NK for Autoimmunity: Is It a Breakthrough or a Bust?

Jeffrey Martin   ·  July 25, 2024

CD19-targeting CAR-T cells have recently shown incredible promise in the clinic for the treatment of autoreactive B cell-associated autoimmune diseases. However, the fact still remains that there are various biological characteristics of T cells that strain the therapeutic process in the form of toxicities, manufacturing difficulties, and high costs. Consequently, several biotech companies are now exploring the use of other cell types, mainly natural killer cells, as an alternative to T cells for autoimmunity, but does it make sense?

In this article, I critically analyze the therapeutic potential of using NK cells to treat autoimmune diseases. Then, I evaluate the various biotech companies that are stepping into the ring to uncover the potential leaders poised to dominate the field.

Success of T Cells

Earlier this year, a paper was published in the New England Journal of Medicine that described the results of a clinical trial in which 15 patients with various autoimmune disorders (including systemic lupus erythematosus, idiopathic inflammatory myositis, and systemic sclerosis) were treated with CD19-targeting CAR-T cells. This trial marked the first time that CAR-T cells were administered to anyone other than a cancer patient, and the results were so incredible that they have sparked a paradigm shift in the field…

Almost immediately upon infusion, the CAR-T cells rapidly expanded and effectively eliminated CD19+ B cells from peripheral blood within just 7 days. This was followed by a dramatic decline in autoantibody concentrations, which plummeted to near zero within 4 months. By 6 months, symptoms had all but disappeared, and remarkably, the vast majority of patients remained in remission and drug-free at the 2-year follow-up, regardless of their initial disease state – absolutely incredible.

I think the final statement of the report truly captivates the significance of these findings:

“Even though it is premature to judge whether these patients are indeed cured of their autoimmune disease, CD19 CAR T cells at least appear to be able to achieve sustained disease- and drug-free remission”.

You don’t normally see a statement like this – one that suggests the discovery of a potential “cure” – in a scientific publication.

An immune system “reset”?

While the overall results are incredible – and I don’t mean to downplay them – the most interesting discovery to come out of this study was the fact that about 4 months after the initial CAR-T infusion, B cell populations began to re-emerge in the patients. The thing is, these new cells didn’t display any signs of autoreactivity and were instead predominantly naive, immature CD38+ B cells, newly differentiated from the bone marrow – very similar to what is seen in oncology. This finding led the researchers to propose that the cell therapy-mediated B cell depletion had effectively “reset” the patient’s immune system to a pre-autoreactive state (Figure 1 A&B).

Figure 1. The concept of an immunological “reset”

Figure 1. The concept of an immunological "reset" (read more)

So, a single CAR-T infusion was able to effectively reset the patient’s immune system…

This should rock your world if you’re a cell therapy company because this means that the administered cell therapy does not need to adopt long-term memory functionality to keep the autoimmune disease at bay, nor are subsequent infusions necessary; a single infusion of relatively short-lived cells seems to do the trick…

In light of this, a question must be asked: is it necessary to use T cells or can a similar effect be attained with another cell type?

Justifying the search for an alternative

This question must be asked because while T cells are, no doubt, incredibly powerful effectors, there are several aspects of their biology that place a significant strain on the overall therapeutic process. I am thinking of two in particular:

First, one of the main reasons that cell therapy for autoimmunity was not pursued earlier is because it was viewed as being too risky. The idea of introducing a highly immunogenic effector into an already hyper-stimulated immune environment seemed a bit like adding fuel to the fire. Although only mild toxicities were reported in this study, CAR-T-induced cytokine release syndrome (CRS) or off-target immune stimulation still pose serious risks and will continue to be of concern moving forward.

Secondly, since T cells possess the ability to recognize foreign antigens, it is difficult to safely administer a donor-derived T cell therapy. As a result, most T cell therapies are either autologous, or require extensive genetic editing to remove TCR machinery. This complicates the manufacturing process resulting in inconsistent, and extremely expensive cell therapy products.

While the risks and high costs of CAR-T cell therapy may be justified for cancer patients who may have no other option but to let the cancer kill them, the equation changes significantly for individuals suffering from autoimmune disorders. So, it is worth exploring alternative cell types with more controllable immunological activity that can be easily manufactured as ‘off-the-shelf’ products, such as natural killer (NK) cells.

Making the Case for NK Cells

NK Cell Basics

Natural killer (NK) cells are a type of cytotoxic lymphocyte that play a vital role in the innate immune system. Equipped with a range of activating and inhibitory receptors, NK cells are capable of recognizing and destroying “stressed” or infected cells without the need for prior activation – they were literally born ready to kill.

NKs also express high levels of Fc receptors (FcRs), which enable them to bind to the Fc portion of antibodies and subsequently engage and eliminate targets that are coated with antibodies. This unique feature, termed antibody-dependent cellular cytotoxicity (ADCC), is a sort of “antigen-dependent” targeting and will become particularly relevant later in our discussion.

Crucially, unlike T cells, which recognize targets via MHC-antigen complexes, NK cells do not rely on MHC presentation to identify their targets. Instead, they use their surface receptors to detect changes in the expression of certain molecules on target cells, allowing them to rapidly respond to potential threats. This aspect of their biology is key as it allows the cells to be administered as an allogeneic cell therapy without the need for ANY genetic editing, making for highly convenient and cost-effective manufacturing of “off-the-shelf” cell therapies.

Several NK cell therapy companies that have been exclusively focused on oncology are now seemingly beginning to do what so many CAR-T companies are doing: setting their sights onto autoimmunity.

Figure 2. NK cells recognize targets in an antigen-independent manner

Figure 2. NK cells recognize target in an antigen-independent manner

Challenging T Cell Hegemony in Cell Therapy

To continue this discussion, we must address the elephant in the room: if NK cells are so great, why do T cells dominate the cell therapy landscape?

It is true that natural killer cells have long been overshadowed by T cells in the realm of cell therapy. However, this is mostly due to a handful of characteristics of NK cells that pose challenges in oncology. Mainly, i) their relatively short lifespan, ii) limited expansion upon target recognition, and iii) the requirement for higher cell numbers per infusion. However, in light of the results from the study mentioned above, these concerns may not pose as significant of a barrier in autoimmune diseases.

For instance, the fact that long-term autoimmune remission does not require prolonged activity from the infused cells is a significant discovery. Remember, the newly emerged B cell population is non-pathological, and autoreactive B cell depletion can occur rapidly, often within just 7 days. This means that the therapeutic cells may not need to persist for an extended period of time. While it’s true that NK cells may not clear B cells as quickly as CAR-T cells, the key point is that we’re not talking about weeks or months of immune cell activity. In fact, a single infusion was enough to send most patients into remission for 2 years, highlighting the potential of a relatively short-lived cell, like NK cells, to provide long-term benefits in this setting.

Also – and this is crucial – to achieve desirable therapeutic activity in oncology, a cell therapy must possess the ability to control the rapid proliferation of the cancerous cells. In this context, the limited expansion of NK cells upon target recognition may pose a bit of a barrier. However, in autoimmune diseases, the situation is different, as the number of autoreactive B cells is typically much lower, and rapid B cell proliferation is not a hallmark of these conditions. As a result, the lack of robust expansion exhibited by NK cells is likely not as significant a limitation in autoimmune diseases.

This opens up an intriguing possibility: leveraging natural killer cells as an alternative to T cells for autoimmune disease treatment. With their unique characteristics and abilities, natural killer cells may prove to be as effective while also being significantly easier and cheaper to manufacture and administer.

NK for Autoimmunity: Key Players

As we’ve seen, the potential for cell therapies in autoimmunity is vast, and the use of NK cells may offer a superior approach to T cells. This belief is obviously not just held by me alone as there are several biotech companies in this space (Table 1).

Coeptis Therapeutics

Coeptis is advancing a universal CAR-expressing effector cell therapy platform that can be targeted to precise antigens with modified antibodies. By administering SNAP-CAR-NK cells with an anti-CD19 antibody, Coeptis is able to target CD19+ B cells for the treatment of hematological malignancies and autoimmunity. The company sources its NK cells from umbilical cord blood-derived CD34+ stem cells (more on this later), which are then differentiated into natural killer cells.

Nkarta Therapeutics

Another company making waves in the field is Nkarta, which has developed a CD19-targeting CAR-NK cell platform called NKX019. Nkarta’s platform utilizes donor-derived peripheral blood-derived NK cells and has recently initiated a phase I clinical trial for systemic lupus erythematosus (SLE).

Artiva Biotherapeutics 

Artiva has also made significant strides in the field, recently receiving a massive funding round to advance its AlloNK platform. This platform utilizes genetically unmodified umbilical cord-derived NK cells, which are used in combination with Rituximab (an anti-CD20 antibody) to target autoreactive B cells. Notably, Artiva’s platform is the only one that leverages the NK cell’s ability to engage in antibody-dependent cellular cytotoxicity (ADCC). They are currently recruiting for a phase I trial.

Cytoimmune Therapeutics

Cytoimmune has taken a unique approach to NK cell therapy, developing TRACK-NK cells that express PD-L1. These cells are derived from umbilical cord blood NK cells and are cultured to express PD-L1, which allows them to bind to PD-1 on hyperactive T and B cells and relieve the symptoms of autoimmunity. Notably, this is the only approach that can target both autoreactive B cells and T cells.

FATE Therapeutics

FATE, a company famous for its iPSC-derived cell therapies, is also developing a CD19-targeting iPSC-derived CAR-NK platform called FT522. 

Century Therapeutics

Similarly, Century Therapeutics is developing a CD19-targeting iPSC-derived CAR-NK platform, CTNY-101. Century is about to start recruiting for a phase I trial using CTNY-101 for the treatment of Moderate to Severe Systemic Lupus Erythematosus

Celularity

Finally, Celularity, a company known for its placenta-derived cell therapies, is developing a placenta-derived CD19-targeting CAR-NK cell therapy that it plans to test in clinical trials for autoimmunity.

The Verdict

Okay, so what’s the verdict?

Overall, I think success is going to come down to manufacturing, which will be heavily dependent on choice of cell source. I’m a firm believer that UCB-derived cells is the way to go (for several reasons). So, in my opinion, companies like Coeptis, Cytoimmune, and Artiva have the right idea in this regard.

I am also a proponent of using genetically unmodified cells as this significantly streamlines the manufacturing and makes the overall process much more scalable – which is key to NK cell therapy because since the cells do not undergo robust expansion in the patient you need many more cells per infusion. Companies like Cytoimmune, Coeptis (they also have a genetically unmodified NK platform), and Artiva are leading the charge on this front.

The biggest problem with this space right now is the complete lack of clinical data. We can speculate all we want and put on our “Molecular Immunologist” hats to make educated guesses, but the clinical data will be the ultimate judge. So, this is desperately needed and we should keep a close eye on the Artiva and Nkarta trials that are poised to initiate soon.

Overall, I am very optimistic about the future of NK cell therapy and believe that, while the field is incredible young, there are big achievement in its future.