Cell therapies have transformed the treatment of certain types of blood cancer, but so far they haven’t been able to safely and effectively treat acute myeloid leukemia (AML), a form of leukemia that is newly diagnosed in more than 62,000 Americans per year. Sascha Haubner, MD, hopes to change that.
Haubner, a senior research scientist at Memorial Sloan Kettering Cancer Center (MSKCC), has developed a chimeric antigen receptor T cell therapy (CAR T) that recently entered human clinical trials to treat AML. Like the six CAR T therapies currently on the market to treat other blood cancers, Haubner’s therapy is made by genetically modifying each patient’s own T cells so they can recognize and kill cancer cells. But the AML-targeted CAR T, called ADCLEC.syn1, is unique in that it uses a two-pronged approach to overcoming the characteristics of AML that have made it so challenging to tackle with conventional CAR T cell therapies.
For his work developing the CAR T therapy, Haubner was named a 2023-2024 recipient of the ASH Peter Steelman Scholar Award, offered in partnership by Deerfield Management, the Deerfield Foundation and the American Society of Hematology. He will be honored on June 18 at the AML Summit at Cure, which is an affiliate of Deerfield Management.
Targeting Patterns in AML
CAR T therapies currently on the market work by attaching to antigens — protein markers on the surface of cancer cells. The problem is, Haubner said, “we have so far not identified any marker that is specific for AML as a single antigen.”
So Haubner and his research team took a different approach: they searched for patterns of “coexpression,” meaning they looked for two or more molecules that are active together in AML. They landed on two targets, ADGRE2 and CLEC12A, which are co-expressed in AML but are not as prevalent in normal blood cells.
“We leveraged that to design a therapy that does not attack normal blood cells,” Haubner said. The hope is that the novel CAR T will eliminate AML cells without depleting normal blood cells, which is a common side effect of existing cell therapies.
ADGRE2 is an antigen that, when highly expressed in AML, is known to correlate with poor patient survival. Targeting this molecule is key to the CAR T’s ability to kill AML cells, Haubner said. Meanwhile, CLEC12A “increases the CAR T’s stickiness to AML cells, assisting in the killing but not directly triggering it,” Haubner said.
A phase 1 trial of ADCLEC.syn1 is currently recruiting adult patients with AML who did not respond to conventional therapies such as chemotherapy and stem cell transplants, or who relapsed after treatment. If the therapy proves successful, Haubner hopes the trial will be expanded to include pediatric patients.
Expanding Immunotherapy Options in AML
Haubner was trained in hematology and oncology at LMU University Hospital in Munich, Germany, and started as a postdoctoral researcher at MSKCC in 2017, just as the first CAR Ts were starting to hit the market. His excitement about the emerging immunotherapies was tempered by the lack of progress in AML.
“I witnessed patient experiences that were depressing because of the lack of effective therapies,” he said. “That motivated me to go to the laboratory and actually try to change what’s available.”
In addition to advancing ADCLEC.syn1, Haubner is interested in tackling other challenges that make AML hard to treat with immunotherapies. For example, the leukemia microenvironment in AML suppresses the immune response to the cancer in ways that are not well understood. And the differences in T cell biology between AML patients and healthy people also need to be explored, he said. “
This is a turning point in my career,” Haubner said. “I’m extremely honored to be supported in my efforts to really improve therapies for AML patients.”