IL-15 Armed TriKEs: Enhancing NK Cell Antigen Specificity and Durability in Cancer Immunotherapy

Natural killer (NK) cells play a crucial role in the immune system, maintaining a balance between activating and inhibitory receptors to perform immune surveillance. A recent study has demonstrated that transferring NK cells into patients with AML that is resistant to standard treatments, in conjunction with chemotherapy and IL-2, can lead to complete remissions in approximately 30-50% of cases. However, the clinical benefits are believed to be hindered by the lack of specific antigen targeting and the induction of regulatory T cells (Treg) by IL-2, which can suppress the proliferation of NK cells.

To address these issues, researchers have developed a novel therapeutic agent known as trispecific killer engagers (TriKE). This approach builds upon the success of bispecific killer engagers (BiKEs), which have been shown to establish immunologic synapses between NK cells and CD33 antigens on AML and MDS targets, enhancing NK cell signaling through the CD16 receptor. The researchers have incorporated a modified human IL-15 crosslinker into the TriKE design, which is known to promote NK cell proliferation, survival, and activation without stimulating Treg cells.

The TriKE construct was successfully produced and purified, showing improved purification dynamics and yield compared to the BiKE. Flow cytometry analysis confirmed the selective binding of TriKE to CD16 and CD33 without interference from the IL-15 crosslinker. In vitro assays demonstrated that TriKE induced higher specific activity and NK cell proliferation compared to BiKE. Additionally, TriKE was found to be more effective in mediating cytokine production by NK cells.

In a xenogeneic model involving human NK cell transfer in mice, TriKE showed significant anti-tumor activity without toxicity and supported the in vivo persistence and expansion of NK cells. The study concludes that the TriKE construct is a promising therapeutic agent that can direct NK cells to target malignant cells while providing cytokine stimulation. This non-gene therapy strategy offers a practical and easily exportable approach for clinical testing, with drug production underway for trials planned in 2016.

Disclosures include affiliations with various speaker bureaus for certain individuals involved in the study.