Permanently Boosting Levels of Natural Killer Cells in Mice to Increase Cancer Resistance

Researchers here demonstrate a very interesting approach to immunotherapy: they introduce engineered stem cells in mice that will give rise to additional natural killer T cells, boosting the capability of the immune system for the entire life span of the mouse. Even if this class of treatment is not actually permanent in the same way in humans, and merely long-lasting, it still seems a promising step towards enhancing the immune system at any age, not just trying to repair it when it fails in later life.

They've been called the "special forces" of the immune system: invariant natural killer T cells. Although there are relatively few of them in the body, they are more powerful than many other immune cells. Scientists have hypothesized that iNKT cells could be a useful weapon against cancer because it has been shown that they are capable of targeting many types of cancer at once - a difference from most immune cells, which recognize and attack only one particular type of cancer cell at a time. But most people have very low quantities of iNKT cells; less than 0.1% of blood cells are iNKT cells in most cases. Still, previous clinical studies have shown that cancer patients with naturally higher levels of iNKT cells generally live longer than those with lower levels of cells.

The researchers' goal was to create a therapy that would permanently boost the body's ability to naturally produce more iNKT cells. They started with hematopoietic stem cells - cells found in the bone marrow that can duplicate themselves and can become all types of blood and immune cells, including iNKT cells. The researchers genetically engineered the stem cells so that they were programmed to develop into iNKT cells.

They tested the resulting cells, called hematopoietic stem cell-engineered invariant natural killer T cells, or HSC-iNKT cells, on mice with both human bone marrow and human cancers - either multiple myeloma (a blood cancer) or melanoma (a solid tumor cancer) - and studied what happened to the mice's immune systems, the cancers and the HSC-iNKT cells after they had integrated into the bone marrow. They found that the stem cells differentiated normally into iNKT cells and continued to produce iNKT cells for the rest of the animals' lives, which was generally about a year.

While mice without the engineered stem cell transplants had nearly undetectable levels of iNKT cells, in those that received engineered stem cell transplants, iNKT cells made up as much as 60% of the immune systems' total T cell count. Plus, researchers found they could control those numbers by how they engineered the original hematopoietic stem cells. Finally, the team found that in both multiple myeloma and melanoma, HSC-iNKT cells effectively suppressed tumor growth.



With all the neoantigen vaccine companies for cancer like Gritstone, Neon, BioNtech, Moderna ... they all have the problem that their target population is older and in older individuals the immune system sucks, off course with neoantigen vaccines you go after T-cells not NK-cells.

Posted by: Tom at September 30th, 2019 5:50 AM

Another issue is that the more you upregulate the immune system the more potential inflammation you have. So it is not so useful as prevention and long-term therapy

Posted by: cuberat at September 30th, 2019 9:25 AM

Aubrey de Grey highlighted work along these lines in his "Commentary on Some Recent Theses Relevant to Combating Aging: February 2018.":

"Stem Cell Engineered Invariant Natural Killer T Cells for Cancer Immunotherapy" -
In the context of cancer, iNKT cells have particular promise precisely because their function is largely agnostic to the specific antigens present - thus rendering immunoevasion less of a barrier to therapeutic efficacy - and because they are especially sensitive to the presence of the pro-inflammatory cytokines found ubiquitously in tumour stroma, which in sufficient concentrations can trigger a robust iNKT response absent any antigen-specific engagement at all. Since iNKT cells are relatively short-lived the source hematopoietic stem cells could in principle be genetically engineered to produce them in vivo not constitutively but rather in response to a bioorthogonal stimulus. Repeatedly producing fresh iNKT cells in vivo from inplanted HSCs would also avoid the problems of T cell exhaustion seen in CAR T cells expanded ex vivo.

Posted by: jimofoz at September 30th, 2019 2:03 PM

Are there any human trails yet or any that are scheduled? If so where and contact information please.

Posted by: John Bonifant at October 14th, 2019 6:10 AM
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