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New Tool Aims to Advance NSC-based Anti-tumor Therapies

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Review of “Human Neural Stem Cell Biodistribution and Predicted Tumor Coverage by a Diffusible Therapeutic in a Mouse Glioma Model” from STEM CELLS Translational Medicine by Stuart P. Atkinson

The tumor-tropic activity of neural stem cells (NSCs) engineered to secrete diffusible anti-tumor agents represents an exciting treatment option for invasive brain tumors such as glioblastoma (GBM) [1, 2]. However, researchers from the laboratory of Michael E. Barish (Beckman Research Institute of the City of Hope, California, USA) noted that a lack of quantitative assessments had restricted further strategic developments.

Now, in a new STEM CELLS Translational Medicine article, Barish et al. describe the quantitative evaluation of the fate of transplanted engineered NSCs in an orthotopic GBM xenograft mouse model via the analysis of immunostained serially-sectioned formalin-fixed-paraffin-embedded (FFPE) brain tissue [3]. Will this standardized tool highlight the advantages and disadvantages of treatment strategies and move NSC-based anti-tumor therapies from the bench to the bedside? 

The new model system employed the administration of a human NSC line [4] loaded with trackable superparamagnetic iron oxide nanoparticles (SPIOs) engineered to secrete an enzyme (cytosine deaminase) [5]. This enzyme converts a systemically administered prodrug into a potent chemotherapeutic agent in a tumor-localized manner to avoid off-target effects. Overall, the study discovered that:

  • Administration of higher NSC doses led to higher NSC migration to the tumor site and greater estimated tumor coverage by the secreted enzyme
  • Intravenous administration requires ten times as many cells as intracerebral administration to achieve a similar  cell density at the tumor site
  • Longer or repeated administrations of smaller concentration of cells represented the best strategy for optimal tumor coverage
    • Higher concentrations of NSCs reduced homing due to unspecified rate-limiting processes active during administration and/or migration
  • Larger tumors attracted a greater number of NSCs and higher densities of NSCs around the tumor, overall leading to an enhanced estimated therapeutic coverage.
    • This finding may be due to higher concentrations of tumor-secreted factors or more extensive brain disruption or injury
  • The degree of NSC clustering directly impacts tumor coverage efficiency by the secreted therapeutic
    • Influencing NSC clustering may improve therapeutic outcome

This new tool is already providing much-required information that may affect the development of this therapeutic strategy. However, the quantitative analysis also generated “scatter” in the data due to sources such as tumor position in the brain, variable NSC penetrance into the tumor, and NSC administration variables, all of which the authors hope to fully identify and control for moving forward.

To keep in touch with the success if this new tool and advances in NSC-based anti-tumor therapies, keep the Stem Cells Portal bookmarked!

References

  1. Brown AB, Yang W, Schmidt NO, et al. Intravascular delivery of neural stem cell lines to target intracranial and extracranial tumors of neural and non-neural origin. Hum Gene Ther 2003;14:1777-1785.
  2. Noble M. Can neural stem cells be used as therapeutic vehicles in the treatment of brain tumors? Nat Med 2000;6:369-370.
  3. Barish ME, Herrmann K, Tang Y, et al. Human Neural Stem Cell Biodistribution and Predicted Tumor Coverage by a Diffusible Therapeutic in a Mouse Glioma Model. Stem Cells Transl Med 2017;6:1522-1532.
  4. Kim SU. Human neural stem cells genetically modified for brain repair in neurological disorders. Neuropathology 2004;24:159-171.
  5. Aboody KS, Najbauer J, Metz MZ, et al. Neural stem cell-mediated enzyme/prodrug therapy for glioma: preclinical studies. Sci Transl Med 2013;5:184ra159.