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Natural Killer Cells from iPSCs – A Pure and Effective Patient Specific Cancer Treatment?

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Review of “Induced Pluripotent Stem Cell-Derived Natural Killer Cells for Treatment of Ovarian Cancer” from Stem Cells by Stuart P. Atkinson

The lack of effective strategies for ovarian cancer [1] has led to the development of novel treatment modalities. One of the most interesting new anti-cancer strategies is immunotherapy, and in particular, the use of natural killer cells (NK) [2]. However, the further development this type of therapy requires a reliable source for the large amounts of homogenous functional patient-specific NK cells needed and this has led to the generation of NK cells from human induced pluripotent stem cells (iPSCs) [3]. iPSC-NKs themselves have already shown efficacy in the battle against leukemia and HIV infection [4, 5] and so researchers from the laboratory of Dan S. Kaufman (University of Minnesota, USA) aimed to assess their anti-tumorigenic capabilities against ovarian tumors [6].

The study set out to compare the anti-tumorigenic capabilities of three different sets of NK cells

  • iPSC-NKs - Derived using previously described differentiation protocols [3, 7] from iPSCs generated from umbilical cord blood CD34+ cells and expanded in vitro
  • Peripheral blood (PB)-NKs - Activated and expanded in long-term culture using artificial antigen presenting cells (aAPCs)
  • Overnight-activated PB‐NKs - Represents the current product used in clinical trials.

The authors administered NK cells via intraperitoneal injection into a xenograft mouse model established using bioluminescent ovarian cancer cell lines which allow for tumor monitoring via bioluminescent imaging (BLI). While the overnight activated PB-NK cells represented a heterogeneous cell population, expansion of NKs in vitro led to the formation of more homogenous cell populations (>97% pure). Excitingly, a single dose of any of the three NK cell populations assessed led to a significant reduction in tumor burden, although the iPSC‐derived NK group demonstrating a trend toward overall better activity. In fact, the anti-tumor effect was so effective that two mice treated with expanded PB‐NKs and one mouse treated with expanded iPSC‐NKs had bioluminescent values similar to the negative control mice suggesting that long-term expanded NK cells may represent an exciting new treatment modality. Encouragingly, this anti-tumor effect converted into a pro-survival effect also, as the authors noted an improvement in the median survival of mice treated with the long-term expanded iPSC-NKs or PB-NKs from 73 days to 98 and 97 days, respectively (See adjoined figure).

The finding that NK cells derived from iPSCs and expanded in vitro function as well, if not better, as compared to PB-NK cells is a great boost for those looking for effective cancer treatments. As long-term iPSC expansion can give rise to huge amounts of NK cells which are not HLA-restricted, they can serve as an allogenic treatment, this option may allow the treatment of large numbers of patients over a prolonged period of time of required. The authors hope that this work may provide the basis for the start of a clinical trial for ovarian cancer, and indeed, for other solid tumors.

Discussion Points

  • Will iPSC-Derived NKs be safe and effective during long-term treatment?
  • Are there any side effects?
  • Which type of cancers will be most suitable for this type of therapy?
  • Will long term-banked iPSC-NKs retain functionality?

References

  1. Armstrong DK Relapsed ovarian cancer: challenges and management strategies for a chronic disease. Oncologist 2002;7 Suppl 5:20-28.
  2. Geller MA, Cooley S, Judson PL, et al. A phase II study of allogeneic natural killer cell therapy to treat patients with recurrent ovarian and breast cancer. Cytotherapy 2011;13:98-107.
  3. Knorr DA, Ni Z, Hermanson D, et al. Clinical-scale derivation of natural killer cells from human pluripotent stem cells for cancer therapy. Stem Cells Transl Med 2013;2:274-283.
  4. Ni Z, Knorr DA, Clouser CL, et al. Human pluripotent stem cells produce natural killer cells that mediate anti-HIV-1 activity by utilizing diverse cellular mechanisms. J Virol 2011;85:43-50.
  5. Woll PS, Grzywacz B, Tian X, et al. Human embryonic stem cells differentiate into a homogeneous population of natural killer cells with potent in vivo antitumor activity. Blood 2009;113:6094-6101.
  6. Hermanson DL, Bendzick L, Pribyl L, et al. Induced Pluripotent Stem Cell-Derived Natural Killer Cells for Treatment of Ovarian Cancer. Stem Cells 2016;34:93-101.
  7. Ng ES, Davis R, Stanley EG, et al. A protocol describing the use of a recombinant protein-based, animal product-free medium (APEL) for human embryonic stem cell differentiation as spin embryoid bodies. Nat Protoc 2008;3:768-776.