Fighting Cancer with Taconic Models: New Applications in Activating Immune Cells

In a study published in The Journal for ImmunoTherapy of Cancer, co-authored by Taconic Field Applications Scientist Mayara Grizotte-Lake, PhD, researchers investigated how the previously reported bispecific killer cell engager (BiKE:E5C1) acts upon CD16+ immune cells in response to ovarian cancer using Taconic mouse models.

Antibody-Based Immunotherapies 

Developing antibody-based immunotherapies for use in oncology is a promising avenue with broad applications. Generally speaking, the Fc region on monoclonal antibodies binds to its corresponding receptor on natural killer (NK) cells, leading to antibody-dependent cell-mediated cellular cytotoxicity (ADCC). Activating this process results in NK cells directly targeting cancer cells. One major challenge in developing these immunotherapies is the low specificity and affinity of the Fc region for the CD16a receptor located on the surface of immune cells, including the aforementioned natural killer (NK) cells. The region will also bind to its receptor on diverse immune cell populations, including macrophages, B cells, and a CD8+ T cell subpopulation. Binding these immune cells leads to several negative consequences, including macrophage inactivation, decreased survival in T cells, and immature B cells.  

Researchers at Rutgers University, previously reported upon their efforts to create a bispecific killer cell engager, which has high affinity and specificity to the CD16a receptor, leading to NK cell activation. In this study, in collaboration with Taconic's Field Applications Scientist, Dr. Mayara Grizotte-Lake, the group sought to evaluate the technology using Taconic’s NOG mice injected with Her2+ ovarian cancer cells, as well as in a human NK cell line.

Leveraging Human Cells and Humanized Mouse Models 

The group used CD16+ peripheral blood NK (PB-NK) cells, NK cells with a low affinity for the CD16 receptor (laNK92 cells), and THP-1 monocytes, which can differentiate into macrophages. The immortal laNK92 cell line has been found to accelerate graft versus host disease, but PB-NK cells have a relatively short lifespan. The researchers report that the BiKE:E5C1 system is able to activate PB-NK cells, leading to significantly increased cell death in cancer cells. It was also found that monocytes expressing CD16a polarized to M1 macrophages and subsequently coincubated with cancer cells (SKOV-3 cells) and the BiKE:E5C1 system resulted in more efficient cancer cell death by the macrophages compared to the best-in-class monoclonal antibody trastuzumab. 

Implications for Clinical Applications 

This was the first study of its kind to assess laNK92 cell proliferation in the humanized hIL-2 NOG and hIL-15 NOG mice mouse strains. Further, mice treated with the BiKE:E5C1 compound in the presence of the laNK92 cell population resulted in cancer cell clearance, a critical step in the in vivo assessment of the tool. Future studies will assess how the BiKE:E5C1 compound affects other tumor models in the context of NK cells and assess efficacy compared to FDA-approved monoclonal antibodies. 

“This study was critical in establishing the efficacy of the BiKE system both in vitro and in vivo,” notes Mayara Grizotte-Lake, adding, “We’re now one step closer to clinical applications.”