Our study is really about applying next generation CAR T-cell engineering to improve the therapeutic responses in relapsed/refractory AML. In our plenary session at EHA we presented our preclinical work on another combinatorial CAR T-cell design that we called ADCLEC.syn1 to improve selective and efficient targeting of AML.

What was the design of the study?

We developed ADCLEC.syn1 guided by a precise profiling of the target antigen as it is in AML cells compared to normal cells which allowed us to identify a promising pair of target antigens and those are called ADGRE2 and CLEC12A which together really provide an improved therapeutic window for efficient AML targeting while sparing vital normal cells.

So we developed this new construct that we call ADCLEC.syn1 and that consists of a CAR targeting the antigen ADGRE2 and a secondary receptor, what we call a chimeric costimulatory receptor, or CCR, which targets the second antigen, CLEC12A. So once this second molecule, the CCR, is co-engaged together with the CAR it really assists CAR-mediated killing. With that we aim to reduce the risk of AML antigen escape due to downregulation of the CAR target but, at the same time, not increase the on-target toxicity.

What were the key results?

So we really connected a series of preclinical efficacy studies where we tested ADCLEC.syn1 versus a range of control constructs and we demonstrated, using AML cell lines first that represent really exactly the target densities that we found in our study patient cohort, that we found high efficacy across a wide range of densities and that included also models to represent potential ADGRE2 low antigen escape. Then, importantly, we also validated the efficacy of ADCLEC.syn1 to eradicate leukemic stem cells. For that we used a PDX model where we saw that ADCLEC.syn1 induced complete remissions in mice, especially in a PDX model that was refractory to an alternative CD33 CAR.

Then, importantly, in terms of toxicity we utilised a humanised mouse model where we saw that normal haematopoiesis, normal human haematopoiesis, did not impact the CAR T-cell efficacy of ADCLEC.syn1. Importantly, we also did not see relevant on-target toxicity against the stem or progenitor compartment.

What’s next for the study?

Next for the study is really that we advance this into phase I clinical testing. So ADCLEC.syn1 CAR T-cells will be tested in a first-in-human phase I trial for relapsed/refractory AML patients at MSKCC and that will start later this year.