EHA 2019 | Redirecting T-cell cytotoxicity and proliferation

We are interested in utilizing T cell recruiting antibody constructs for the treatment of AML. These constructs recruit T cells through the engagement to CD3 on T cells and if you look at text book, Janeway, at how T cells get activated it’s always the case that you need two or even three signals, so you need the engagement with the T cell receptor that is mimicked by CD33, but for activation at least of a naïve T cell you also need positive co-stimulatory signals like engagement of CD28. So we developed a pre-clinical in vitro model system where we used marine Bar-3 cells which we transfuse with CD33 as a target antigen but also different positive but also negative co-stimulatory molecules to look at the relevance of these molecules on activation of the T cells through T cell recruiting antibody constructs. And what we could show is that clearly if you add 80 or 86 as positive co-stimulatory molecule you have an enhanced T cell proliferation and an enhanced T cell mediated cytotoxicity of AML cells. But interestingly, if you then also cotransfuse PD-L1 into these cells this effect is abrogated, so it has a dominant negative effect.

In our prior work we could show the T cell recruiting antibody constructs induce pro inflammatory cytokines interferon gamma and TNF and that induces upregulation of PD-L1. So we are concerned that T cell recruiting antibody construct, through secretion of pro inflammatory cytokines, also upregulate negative inhibitory signals and that these overrule even coexisting positive co-stimulatory molecules, so we hypothesize that the addition of a checkpoint molecule inhibiting antibody construct would clearly enhance the efficacy of T cell recruiting antibody constructs.