Week 10: The Promise of CAR-NK Cells

Hello! This week I’ll discuss how to engineer “off-the-shelf” CAR-NK cells and why they might be a better alternative to CAR T-cells.

CAR T-cells have been successful in treating leukemias and lymphomas. However, it is important to investigate CAR-NK cells which may have a similar therapeutic potential, safer side effects, and a better ability to be produced “off-the-shelf”.

What are Natural Killer (NK) cells?

Natural Killer (NK) cells are cytotoxic (cell-killing) white blood cells that are already programmed to kill cancer cells in a nonspecific manner. In contrast, T cells require an antigen to guide itself to the cancer cell. NK cells are activated by a variety of activating and inhibitory receptors. The killer-cell immunoglobulin-like receptor (KIR) is a protein receptor on the surface of NK cells and some T cells that recognizes MHC I complexes. KIR receptors can distinguish between self and foreign MHC complexes; when they recognize self-MHC class I molecules with other signals, they can suppress NK cell cytotoxicity. NK cells are also activated by certain antibodies (Immunoglobulin G) which attach to a CD16 receptor on NK cells. (Xie et al., 2020)

Why are NK cells a good source?

NK cells don’t have T cell receptors so they have a lower likelihood of causing graft v. host disease. Additionally, NK cells release different cytokines compared to T cells. These cytokines do not result in the potentially life-threatening cytokine release syndrome. Current reports demonstrate that it is possible to expand transferred NK cells in vivo using a high dose of immunosuppressants. One study demonstrates that 5 out of 19 patients with AML achieved complete remission (CR) with haploidentical NK cells, while the prognosis was significantly better when KIR-ligand mismatched donor cells were used. (Miller et al., 2005) Additionally, another report concludes that alloreactive donor NK cells reduce the risk of GVHD by destroying antigen presenting cells, which are thought to be responsible for GVHD. (Ruggeri et al., 2002)

To create a potent therapy using NK cells, KIR-ligand mismatching is likely crucial; immunosuppressant treatments could be used to prevent any adverse reactions. Further research and clinical trials must be conducted to assess the extent of HLA and KIR matching that is required.

I created a graphic (shown below) that illustrates some of the mechanisms of NK cells:

Further Questions

Reading about the prospect of a CAR-NK cell therapy has forced me to ask some important questions. How should NK cells be generated? Is HLA matching required? Will immunosuppressant treatments be required? How can scientists ensure that NK cells proliferate in the body? Through my research, I’ve found some answers and even more questions.

Be sure to tune in next week as I continue my quest to “Off-the-Shelf” CAR T-cells. Hope to see you at my senior project presentation on June 17th at 4pm!

Sidharth