Engaging Natural Killer Cells
By Zachary Bradley
Immuno-oncology has identified a number of promising pathways forward in the battle against cancer. Some of the treatments on the market or in clinical trials include immune checkpoint inhibitors (such as PD1/PD-L1 and CTLA-4), chimeric antigen receptor T cell (CAR-T) and bispecific T-cells (BiTEs). As is the case with the aforementioned, most immune-oncology approaches focus on T-cells, specifically removing the barriers hindering T cells from “recognizing” cancerous cells and increasing the cytotoxic activity in T Cells. Advances are also underway to allow the use of other immune cells in targeting cancer, such as Natural Killer cells (NK cells).
“Why Target Natural Killer Cells for Immuno-Oncology?”
Natural Killer cells are categorized as lymphocytes, often being described by flow cytometry as either CD16hiCD56+ or CD16+CD56hi. Unlike other lymphocytes (B and T cells), Natural Killer cells are part of the innate immune system with the ability to bind an array of antigens without the need for priming by antigen-presenting cells. Natural Killer cells act to target cells for apoptosis by binding activating receptors (such as CD16) to antigen ligands in the absence of MHC receptors. The presence of MHC inhibits the NK cellular response preventing the Natural Killer cell from destroying healthy self-cells. When a Natural Killer cells binds with a healthy self-cell, the inhibitory response does not cause the Natural Killer cell to become anergic like it does with an incomplete TCR binding in T cells. This allows Natural Killer cells to bind to a variety of cells either delivering a cytolytic payload or recognizing a self-cell and moving on to bind with more cells.
Natural Killer cells are able to help regulate tumors through cytotoxic activity, similar to that of cytotoxic T cells. The cytoplasm of Natural Killer cells contain granules hosting specialized proteins such as perforin and granzymes. Once activated, Natural Killer cells are able to deliver these apoptosis-inducing molecules to the targeted cell. This function makes Natural Killer cells a prime candidate for immuno-onocology.
“How are Natural Killer cells being utilized in Immuno-Oncology?”
Natural Killer cells are being utilized through Natural Killer Cell Engagers (NKCEs). Similar to BiTEs, NKCEs are monoclonal antibodies designed to target a receptor on Natural Killer cells as well as a tumor antigen. When the NKCEs bind to both a tumor antigen and Natural Killer receptors, the effector function of the Natural Killer cell is activated and a cytolytic payload is delivered to the tumor cell. NKCEs can be categorized as bispecific (BiKEs) or trispecific (TriKEs) based on how many receptors the monoclonal antibody (mAb) can bind with. NKCEs are currently undergoing clinical development for both hematological cancers as well as solid tumors. Receptors on the Natural Killer cell that have been targeted through NKCEs include CD16, NKp46 and NKG2D.
“What are the advantages to NKCEs?”
NKCEs have shown a positive correlation with reducing tumor growth in vivo mice as well as recruitment of Natural Killer to the tumor site. While CAR-T and BiTE treatments have shown similar results as NKCEs, negative consequences of the treatments have been observed. CAR-T cell therapies and BiTE treatments targeting CD3 have been associated with toxicity as a result of large activation of lymphocytes. The half-life of BiTEs is short in an effort to reduce the potential for toxic side effects; however, this can lead to an inconvenient dosing regimen. NKCEs have shown promise of having little to no off-target effects while also being engineered for short (24 hours) or long (10 day) half-lives. NKCEs have also demonstrated the potential to have stronger anti-tumor activity than mAbs currently on the market.
“How can ImmunoPrism help?”
The immune system is comprised of many different cell types sending a multitude of signals between cells creating a variable and complex environment. The out of date method of using a single analyte-biomarkers has proven to be ineffective in predicting which treatment is the most appropriate in cancer therapies. Through ImmunoPrism’s Health Expression Models and subsequent biomarker report, we have a more comprehensive view of the tumor microenvironment. By understanding the multidimensional variables present, such as escape genes, the population of cells available and in what number they’re presented, a more personalized approach to treatment can be used in fighting cancers. Whether that treatment is using a T cell therapy or Natural Killer cell therapeutic approach – we can really ask, what is the big picture benefit?
Gleason, Michelle K. et al “CD16xCD33 bispecific killer cell engager (BiKE) activates NK cells against primary MDS and MDSC CD33+ targets.” Blood123.19 (2014): 3016-3026.
Gauthier, L. et al. “Multifunctional natural killer cell engagers targeting NKp46 trigger protective tumor immunity.” Cell (2019); Jun13, 177(7):1701-1713