A CD38-directed, single-chain T-cell engager targets leukemia stem cells through IFN-gamma-induced CD38 expression.
Publication Year:
2024
PubMed ID:
38394668
Public Summary:
Our research focused on a new approach to treating Acute Myeloid Leukemia (AML), particularly the hard-to-treat leukemia stem cells (LSCs). These LSCs are a big challenge because they can resist treatment and hide from the immune system, which makes curing AML difficult.
We found that a molecule called interferon gamma (IFN-γ) helps make LSCs more vulnerable by increasing the levels of a marker called CD38 on the surface of these cells. Normally, LSCs have low or no CD38, which makes them harder to target, but IFN-γ changes that.
Building on this, we designed a special protein, called BN-CD38, that helps the body’s immune T cells attack leukemia cells with CD38 on them. This protein brings the leukemia cells and T cells closer together, making the T cells better at killing the cancer. Even better, BN-CD38 also boosts the release of IFN-γ, which in turn makes even more LSCs show CD38, allowing them to be destroyed.
The treatment worked well in lab tests and in mice models with human AML cells, eliminating leukemia cells without harming healthy blood stem cells or other important immune cells. This study offers a promising way to target and destroy the tough-to-kill LSCs in AML.
Scientific Abstract:
Treatment resistance of leukemia stem cells (LSCs) and suppression of the autologous immune system represent major challenges to achieve a cure in acute myeloid leukemia (AML). Although AML blasts generally retain high levels of surface CD38 (CD38pos), LSCs are frequently enriched in the CD34posCD38neg blast fraction. Here, we report that interferon gamma (IFN-gamma) reduces LSCs clonogenic activity and induces CD38 upregulation in both CD38pos and CD38neg LSC-enriched blasts. IFN-gamma-induced CD38 upregulation depends on interferon regulatory factor 1 transcriptional activation of the CD38 promoter. To leverage this observation, we created a novel compact, single-chain CD38-CD3 T-cell engager (BN-CD38) designed to promote an effective immunological synapse between CD38pos AML cells and both CD8pos and CD4pos T cells. We demonstrate that BN-CD38 engages autologous CD4pos and CD8pos T cells and CD38pos AML blasts, leading to T-cell activation and expansion and to the elimination of leukemia cells in an autologous setting. Importantly, BN-CD38 engagement induces the release of high levels of IFN-gamma, driving the expression of CD38 on CD34posCD38neg LSC-enriched blasts and their subsequent elimination. Critically, although BN-CD38 showed significant in vivo efficacy across multiple disseminated AML cell lines and patient-derived xenograft models, it did not affect normal hematopoietic stem cell clonogenicity and the development of multilineage human immune cells in CD34pos humanized mice. Taken together, this study provides important insights to target and eliminate AML LSCs.
