T-cells attacking cancer cells

AML Breakthrough: Can a New Antibody Treatment Conquer Leukemia by Targeting Immune Suppression?

Nico Varela in Health & Wellness August 2025 • 4 min read.

"A novel bispecific antibody shows promise in not only attacking leukemia cells but also dismantling the defenses they use to evade the immune system, potentially revolutionizing AML therapy."

Acute myeloid leukemia (AML) remains a formidable challenge in adult oncology, characterized by aggressive progression and a stubbornly low long-term survival rate of under 30%. Recent studies increasingly highlight the role of immune evasion in AML, suggesting that leukemia cells can cleverly dodge or suppress the body's natural defenses, leading to relapse and treatment failure. This has spurred interest in innovative immunotherapeutic approaches that can restore or enhance anti-leukemic immunity.

Among the key players in this immune evasion are myeloid-derived suppressor cells (MDSCs), a heterogeneous population of immune cells that share the ability to suppress T-cell responses. MDSCs accumulate in AML patients and create an environment that shields leukemia cells from immune attack, hindering the effectiveness of conventional therapies. Therefore, strategies to eliminate or neutralize MDSCs are gaining traction as a means to boost anti-leukemic immunity.

Now, researchers are exploring a promising approach using a bispecific antibody called AMG 330, which is designed to simultaneously target CD33, a protein expressed on both AML cells and MDSCs, and CD3, a protein on T cells. By bringing these cells together, AMG 330 aims to redirect T cells to eliminate both leukemia cells and immune-suppressing MDSCs, potentially offering a powerful two-pronged attack against AML.

Unveiling the Dual Action of AMG 330: A Novel Approach to AML Therapy

The groundbreaking research published in the Journal for ImmunoTherapy of Cancer sheds light on the potential of AMG 330 to overcome immune suppression in AML. The study reveals that AMG 330 not only targets and eliminates CD33-expressing AML cells but also effectively engages T cells to eradicate CD33+ MDSCs. This dual action is particularly significant because MDSCs are known to dampen the immune response and protect leukemia cells from destruction.

The researchers found that AML cells induce the formation of a specific type of MDSC characterized by low HLA-DR expression (HLA-DRlo). These HLA-DRlo MDSCs suppress T-cell activity and express indoleamine-2,3-dioxygenase (IDO), an enzyme that further inhibits T-cell function. Importantly, the study demonstrated that AMG 330 can effectively redirect T cells to eliminate these IDO+ MDSCs, restoring T-cell responsiveness and enhancing anti-leukemic immunity.

Increased Frequencies of MDSCs in AML: The study confirms that patients with newly diagnosed AML have higher levels of CD14+ monocytic MDSCs that co-express CD33 but lack HLA-DR (HLA-DRlo).
AML-Blasts Induce HLA-DRlo Cells: AML-blasts can induce HLA-DRlo cells from healthy donor-derived monocytes in vitro, which suppress T-cells and express indoleamine-2,3-dioxygenase (IDO).
T-Cells Eliminate IDO+CD33+ MDSCs: T-cells eliminate IDO+CD33+ MDSCs in the presence of AMG 330.
IDO Inhibition Promotes AML-Blast Clearance: IDO inhibition promotes AMG 330-mediated clearance of AML-blasts.

Further experiments revealed that depleting all CD14+ cells, including MDSCs, in AML patient samples did not enhance AMG 330-triggered T-cell activation and expansion but boosted AML-blast lysis. This suggests that MDSCs, while suppressing T-cell activity, also compete with AML cells for T-cell engagement. Adding MDSCs to co-cultures of T- and AML-cells reduced AML-blast killing, further highlighting their protective role. However, inhibiting IDO, an enzyme produced by MDSCs, promoted AMG 330-mediated clearance of AML-blasts, underscoring the importance of targeting MDSC-mediated immune suppression.

Future Directions: MDSCs as Predictors of Treatment Response

These findings suggest that AMG 330 may achieve anti-leukemic efficacy not only through T-cell-mediated cytotoxicity against AML-blasts but also against CD33+ MDSCs. The research team proposes exploring the predictive role of MDSCs for responsiveness towards an AMG 330-based therapy. By identifying patients with specific MDSC profiles, clinicians may be able to better tailor treatment strategies and improve outcomes in AML.

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Everything You Need To Know

What is the primary challenge in treating Acute Myeloid Leukemia (AML), and how does the bispecific antibody AMG 330 address it?

The primary challenge in treating AML is the aggressive nature of the disease and its low long-term survival rates. This is compounded by immune evasion, where leukemia cells avoid the body's immune defenses, leading to treatment failure and relapse. AMG 330 tackles this by being a bispecific antibody that targets both AML cells and immune-suppressing cells, specifically myeloid-derived suppressor cells (MDSCs). By redirecting T cells, it aims to eliminate both the cancer cells and the cells that protect them, offering a dual-action approach to improve outcomes.

How does AMG 330 work at a cellular level to combat Acute Myeloid Leukemia (AML), and what is the significance of targeting myeloid-derived suppressor cells (MDSCs)?

AMG 330 is designed to simultaneously target CD33, a protein found on both AML cells and MDSCs, and CD3, a protein on T cells. By bringing these cells together, it enables T cells to eliminate the AML cells and the MDSCs. MDSCs are significant because they accumulate in AML patients and suppress T-cell responses, creating an environment where leukemia cells are shielded from immune attacks. By eliminating or neutralizing MDSCs, AMG 330 aims to restore T-cell responsiveness and enhance anti-leukemic immunity, thereby increasing the effectiveness of treatment.

What role do HLA-DRlo MDSCs and IDO play in the context of AMG 330 treatment for AML, and why are they important?

HLA-DRlo MDSCs are a specific type of MDSC found in AML patients. They are characterized by low expression of HLA-DR and the ability to suppress T-cell activity. These cells also express indoleamine-2,3-dioxygenase (IDO), an enzyme that further inhibits T-cell function. The study demonstrated that AMG 330 can redirect T cells to eliminate these IDO+ MDSCs, restoring T-cell responsiveness and enhancing anti-leukemic immunity. IDO inhibition has also been shown to promote AMG 330-mediated clearance of AML-blasts, underscoring the importance of targeting MDSC-mediated immune suppression to boost treatment efficacy.

Besides attacking leukemia cells, what other therapeutic effects does AMG 330 demonstrate in the treatment of AML, and how is this achieved?

AMG 330 not only targets and eliminates CD33-expressing AML cells but also engages T cells to eradicate CD33+ MDSCs. The research showed that AMG 330 can effectively redirect T cells to eliminate IDO+ MDSCs. Depleting all CD14+ cells, including MDSCs, in AML patient samples did not enhance AMG 330-triggered T-cell activation and expansion but boosted AML-blast lysis. This is because MDSCs also compete with AML cells for T-cell engagement, and inhibiting IDO, an enzyme produced by MDSCs, promoted AMG 330-mediated clearance of AML-blasts.

How might the presence and characteristics of myeloid-derived suppressor cells (MDSCs) influence future treatment strategies for Acute Myeloid Leukemia (AML) using AMG 330?

The research suggests that MDSCs may serve as predictors of treatment response to AMG 330-based therapy. By identifying patients with specific MDSC profiles, clinicians may be able to tailor treatment strategies and improve outcomes in AML. The study found that patients with newly diagnosed AML have higher levels of CD14+ monocytic MDSCs that co-express CD33 but lack HLA-DR (HLA-DRlo). Future directions will likely explore the relationship between specific MDSC characteristics, such as the expression levels of IDO, and the efficacy of AMG 330, potentially leading to personalized treatment approaches based on individual patient's immune profiles.