Harnessing NK Cell Antigen Specificity and Expansion with IL-15 Containing TriKEs: Advancing Cancer Immunotherapy

The abstract discusses the role of Natural Killer (NK) cells in immune surveillance and their potential in treating Acute Myeloid Leukemia (AML). The study shows that the transfer of NK cells, combined with chemotherapy and IL-2, can lead to remissions in 30-50% of patients with refractory AML. However, the clinical benefits are limited due to the lack of antigen specificity and the inhibitory effect of IL-2 on NK cell proliferation by inducing regulatory T cells (Treg).

To address these limitations, the researchers developed trispecific killer engagers (TriKEs), which are an advancement from bispecific killer engagers (BiKEs). BiKEs were found to create immunologic synapses between NK cells and CD33 antigens on AML and MDS targets, enhancing NK cell signaling through the CD16 receptor. The TriKE incorporates a modified human IL-15 crosslinker, which unlike IL-2, supports NK cell proliferation and survival without stimulating Treg.

The TriKE construct was found to be more effective than BiKE in promoting NK cell killing, proliferation, and cytokine production. In a xenogeneic model involving mice, the TriKE demonstrated significant anti-tumor activity without toxicity and supported the in vivo persistence and expansion of NK cells.

The study concludes that the novel TriKE construct can effectively target CD33 antigens on malignant cells while providing cytokine stimulation, offering a non-gene therapy strategy for redirecting NK cells to malignant targets. The drug is currently in production for clinical testing.