I was invited to give a presentation about bispecific immunotherapy in ALL, so the topic is to discuss what has been developed so far. Bispecifics are a new class of biologicals which should bridge the T-cells to engage with the respective tumour targets. It’s highly specific because you select a tumour target that’s only expressed in a certain lineage, like in ALL it would be CD19, and the current lead technology is being presented basically by the data generated through blinatumomab which is a very simple construct as it is only taking out the VL-VH regions of a respective C3 antibody to attract the T-cells and the corresponding VL-VH region targeting CD19, an abundantly expressed antigen on the cell surface of ALL and healthy B-cells.

Blinatumomab has been explored in large phase II and phase III trials leading to registration of blinatumomab by EMA, FDA and also by other health agencies across the world. The first indication where a bispecific has been successfully used is in MRD positive ALL so those are patients who have still trace of the leukaemia by minimal residual disease assessment. There are two buckets of patients, one is the patients which are in continuous first remission versus patients in second or third continuous remission so they have really relapsed and had a salvage chemotherapy and still are MRD positive. Blinatumomab was then used as a single agent to convert MRD positivity into MRD negativity and if the patients were responding then they would go on to receiving a transplant, an allotransplant, because that is the traditional way of treating patients who are MRD positive after front line therapy.

So the key result is that 80% [?] of these patients actually achieved this primary endpoint and that when you look at it in overall survival at about five years there’s a significant difference in favour of blinatumomab treated patients who reached an MRD negativity versus patients who were MRD positive after blinatumomab. The other key result is what is the role of transplantation in this cohort of patients? It appears that patients who get consolidation, an allotransplant, after blinatumomab induced CR, do better than the ones who don’t get a transplant.

The second bucket indication is in refractory ALL where traditionally the response rates to chemotherapy are somewhere between 20-30% with just an overall survival of roughly 3-4 months. Here we have a phase III trial where the patients were randomised between both blinatumomab versus chemotherapy, intensified chemotherapy. The key messages of that trial that was published in The New England Journal is that 45% of the patients treated with blinatumomab reached a CR whereas the patients treated with chemotherapy was lower than 30%, so that’s significant, which then led to an almost doubling of the overall survival in the patients who were treated with blinatumomab to 7.7 months versus 4.0 months. If you ask the question which patients do benefit most from this approach it is the patients in salvage one, so the first relapse. Here we can show that 11.1 months is the overall survival of those patients so that is highly significant, of course, when compared to chemotherapy.

We’ve done also now a small subgroup analysis based on the phase II trial where patients were taken to a transplantation after blinatumomab induced CR. The treatment related mortality was 12% and for patients under the age of 35, so the sequence, CR induced by blinatumomab, on to transplant, the median overall survival has not yet been reached. So this seems to be quite beneficial when compared to historical controls in that context.

The problem that we are facing with this monotherapy is twofold. We have patients relapsing which have lost CD19 expression and we have patients who don’t respond. So to the first, CD19 negativity occurs in about 20% of the patients and it’s actually a little bit lower than with the CAR T-cell therapy which also engages with CD19 targets where there has been about 50-60% of the patients who relapse have lost expression of CD19. There has been some elaborate work looking at the mechanisms, at least it appears in CAR T-cells that it is just exon splicing that is the major resistance mechanism. With blinatumomab induced it appears that it’s a different mechanism and Monika Brüggemann will report on that at EHA. But what we sometimes also do see is myeloid outgrowth or lineage switch so the cells just become completely devoid of any B-cell markers and expressed myeloid markers and still yet can be easily traced to be derived from the original leukaemic clone.

So that is one problem that we’re facing and how do we get round this problem is there are other antigens that are expressed by B-ALL that can be targeted – CD20, CD22 and CD123 – and my lab has looked into this a little bit more in detail because there is a bispecific out there, it’s in clinical trials for AML and has shown CR rates or objective response rates at ASH of about 22% as monotherapy. So in the lab we looked at that and how to use this as an antigen to target also B-ALL and it appears that with fresh bone marrow samples and fresh [?? 6:42] that we can purge this bone marrow from the ALL. The most interesting thing is if we combine that with blinatumomab we can actually lower the amount of blinatumomab and flotetuzumab, which is the drug targeting CD123, quite significantly leading to a greatly reduced production of cytokines because that is the hallmark of side effects is cytokine driven. So it appears that we can kill two birds with one stone – antigen escape, more pressure by targeting two antigens and, on the other hand, lowering the rate of cytokines that are produced by the respective T-cells in the in vitro assay.

So that is one problem that we do see and the other one is that the T-cell compartment differs between patient to patient. So some patients have fairly normal T-cell compartment with normal ratios between CD4, CD8 cells and Treg cells then there are other patients who have a completely altered proportion of these different subsets of T-cells. We looked at this and we found that patients who have a very high number of T regulatory T-cells, and there’s a threshold above 8% that none of these patients responds to blinatumomab in that context. With that said, you can really think about strategies how to reduce the amount of regulatory T-cells up front and cyclophosphamide is an agent that we would highly recommend because it has been shown in the past by other groups that that can actually specifically deplete the T-cell population and potentially we can overcome here a deficit with that.

So, in summary, we have with the bispecifics one agent that is now approved for two indications in ALL, MRD positive ALL as well as relapsed/refractory ALL, but there’s more to come as we learn more about what are the resistance mechanisms and how can we improve on the tweaking of the immune system to be even doing a better job.