Future Research Aims to Examine Blocking STAT3 in Acute Myeloid Leukemia

Marcin Kortylewski, PhD, a professor in the Department of Immuno-Oncology at the City of Hope Comprehensive Cancer Center, discusses what research he believes is next to come in the acute myeloid leukemia (AML) space.

Within his own research, Kortylewski examined gene expression and reprogramming of transcriptional events using RNA sequencing to determine what changes occurred due to deletion and activation for AML cells. It was determined that a rapid regression in leukemia was linked to blocking STAT3 in these AML cells as a result of immune mediated circulating tumor DNA responses.

While there are many updated strategies being examined in the AML field, including chimeric antigen receptor (CAR) T-cell therapies, STAT3 inhibitors, and more, many have been met with challenges when targeting leukemic cells. According to Kortylewski, 2 main focuses for the future will aim at immune stimulation through CpG and TLR9 receptor activation, as well as blocking STAT3.

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0:08 | There have been a lot of interest in 2 aspects of our molecule about immune stimulation through CpG TLR9 receptor activation, as well as in blocking STAT3. There are several approaches combining CpG with the checkpoint blockade, that have been of interest in developing small molecules of STAT3 that have been relatively small. From our data, what strikes me is the fact that it's really a combination of these 2 effects. STAT3 is a negative regulator of the immune system, but it's a brake. Removing STAT3 on its own, removing the brake doesn't really move us forward. TLR9, immune activation is like pressing the accelerator, but without removing the brake, it's not effective.

1:05 | We do need those 2 effects to come together and that can effectively happen when a STAT3 inhibitor is incorporated into the immunostimulatory domain, like CpG and STAT3 decoy, the molecule will have this bifunctional effect of a single molecule. That actually allows us to cross the threshold of immune activation even in the context of myeloid leukemia cells. I think the bifunctionality is the key. We need to go over the concept of single trait molecules and approaches and complex immunotherapy.