Cancer killing efficacy by human embryonic stem cell derived NK cells

by Alexey Bersenev on June 1, 2009 · 0 comments

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This is the first demonstration of anti-cancer activity in a living organism by cells derived from human embryonic stem cells.

Dan Kaufman (University of Minnesota)

A while ago I wrote about the difficulties on the way to generating functional hematopoietic stem cells from human embryonic stem cells (hESC) and I was even trying to challenge the significance of this research for clinical applications. I’d like to notice that generation of mature blood cells from hESC has been much more successful. Thus functional T-cells, NK cells and erythrocytes were efficiently derived from hESC. But only a few of them have been studied for functionality of derived cells in live organism (in vivo) models, which are very important for estimation of therapeutic potential.

Now Dan Kaufman’s lab from University of Minnesota demonstrate for the first time efficient cancer killing activity in vivo, mediated by immune cells derived from hESC. They generated natural killer (NK) cells using previously published protocol and investigated their anti-cancer activity on the range of tumors in vitro and in mouse leukemia model.

In my opinion this study has 2 most important advantages:
1. They used in vivo mouse model of human leukemia to estimate therapeutic potential of hESC-derived NK cells.
2. The authors compared activity and function of NK cells derived from hESC versus cord blood (CB) derived counterparts. I remember only 1 or 2 studies (correct me if I’m wrong) which were done to functionally compare hESC-derived cell types vs adult stem cell derived counterparts. Surprisingly CB-derived NK cells showed less cytolytic activity versus range of cancer lines in vitro and less anti-tumor activity in mouse model compared to hESC-derived NK!

Remarkably, all mice (13 of 13) treated with hESC-NK cells demonstrated rapid and complete clearance of the primary tumor within two weeks after tumor inoculation. In contrast, mice treated with UCB-NK cells had significantly less anti-tumor activity in vivo, with only 5 out of 13 tumor-free animals treated with UCB-NK cells.

This anti-tumor effect of hESC-derived NK cells (sorted and unsorted) was so strong that there was no cancer recurence observed and it was protective against metastasis.

The author’s explanation of enhanced activity of hESC-derived NK cells is that they are more mature and acquired more activation receptors compare to cord blood, which contain more immature and NK progenitors.

Now, I’d like to notice why if hESC-derived cells will ever reach the clinical endpoint, NK cells will be one of the first candidates:

1 NK cells could be used only for anti-cancer therapies, usually in “nothing to lose” cohort of patients. Allogeneic HLA-mismatched NK cells will be safe and not immunogeneic.

2 Kaufman”s group study described protocols for efficient generation of functional NK cells and could be considered preclinical. Protocol is easy and not so costly.

3 hESC-derived NK cells appears to be on the final step of maturation with remarkable killing activity. The strongest functional maturation also means that after they do their job (kill cancer cells) they will undergo to apoptosis and finally be eliminated from the body. Also the authors showed that these NK cells don’t “home and stay” in organs such as spleen, bone marrow and peripheral blood.

I wonder if these NK cells will be as effective in other solid tumor or metastatic models as in the one described here. I don’t even think that we should try to do the same trick with iPS cells, because allogeneic NK cells could be the “perfect drug”.

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