Basically, the role of the immune microenvironment in the control and eradication of CML has been shown in different contexts, whether this was in the era of stem cell transplant, where the successful graft-versus-leukemia effect was shown to confer higher survival. Or even in the era of TKIs, where it was shown that the restoration of T-cell or natural killer cell activity was important prior to discontinuation of treatment in patients seeking treatment-free remission...
Basically, the role of the immune microenvironment in the control and eradication of CML has been shown in different contexts, whether this was in the era of stem cell transplant, where the successful graft-versus-leukemia effect was shown to confer higher survival. Or even in the era of TKIs, where it was shown that the restoration of T-cell or natural killer cell activity was important prior to discontinuation of treatment in patients seeking treatment-free remission. Now, in order to further understand what are additional immune factors that might be important in achieving deeper responses in CML, we decided to conduct an analysis using cytometry by time of flight or also known as CyTOF in different patients. And we categorized our patients into two main groups, those who had what we defined as optimal response, meaning that they didn’t have detectable disease by PCR, which translates to response levels of MR 4.5 or less, and compared them to patients who failed to meet at least one criteria of ELN response, whether this is 10% at three months or 1% at six months, et cetera.
And we really collected prospective samples from these patients, blood and bone marrow, to try to better understand what are the immune determinants of deep response in CML. So, we had quite interesting findings including that, for example, patients who had suboptimal response really had higher expression of exhaustion markers on their T-cells, and also they had lower proportion of natural killer cells that produce interferon gamma. Now, one interesting finding that we show, and this was the first time that we show this association in a hematological malignancy, was actually that patients who had suboptimal response had higher proportion of macrophages expressing the VISTA marker. Now, what is VISTA marker? VISTA marker or also known as the V-domain immunoglobulin suppressor of T-cell activation is like the PD-L1 basically. It’s a B7 family ligand and it attenuates the T-cell response to antigens.
Now, how do we know this? Because the role of VISTA actually has been studied in solid malignancies where it was shown that higher expression of VISTA is really associated with resistance to immune checkpoint blockade. Now with this is the first time that the role of VISTA is described in a hematological malignancy, and it could potentially be found in other leukemias or hematological malignancies. And this is another, as we said, another evidence or another layer of evidence that really there is a huge role of the immune microenvironment in response to therapies or targeted therapies such as the TKIs in CML.
