Preclinical Research Suggests Role for ITK Inhibition in Monocytic MDSCs in CLL

Monocytic myeloid-derived suppressor cells (MDSCs) were found to increase with ibrutinib (Imbruvica) but not with acalabrutinib (Calquence) treatment in a preclinical model of chronic lymphocytic leukemia (CLL), suggesting a role for ITK inhibition in this cell population, according to results presented at the 2019 European Hematology Association Congress.

“We need to be aware of what drugs are actually doing to the microenvironment and if they're targeting anything else,” said lead study author Arantxa Romero-Toledo, PhD student, at the Centre for Haemato-Oncology, Barts Center Institute. “It's really important to look at the mechanisms of action in other cells.”

For the study, Romero-Toledo and colleagues set out to determine the role of MDSCs in CLL and the impact of the BTK inhibitors ibrutinib and acalabrutinib on 2 major subsets of MDSCs—monocytic and granulocytic cell populations—in vivo. To do this, mice induced with CLL cells were randomized to receive either ibrutinib or acalabrutinib for 21 days. Investigators assessed 15 animals from each group.

Results showed that the overall ratios of granulocytic and monocytic MDSCs over non-B cells were significantly reduced in the peripheral blood as the population of malignant cells expanded in the peripheral blood.

Investigators noted an increase in the monocytic MDSC population following ibrutinib treatment (P <.001), but not with acalabrutinib; this suggests that this MDSC subpopulation is ITK-dependent, providing the rationale for further study of ITK inhibitors in CLL. Moreover, the presence of granulocytic MDSCs increased with both BTK inhibitors. Notably, acalabrutinib led to a higher restoration of macrophages in spleens (P <.001) compared with ibrutinib (P <.05).

In an interview with OncLive, Romero-Toledo provided additional insight into the preclinical study, the clinical implications of these data, and the next steps for this research.

OncLive: What did you set out to do with this research?

Romero-Toledo: The goal of the study was to see what MDSCs were doing in CLL using a mouse model. First, we tried to look at both granulocytic and monocytic [MDSC] populations and determine how they behaved upon CLL progression. We saw that, on the contrary to what has been seen in humans, the MDSC populations are lost with disease progression. They're supposed to accumulate, but in our model, we saw that they are actually lost. [We believe that this] is due to the granulocytic population in peripheral blood.

Then when we looked at our samples after treatment with the BTK inhibitors acalabrutinib and ibrutinib. We saw that in the spleen, the monocytic population was regained. Therefore, we believe that there is obviously a role for ITK inhibition in this population and that's why we're interested in comparing both BTK inhibitors. There has been reported ITK inhibition with ibrutinib but not for acalabrutinib. Interestingly, in terms of macrophages, we saw that acalabrutinib restored the population of macrophages in spleens, which is the contrary [to what has been previously observed].

What are some of the next steps for further investigation?

I will try to further understand the mechanism of these inhibitors in CLL and also how MDSCs work in this disease. Thus far, we have only seen this behavior, but we haven't looked into the actual mechanism of action with T cells, if they actually suppress T cells in CLL or if they interact with CLL cells. We know very little about this, but we believe that the animal model, the adoptive transfer Eµ-TCL1 model, is a good model to study this in.

What is your take-home message to practicing oncologists regarding this preclinical work?

We have to understand what a drug is actually doing. I know very little about how clinic works, since I'm not a medical oncologist, but as I understand, ibrutinib hasn't been there for a very long time. We have to see what the actual secondary effects are on other cell populations that are not the malignant ones that we are targeting, because in every disease the microenvironment is very important.

Is it actually a good idea to target all other cells that are not malignant CLL cells? Thus far, I believe MDSCs are not a target yet. Maybe they are doing something else, maybe they're there for a reason, but I still don't know. I would like to do further investigation into these cells to find out.

Romero-Toledo A, Schwarzbich M, Sanderson R, et al. Monocytic but not granulocytic MDSCs increase with ibrutinib but not acalabrutinib treatment in Em-TCL1 mice with CLL, suggesting a role for ITK inhibition in monocytic MDSCs. HemaSphere. 2019;3:514. doi: 10.1097/01.HS9.0000562824.01603.f1.