A pioneering study from Osaka University has identified a novel target for precision CAR-based immunotherapy, offering renewed hope to patients with relapsed acute myeloid leukemia (AML) after stem cell transplants—without harming healthy donor cells.
Key Points at a Glance
- Researchers identified a leukemia-specific version of the molecule HLA-DRB1 as a therapeutic target.
- Newly engineered CAR T and NK cells using antibody KG2032 attack AML cells without harming normal tissue.
- The approach focuses on patients whose AML relapsed after allogeneic stem cell transplants.
- Preclinical results show strong anti-leukemic effects with no overt toxicity in mouse models.
- Clinical trials are being prepared to validate these findings in humans.
Acute myeloid leukemia (AML) is a devastating cancer of the blood and bone marrow that often relapses even after aggressive treatments like allogeneic hematopoietic stem cell transplantation (allo-HCT). In such cases, options for therapy become scarce and survival odds drop drastically. Now, an international team led by researchers from Osaka University has made a breakthrough that could transform treatment for these high-risk patients.
In a paper published in Nature Cancer, the researchers describe how they developed a novel form of CAR (chimeric antigen receptor) therapy that targets a unique molecular marker found on AML cells. The key lies in a variant of a molecule called HLA-DRB1—one that contains a specific amino acid substitution at position 86. This variation makes it possible to selectively attack leukemia cells while sparing the healthy ones introduced via transplant.
Lead researcher Professor Naoki Hosen and his team began by screening thousands of monoclonal antibodies (mAbs) for their ability to bind AML cells, but not normal blood cells. One antibody stood out: KG2032. Through molecular analysis, they determined that KG2032 binds to a specific form of HLA-DRB1 found in certain AML patients, but crucially, not in the donor cells used for allo-HCT.
This discovery opens the door for highly personalized therapy. The team engineered CAR T cells based on KG2032 and introduced them into mouse models with human-like AML. The results were dramatic: leukemia progression was halted without damaging healthy blood-forming cells. Similar outcomes were observed using cord blood-derived CAR NK (natural killer) cells.
What makes this strategy so promising is its precision. Many current CAR T therapies for AML fail because the antigens they target are also found on normal cells, leading to toxic side effects. In contrast, KG2032 CAR cells only target mismatched HLA-DRB1 molecules—making it a “smart bomb” in the fight against AML.
Importantly, this treatment is specifically designed for a subset of AML patients who relapse after allo-HCT and have the KG2032-reactive HLA-DRB1 profile. The idea is to use donor T or NK cells—genetically modified to express KG2032-derived CARs—so they attack only the patient’s remaining leukemia cells and leave donor-derived healthy cells untouched.
Professor Hosen emphasizes the potential impact of this research: “For patients who have exhausted conventional treatment options, this could represent a lifesaving innovation.” With preclinical success now validated, preparations for clinical trials are underway.
This research is a powerful example of the future of oncology: precise, molecularly guided therapies tailored to the genetic and immunological profile of each patient. It also highlights how strategic use of transplant mismatches—once seen as a risk—can become an asset when combined with cutting-edge bioengineering.
In the battle against AML, science is finding smarter, safer, and more selective weapons—and they’re getting closer to the clinic.
Source: Osaka University
