Cytokine-mediated CAR T therapy resistance in AML

Area of Science:

• Hematology
• Immunology
• Oncology

Background:

• Acute myeloid leukemia (AML) presents a significant therapeutic challenge, especially in relapsed or refractory cases.
• Chimeric antigen receptor (CAR) T cell therapy has shown remarkable success in B cell malignancies but limited efficacy in AML.

Purpose of the Study:

• To evaluate the feasibility and efficacy of autologous anti-CD123 CAR T cell therapy in adults with relapsed or refractory AML.
• To investigate resistance mechanisms limiting CAR T cell therapy effectiveness in AML.

Main Methods:

• A pilot study involving 12 adults with relapsed or refractory AML treated with autologous anti-CD123 CAR T cells.
• Manufacturing success rates, cytokine release syndrome incidence, and clinical response were assessed.
• Mechanisms of resistance, including cytokine-mediated AML blast survival and CAR T cell exhaustion, were analyzed.

Main Results:

• Successful CAR T cell manufacturing was achieved in 90.4% of runs.
• Cytokine release syndrome occurred in 83.3% of patients, and 25% achieved a clinical response.
• Myeloid-supporting cytokines secreted during therapy promote AML blast survival via kinase signaling, causing CAR T cell exhaustion.

Conclusions:

• Autologous anti-CD123 CAR T cell therapy is manufacturable for AML but associated with high rates of cytokine release syndrome and modest clinical efficacy.
• Therapy-induced cytokines represent a unique AML resistance mechanism.
• Combining CAR T cell therapy with cytokine signaling inhibitors may improve outcomes in AML.