Targeting HLA-DRB1 Molecule: A New Frontier in CAR Therapy for Relapsed Acute Myeloid Leukemia

Overview

Recent research highlights the potential of the HLA-DRB1 molecule as a target for chimeric antigen receptor (CAR) therapy in patients with acute myeloid leukemia (AML) who have relapsed following allogeneic hematopoietic stem cell transplantation (allo-HCT). The study, conducted by a collaborative team led by Osaka University, seeks to address the challenge of effectively treating AML, a cancer that often resists conventional therapies.

Challenges in AML Treatment

AML is notoriously difficult to treat due to the limited availability of tumor-specific antigens that enable targeted therapy without harming normal cells. Allo-HCT is a common treatment for AML, where patients receive stem cells from a donor to rebuild their blood and immune systems. However, many patients still experience relapses after undergoing this procedure.

Discovering the HLA-DRB1 Target

In their quest to find effective targets, the research team screened a vast array of monoclonal antibodies (mAbs) against AML cells, ultimately identifying 32 mAbs that specifically bind to AML cells. Among these, one mAb, identified as KG2032, demonstrated a significant binding affinity to AML cells in more than half of the patient samples tested.

The researchers determined that KG2032 targets a specific subset of HLA-DRB1 molecules, which are critical for the immune response. Notably, KG2032 binds to HLA-DRB1 variants that possess an amino acid different from aspartic acid at position 86. This specificity means that the therapy could be effective in patients whose HLA-DRB1 variant is incompatible with that of their allo-HCT donor.

Implications for CAR T Cell Therapy

This discovery opens a new avenue for developing CAR T cell therapies tailored to individual patients' genetic profiles. The research team engineered CAR T cells that express KG2032 while excluding the reactive HLA-DRB1 allele. These engineered CAR T cells exhibited robust and targeted anti-AML activity in laboratory and animal model studies, with no significant toxicity observed.

Additionally, the study found that cord blood-derived natural killer (NK) cells engineered to express KG2032 also achieved similar therapeutic results, further supporting the versatility of this approach.

Future Directions

The promising outcomes from this research indicate that KG2032-derived CAR T or NK cells could be a pivotal treatment option for AML patients facing relapse after allo-HCT. Plans for clinical trials are currently underway to further evaluate the safety and efficacy of this innovative therapy.

As the field of immunotherapy evolves, the identification and targeting of specific antigens like HLA-DRB1 could significantly enhance treatment outcomes for patients with difficult-to-treat cancers like AML.