Medical XpressFailure in a CAR T-Cell Trial Could Unlock Multiple Treatments for Acute Myeloid Leukemia

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A recent study published in Nature Medicine investigates the use of anti-CD123 CAR T-cell therapy in treating adults with relapsed or refractory acute myeloid leukemia (AML). Although the therapy showed promise, researchers encountered significant challenges, particularly with cytokine release syndrome and low clinical response rates. The findings suggest that combining CAR T-cell therapies with cytokine signaling inhibitors may improve treatment outcomes for AML patients.

Key Points:

• Researchers at the University of Pennsylvania conducted a clinical trial using patient-derived anti-CD123 CAR T-cells to treat adults with relapsed or refractory AML.
• The study enrolled 22 patients, with 20 confirmed eligible. The median age of participants was 60 years.
• Manufacturing of CART-123 cells was successful in 90.4% of attempts, achieving a median T cell purity of 98.5%.
• Of the six patients evaluated for response, two achieved molecular complete responses, one achieved measurable residual disease complete response with incomplete hematologic recovery, and three had stable or progressive disease.
• Cytokine release syndrome (CRS) occurred in 83% of patients, with severe cases leading to dose-limiting toxicity and death in two individuals.
• Analysis revealed that myeloid-supporting cytokines promoted AML blast survival via kinase signaling, reducing AML cell susceptibility to CART-123.
• Blocking the JAK/STAT signaling pathway with ruxolitinib restored the sensitivity of AML cells to CART-123, suggesting potential for combination therapies.

“Our study, thus, illuminates a blind spot in previous AML-directed immunotherapy studies and provides strong rationale for combination therapies involving CAR T cells and signaling blockade in the context of myeloid cancers”

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