This talk highlights our recent work which investigates the mechanisms of survival of chronic lymphocytic leukaemia cells in the lymph node microenvironment. In the current era of targeted therapies there have been significant advances in the therapy of CLL with inhibitors of B-cell receptor signalling. However, those B-cell receptor inhibitors do not provide for complete responses, so disease eradication. We believe that part of the reason why is because in addition to the B-cell receptor signalling pathway there are several other pathways in the lymph node which are very important in promoting malignant B-cell survival. One of those pathways is actually BAFF, B-cell activating factor. BAFF is ubiquitously expressed as a ligand by many types of cells in the lymph node.
So how do you study it? What we actually have done is we mimicked the microenvironment BAFF expressing niche by using [?? 1:18] cells, which we used the stromal cells and cultured them with CLL cells. So those cells express BAFF and continuously delivered BAFF to the neoplastic primary B-cells which we took from patients. What we wanted to study is to figure out how BAFF signalling behaves in the setting of B-cell receptor signalling inhibition. What we found is that BAFF actually induced B-cell receptor signalling by itself, just like IgM cross-linking. What we would do in CLL cells in the lab normally in vitro to induce B-cell receptor signalling, BAFF ligand just did exactly the same, it induced activation of B-cell receptor associated kinases in CLL cells including BTK, ERK kinase and SYK kinase as well as some others that we looked at. So what we determined further is that obviously it resulted in activation of NF-kappa B pathways, both canonical and non-canonical and the canonical pathway activation happened via this BAFF-BCR crosstalk and was abrogated by B-cell receptor signalling inhibitors.
One other piece of this work is that it seemed that in these BAFF expressing conditions that an important anti-apoptotic element was induced called MCL1. It’s been shown in the past that MCL1 predicts resistance to conventional chemotherapies in CLL and also to some novel agents like the BCL2 antagonist venetoclax. So we have shown that one of those BCR signalling inhibitors called entospletinib which targets SYK, spleen tyrosine kinase, specifically but not other BCR inhibitors, not ibrutinib, not idelalisib. It actually abrogates this BAFF mediated induction of MCL1. So we believe that this is a very interesting point there where entospletinib targeting SYK specifically disrupts this co-operation between BAFF and B-cell receptor signalling and thereby counters BAFF mediated CLL cell survival.
So in part this work is actually leading to a clinical trial that we are launching together with Gilead, a phase I clinical trial of entospletinib in combination with obinutuzumab which we will be opening in the United States very soon. So this is basically direct bench to bedside translational work.
What will be the endpoints for that trial?
The phase I component is looking at safety for this drug combination and phase II is specifically focussed on CLL and is looking at efficacy – how much response are we achieving with this combination.
Are there any plans to go back to, for example, an organoid model to figure out some of the interactions that you said there and any more, for example pharmacokinetic states?
We certainly will have a lot of translational pharmacodynamics endpoints on the study. So we will be looking at some of the PD endpoints that we have identified in the lab, looking at MCL1 expression, NF-kappa B activation and how it will be affected by [?? 4:56] entospletinib. Generally this work opens a whole can of worms in terms of how exactly BAFF induces BCL receptor signalling. There are several receptors there which can respond to BAFF and we don’t know exactly how this interaction occurs.
The other thing is there is another ligand called APRIL which is a BAFF ligand cousin. It’s also very prominent in the CLL microenvironment so we don’t know if that might also be important, whether that will also induce BCR signalling just like BAFF does. So there are certainly a lot of unanswered questions there.
On a final note about SYK, we heard from I think it was Dr Hamlin yesterday talking about cerdulatinib, a dual JAK/SYK inhibitor. Do you think there might be some crossover there?
Possibly, possibly. Yes, the entospletinib is a very selective SYK inhibitor. There is some history there with fostamatinib which was a fairly dirty kinase inhibitor, so it inhibited a bunch of things in addition to SYK. Entospletinib is a better designed drug which is a fairly selective inhibitor of SYK. In terms of concurrent JAK/SKY inhibition it’s a very good idea. Time will tell in terms of what you’re leading it to achieve, how much inhibition you would need to achieve. We would need to have good PD data, whether we are really saturating the target PD-wise in terms of inhibiting all the downstream signalling pathways appropriately. Entospletinib has not been associated with a whole lot of toxicities; a phase II study in CLL as single agent has shown good tolerability of the drug. With JAK/SYK inhibition it remains to be seen how well that will be tolerated because you are certainly adding another very ubiquitous target. But, yes, there certainly could be a cross-semination there as well.
