Rise of the Natural Killer Cell

In immunotherapy, a lot of research and clinical development programs have so far focused on T-cell mediated tumor killing. PD1 has become the backbone for many cancer therapies and with IDO, ICOS etc. more T-cell specific checkpoint therapies are about to follow. At the same time, much less focus has been given to the possibility to recruit Natural Killer cells instead of T-cells to attack tumors. With the arrival of several important programs to the clinic, this is about to change.

Natural Killer (NK) cells belong to the category of lymphoid cell (CD56+ and CD3-) and
are part of the innate immune system. They also bridge innate and adaptive immunity via secretion of cytokines, while complementing cytotoxic effector T-cell immune surveillance by recognizing pathogens with absent or diminished MHC class I expression. NK cells have three distinct families of receptors: C-type lectin-like receptors (NKG2D, CD94/NKG2), natural cytotoxicity receptors (NCRs) and killer cell immunoglobulin-like receptors (KIRs). Activating receptors include the NCRs (NKp46, NKp30 and NKp44) and NKG2D. Inhibitory receptors include KIRs and CD94/NKG2. NKs can recognize tumor cells mainly via stress or danger signals but unfortunately tumor recognition is rather complex and involves alteration in the balance between multiple activating and inhibitory signals and inhibitory signals are generally stronger than activating ones. Despite these difficulties, various different approaches are emerging to harness the power of NK cells:

The checkpoint approach

Learning from the PD-1 playbook, the most obvious way to use Nautral Killer cells is to block the inhibitory receptors or ligands and so enable the cells to do their killing. Innate Pharma, which is based in Marseilles, France, has pioneered this approach. Innate has created a fully human monoclonal antibody, called Lirilumab, which is designed to block KIR2DL-1, -2 and -3. By blocking these checkpoints, Innate hopes to kick the Natural Killer cells into action and attack the tumor. Lirilumab is partnered with Bristol Myers Squibb which is currently running studies of the drug as a standalone therapy and in combination with their PD-1 antibody Opdivo. While an early standalone study in ALM consolidation failed earlier this year, data from a combination therapy with Optivo shows more promising results. In Squamous Cell Carcinoma of the Head and Neck, overall response rates were increased from 13.3% (Opdivo) to 24.1% for the combination. Further studies are pending but it could well be that the combination Opdivo and Lirilumab will one day become an important pillar for various tumor types.

The Natural Killer Cell approach

Probably one of the most advanced NK cell therapy approaches is pursued by Patrick Soon-Shiong’s NantKwest which uses genetically modified NK-92 cells to fight cancer. NK-92 is a cell line derived by Dr. H. Klingemann from a NK cell lymphoma patient in the 1990ies. It expresses a large number of activating receptors and lacks most of the inhibitory receptors which makes it an ideal candidate to fight cancer cells. NantKwest is currently exploring genetically modified NK-92 as a single agent but also in combination with various antibody therapies, where the antibody spots the target and a NK-92 cell, genetically modified to express CD-16 receptors, binds the antibody and kills the target. One big advantage of NantKwest’s approach compared to traditional CAR-Ts is that their cells are off-the-shelf and no preconditioning regiments are required for the cells to be effective. Another big plus is the lack of cytokine release syndrome.  One big disadvantage of this cell approach is the tumor origin of NK-92 which makes it hypo-immunogenic. So as a safety measure the cells are pre-treated by irradiation so that they don’t proliferate in vivo. That makes them more controllable on one hand, but not too durable on the other. There is of course also the chance that the host immune system starts to reject NK-92 cells rather quickly, preventing the cells from doing their work.
Similar work is also done by CytoSen, a small biotech company based on Orlando. CytoSen uses the K-562 cell line, isolated from a leukemia patient in the 70ies. Compared to NK-92, this cell line has however not reached the clinic yet.

The CAR-T approach

Yet another interesting approach is championed by the French biotech company Celyad, which uses Natural Killer cell biology but applies this to a T-cell setting. Taking advantage of the fact that NKG2D is a widespread Natural Killer cell receptor, they have fused a NKG2D protein, to the CD3ζ cytoplasmic domain of the T-cell receptor to initiate the activation signal. This elegant approach combines the rapid response of the NK cell with the potency and immunological memory generating power of the T-cell. Celyad believes that their construct can bind to eight different ligands commonly expressed on the surface of stressed cells including tumor cells. If it works – and there is early clinical evidence that it does – the therapy can possibly be used in a very broad set of tumor types.

In conclusion, many of these approaches are still early days and probably not all of them will reach patients. But what seems increasingly clear is that Natural Killers cells are set to play a more prominent role in the fight against cancer quite soon.