Oncoleader, LLC – Therapeutic Advantage of Natural Killer Cells
Natural killer cells are an excellent cell type for “off-the-shelf” cell therapies. Here’s one reason why.
By: Jeff Martin – Jeff is the Founder and Principal Consultant at Oncoleader, LLC, a Competitive Intelligence and Scientific Communications consulting firm specializing in immuno-oncology.
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Natural killer cells are an excellent cell type for “off-the-shelf” cell therapies. Here’s one reason why.
Limitations of Autologous T Cell Therapies
When you think of cell therapy, you most likely think of T cell-based therapies. More specifically, you are probably thinking of CAR-T cells, and even more specifically, you are thinking of autologous (derived directly from the patient) CAR-T cells. This is to be expected as autologous CAR-T cell therapy are the most commonly used cell therapies for cancer.
However, there are several limitations associated with autologous T cell-based cancer therapy, including (but not limited to):
1) the patient (from which the T cells are extracted and used as a therapy) is usually heavily pre-treated with chemo/radiation prior to T cell extraction, so their T cells are not exactly the best starting material. This can significantly damage the therapeutic process and result in drastically inconsistent cell therapies from patient-to-patient.
2) the extraction, manufacturing, and administration process can take weeks-months to complete. This is not an ideal therapeutic strategy for a patient suffering from rapidly progressing disease. Not to mention the enormous cost associated with this type of manufacturing.
3) Genetic manipulation techniques can be complex making it difficult to consistently produce a homogenous cell population; this increases the odds of batch-to-batch variations which, ultimately is not good for GMP.
4) Obtaining cells from an allogenic (healthy donor) source is difficult due to the tendency for foreign T cells to attack healthy tissue; this is referred to as graft-versus-host disease (GvHD).It is for these reasons (and others) that many in the industry are looking for a potential solution. Luckily, there is a potential solution to these limitations, but to get there, we’ll have to stray away from T cells and venture over the innate immune system.
Therapeutic Advantage of Natural Killer Cells
NK cells are cytotoxic effector cells of the innate immune system and they offer a beautiful solution to many of these issues. Why? One major reason has to do with the different mechanisms by which T cells and NK cells identify target cells.
You see, as our body generates T cells, any T cells that can bind to other, healthy cells in the body are killed, in a process called tolerance. Any T cell that can’t bind to your own body is left to survive. This creates a situation where the T cells in your body are only able to recognize (and then kill) foreign entities. This is good, because we generally don’t want “foreign entities” surviving inside our body.
This also means that if you were to take my T cells, and put them into someone else’s body, my T cells would look around and see everything as being foreign and start killing everything – this is referred to as graft-versus-host disease.
NK cells on the other hand, are able to recognize a much broader array of “generic” targets.
NK cells (and other cells of the innate immune system such as macrophages and neutrophils) recognize various ligands that are expressed by stressed, damaged, or infected cells. This allows them to rapidly respond to infection or various tissue damage quickly. Also, it is important to point out that cancer cells typically express very high levels of these types of ligands and can therefore naturally be recognized and targeted by NK cells.
This is mechanism of target cell recognition is highly beneficial for cancer cell therapy because it means that someone else’s NK cells can be infused into you and pose very little risk of GvHD. Also, since they are naturally inclined to recognize and kill cancer cells, there is no need for additional genetic engineering – to express a chimeric antigen receptor, for example.
Summary
So, to put it simply, NK cells can easily:
i) be extracted from healthy patients – good starting material.
ii) expanded and isolated ex vivo WITHOUT the need of genetic manipulation – less complicated manufacturing, and there is a lower risk of batch effects, allowing for a more consistent cell therapy product.
iii) cryopreserved, stored for months to years, and administered on the patient’s timeline – convenient, cheap, quick, and enables easy access to multiple doses.Now, to be clear, while there are plenty of platforms that do genetically enhance NK cells for cancer therapy, the genetic manipulation is not necessary. On the other hand, genetic manipulation is absolutely necessary for T cell-based therapies, especially allogenic T cells.
Here I’ve compiled a list of companies that are developing unmodified NK cell therapies in oncology.
