Marcin Kortylewski, PhD

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 

in these AML cells as a result of immune mediated circulating tumor DNA responses.

 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 

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 

. There are several approaches combining CpG with the checkpoint blockade, that have been of interest in developing small molecules of 

 that have been relatively small. From our data, what strikes me is the fact that it's really a combination of these 2 effects. 

 is a negative regulator of the immune system, but it's a brake. Removing 

 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.

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 

 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.

Videos

Marcin Kortylewski, PhD, discusses what research he believes is next to come in the acute myeloid leukemia space.


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 some of the goals and findings of his research on blocking 

According to Kortylewski, it can be difficult to target the genetics of leukemia cells as their background is diverse. Due to AML always progressing and being very heterogeneous, a molecule targeting 

His research aimed to look at gene expression and gene reprogramming of transcriptional events using RNA sequencing to examine the changes found from deletion and activation for AML cells. What Kortylewski found was that a rapid regression in leukemia was linked to blocking 

in these AML cells, caused by immune mediated circulating tumor DNA responses.

We wanted to know what is the mechanism of action of this strategy? Was it actually driving immune responses? It turned out that when we looked at the leukemic cells, and we showed in this presentation, leukemic cells were undergoing very dramatic change. When we isolated them from mice, we could take a look at using electron microscopy, finding the subcell structure completely changed. We have observed differentiation of these leukemic cells into a macrophage-like phenotype. Initially, we could speculate whether it's a macrophage monostatic or gnotobiotic phenol type, but we have basically confirmed this data later using a gene expression study.

 In about 10% of leukemic cells, these changes cause their differentiation, and they tend to gain the ability to present the antigen. These cells, which were originally leukemia and have markers of leukemic cells, also express GFP, so we can track them. They become GFP positive antigen presenting cells, which is really interesting. This affects about 10-15% of leukemic cells in mice, but this is enough of the pool of antigen presenting cells to induce anti-tumor immune responses.

 We decided to dig deeper into a gene expression and gene reprogramming of transcriptional events in those myeloid cells using RNA sequencing analysis and looking at changes that are caused by a start with deletion, as well as by triggering activation of this receptor TLR9 that we use as a gateway into those cells, and by a combination of those 2 effects. What was really interesting was that RNA sequencing data has basically shown us that neither of these effects alone, so TLR9 activation nor 

 deletion alone, had the same effect as a combination of these 2 effects.

 elimination by silencing or by using a molecule was able to trigger dramatic reprogramming of the cells from leukemic cells into a macrophage-like phenotype that have been confirmed at the gene expression level by their activity and ability to phagocyte different molecules creating a population of differentiated cells with expression of 

and decreased expression of transcription factors which are normally found in leukemia, such as 

. These changes seem to be a driver of immune activation that we see in this model.

Marcin Kortylewski, PhD, discusses some of the goals and findings of his research on blocking STAT3 in acute myeloid leukemia cells. 


Examining the Role of Blocking STAT3 in AML

Marcin Kortylewski, PhD, a professor in the Department of Immuno-Oncology at the City of Hope Comprehensive Cancer Center, discusses observations regarding research on blocking 

AML has 1 of the highest unmet needs for new therapies in the context of all human cancers, according to Kortylewski. Because of this, a molecule targeting 

Findings revealed encouraging initial results as blocking 

 in AML cells led to rapid regression of the leukemia. This regression was not caused directly by the cytotoxic effect on leukemia cells, but by immune mediated circulating tumor DNA responses.

The extent of integration by key cells into leukemic cells in different organs, especially in the spleen and bone marrow, was also highlighted in the study as it led to regression of leukemia.

 What we observed and what was very encouraging in these initial results that we have already reported before are blocking 

 in acute myeloid leukemia cells, specifically in the model that we use, which is inversion(16) leukemia, 

-positive leukemia, leads to very rapid regression of the leukemia, and this regression is caused not by direct cytotoxic effect on leukemia cells, but by immune mediated circulating tumor [ct]DNA responses.

 We also show some convincing data in this poster illustrating the extent of integration by key cells into leukemic cells in different organs, especially in the spleen and bone marrow. That leads to regression of completely rational leukemia in the majority of treated mice, which was very encouraging.

Marcin Kortylewski, PhD, discusses research demonstrating blocking STAT3 in acute myeloid leukemia (AML) cells. 

Marcin Kortylewski, PhD | Authors

Articles

Future Research Aims to Examine Blocking STAT3 in Acute Myeloid Leukemia

Examining the Role of Blocking STAT3 in AML

Research Shows Blocking STAT3 in AML May Lead to Regression of Leukemia