BIONIC leads to an efficient immune system connection point with the CD38-positive blast, which drives IFNγ production.” This results in the leukemia stem cells revealing themselves, coated in CD38, and vulnerable to targeted treatment.

Marcucci adds a note of cautious optimism, emphasizing the need for further research to transition this preclinical study into human treatment. The ultimate aim, as he puts it, is to “eliminate otherwise dormant leukemia stem cells,” potentially reducing or even eradicating the risk of disease relapse in AML patients.

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