Targeting CD70 with cusatuzumab eliminates acute myeloid leukaemia stem cells in humans

Prof Adrian Ochsenbein - University and University Hospital of Bern, Bern, Switzerland

I presented new data about targeting CD70 to eliminate leukaemia stem cells with a novel antibody cusatuzumab. The background is that CD27 signalling which is the receptor of CD70 promotes leukaemia cell expansion and differentiation. CD70 has quite a unique expression pattern, it’s only expressed on leukaemia stem cells but not on normal human stem cells, therefore it’s a good target. Cusatuzumab is a CD70 specific antibody that blocks signalling with CD27 and therefore mediates differentiation and reduces proliferation but, on the other hand, it’s an ADCC enhanced antibody that directly kills leukaemia stem cells.

What we presented was some preclinical work, how the strategy was designed and how the antibody was tested in preclinical experiments and then an update on the phase I trial. Actually the combination of cusatuzumab together with HMAs had quite astonishing response rates with a very low toxicity. So we think at this point, given the limited number of patients, it looks quite promising.

It was a dose escalation part with twelve patients and we just reported on these twelve patients. It was an expansion phase with an additional 26 patients but we do not have the mature data on these additional 26 patients. So the response rate we reported was on the phase I and this was a response rate of 100% with eight patients having a CR, two patients CRi and the remaining two are PR. So everybody in every risk class and at every dose level responded to cusatuzumab treatment.

The next steps are definitely to await the maturation of the expansion phase data so to have then more insights about potential biomarkers. We will look at NK cell levels, it’s an ADCC optimised antibody on soluble CD27 which is a biomarker. This is more to work out which patients respond in the ongoing trial and then two additional trials are already recruiting or in the start-up phase, a larger globally recruiting phase II trial that compares 10mg/kg cusatuzumab to 20mg/kg, so to define the dose to put further. Another platform study is just in start-up where we look at additional or interesting combination partners for cusatuzumab and we think one of the most interesting that we currently know is venetoclax together with cusatuzumab without cytotoxic drugs.

So in the dose escalation phase we didn’t achieve maximal tolerated dose so from this side we didn’t have some alarming signals. The treatment related side effects that we observed were very comparable to what is known from azacitidine. So we didn’t observe anything special, just two patients with infusion related reactions at the lower dose level of the study. So we think that the safety profile is quite good of the monoclonal antibody.