Novel BTK Inhibitor Appears Promising in Mantle Cell Lymphoma and Other NHLs

Gaël Roué, PhD

A novel irreversible Bruton’s tyrosine kinase (BTK) inhibitor, TG-1701, demonstrated early activity in mantle cell lymphoma (MCL) cells, providing evidence for scientific rationale for the combination of TG-1701 with ublituximab and umbralisib in non-Hodgkin lymphoma. The agent appears particularly promising in MCL lines resistant to ibrutinib (Imbruvica) treatment.

In patients with relapsed or refractory MCL, the development of BTK C481S mutation or overactivation of the NF-kB pathway, can lead to resistance to BTK inhibitors. Only TG-1701, in comparison with other reversible and irreversible BTK inhibitors, showed inhibitory activity when tested in REC-1 BTK C481S–mutant MCL cell lines.

This agent has also demonstrated similar cytotoxic activity compared with other BTK inhibitors in ibrutinib-sensitive MCL cell lines.

In an interview with Targeted Oncology, Gaël Roué, PhD, senior scientist at Vall d'Hebron Institute of Oncology and Idibaps research institute Hospital Clinic Barcelona, discussed the rationale for evaluating TG-1701 in combination with ublituximab and umbralisib in ibrutinib-resistant MCL.

TARGETED ONCOLOGY: What inspired this research?

Roue: Interest in this new BTK inhibitor comes from the fact that there is a large interest in BTK inhibitors for B-cell malignancies due to the fact that although there is no specific activity with this, it could affect other kinases and signaling within the tumor B-cells. We are interested in this molecule which is much more specific to BTK. When we compare this second-generation molecule with the first-in-class ibrutinib, we observed it retains some activity in cases of resistance to ibrutinib.

TARGETED ONCOLOGY: Could you elaborate the mechanism of action associated with TG-1701 and its potential synergy with ublituximab.

Roue: There was some interest in the possibility of combining BTK inhibitors with an anti-CD20 antibody due to the fact that in some studies the addition of BTK could lead to degradation of CD20. This could antagonize the activity of the anti-CD20 antibody, so we focused on this point by testing whether ibrutinib with TG-1701 could either sensitize or decrease the response of MCL cell lines to the first-in-class antibody rituximab (Rituxan) with ublituximab and also with umbralisib, which is a second-generation CD20 antibody

The readout of the supplements was the ADCC antibody delivered cell cytotoxicity which is one of the main effects of these antibodies in tumor B-cells, and we observed this when there was an antagonistic activity between the ibrutinib and rituximab or ublituximab in the cell lines. When we use TG-1701 instead of ibrutinib, this antagonism was not observed. We are able to maintain the cytotoxic activity of the antibody in this setting.

TARGETED ONCOLOGY: Were there any notable results that you wanted to emphasize?

Roue: The results were interesting in detecting the mechanism of action of this combination, but why with not only the use the anti-CD20 antibody but we used the U2 doublet, which is used in the clinical [setting]. This is a ublituximab and umbralisib, which is a new PI3K-delta inhibitor, so when we use this combination, there is very nice synergistic activity both in in vitro and in vivo. We could observe that this was due to a modulation of the inflammatory microenvironment in a sense, and we pass from anti-inflammatory environments to pro-inflammatory environments. Surgical analyses allow the immune factors to enter to the tumors, and then this could explain why the anti-CD20 antibody is working well in these settings.

TARGETED ONCOLOGY: What are the next steps following this research?

Roue: We have to characterize the tumors we use, so we are only calculating the prediction of inflammatory cytokines. We have characterized the infiltration of mouse cells and mouse macrophages, and we now have to validate our original analysis. We also have to validate the expression of these cells within the tumors. We are trying to explain why the activity of TG-1701 is maintained in case of a mutation of BTK, but why this activity is lost when we have activation of the NF-kB pathway? We have some evidence that the older kindnesses can be inhibited by TG-1701, allowing the compound to work in case of tissue decay. However, in case of over expressed signaling, the activity of this molecule is broad. We are waiting for the proper technical analysis of the different cell lines to observe the PI3k inhibitor, which [might] explained how this molecule can work in case of BTK inhibition.

TARGETED ONCOLOGY: Is there any other research in MCL that you are involved in that you would like to highlight?

Roue: We are also working with some new immunotherapy based on the inhibition of CD47. We know CD47 is really relevant to immune checkpoint in B-cell malignancies, so we are using this specific antibody from TG Therapeutics which is called TG-1801, to this antibody could block a CD47 immune checkpoint, specifically on tumor B-cells. We have evidence that this blockade can augment the infiltration of macrophages to give you all the immune effector activity against the tumor.