AML exposure to cytokines results in CART-123 exhaustion. Credit: Nature Medicine (2024). DOI: 10.1038/s41591-024-03271-5

In the clinical battle against leukemia, recent breakthroughs in chimeric antigen receptor T cells (CAR T) have given patients and doctors an unprecedented weapon. CAR T cell therapy has demonstrated efficacy in treating B-cell malignancies, achieving high response rates and durable remissions. However, translating this success to acute myeloid leukemia (AML) has proven difficult.

Researchers at the University of Pennsylvania investigated the use of patient-derived anti-CD123 CAR T cells in treating adults with relapsed or refractory AML. They detail their findings in a paper, “Cytokine-mediated CAR T therapy resistance in AML,” published in Nature Medicine.

While the therapy was successfully administered to most participants, the findings highlighted significant challenges with cytokine release syndrome (CRS) and relatively low clinical response rates. This suggested that combining CAR T cell therapies with cytokine signaling inhibitors might improve treatment outcomes for AML patients.

CAR T cells are created from a patient’s own T cells. The T cells are collected and re-engineered in a lab to produce synthetic proteins on their surface (the chimeric antigen receptors). These proteins recognize and bind to specific proteins, or antigens, on the surface of cancer cells.

Before being put back into the patient, the CAR T cells are multiplied into the millions, giving them a good starting advantage. The CAR T cells will continue to multiply in the patient’s body and, with newly engineered receptors, be able to identify and kill cancer cells with the targeted antigen on their surfaces throughout the body.

AML is aggressive, and there are few effective treatment options for relapsed or refractory cases. Despite advancements in therapeutic strategies, the outcomes for these patients remain poor. Previous studies have noticed that AML cells frequently express a protein called CD123 and have linked it to poor prognosis.

Preclinical studies have suggested that CAR T cells that target CD123 (CART-123) could be effective. The current study evaluates the safety and efficacy of CART-123 in adult patients with relapsed or refractory AML.

The study enrolled 22 patients, with 20 confirmed eligible. The median age of participants was 60 years. Manufacturing of the CART-123 cells was successful in 90.4% of attempts, achieving a median T cell purity of 98.5%. All patients received a standard conditioning treatment of fludarabine and cyclophosphamide lymphodepletion before infusion with CART-123.

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.

The overall response rate was 25%. The median duration of remission for these responding patients ranged from 84 to 381 days, with a median overall survival from infusion of 160 days.

CRS was a significant adverse event, occurring in 83% of patients, with severe cases leading to dose-limiting toxicity and death in two individuals.

Analysis revealed that myeloid-supporting cytokines such as IL-3, GM-CSF, and FLT3L were secreted during the CART-123 therapy, promoting AML blast survival via kinase signaling. This cytokine activity essentially reduced AML cell susceptibility to specifically engineered CART-123.

These findings aligned with established knowledge that myeloid-supportive cytokines are linked to AML chemoresistance, and previous studies have associated these cytokines with higher relapse rates and worse overall survival in AML.

The research team reasoned that blocking the JAK/STAT signaling pathway with ruxolitinib could restore the sensitivity of AML cells to CART-123, suggesting that combination therapies might enhance treatment efficacy.

They tried it, and it worked.

Blocking the cytokine signaling with the JAK1/2 inhibitor ruxolitinib restored CART-123 efficacy against AML. The researchers conclude that their results may not be isolated to just CART-123 therapy, suggesting that other immunotherapy methods could be undermined by the same cytokine pathways found in their study.

From the paper’s conclusion, “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”