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Trial Suggests MSC Homing Not Sufficient for Development of Prostate Cancer Therapies

Review of “A Phase I Study to Assess the Safety and Cancer‐Homing Ability of Allogeneic Bone Marrow‐Derived Mesenchymal Stem Cells in Men with Localized Prostate Cancer” from STEM CELLS Translational Medicine by Stuart P. Atkinson 

Newly developed therapeutic strategies for prostate cancer treatment have sought to take advantage of the tumor-homing ability of mesenchymal stem cells (MSCs). Recent research from the laboratories of Michael T. Schweizer (University of Washington, Seattle, Washington) and Samuel R. Denmeade (Johns Hopkins University, Baltimore, Maryland, USA) exploited the natural homing ability of MSCs loaded with microparticles encapsulating prodrugs or genetically engineered to express a modified form of a potent bacterial protoxin, both of which are selectively activated by the proteolytic activity of prostate‐specific antigen, a glycoprotein enzyme present at elevated levels in prostate cancer [1-3].

Now, the duo returns with a new STEM CELLS Translational Medicine article that sensitively assessed the homing capacity of MSCs to prostate cancer sites to confirm the practical use of MSCs as a targeting vehicle [4]. Unfortunately, the results of this phase I study determining the safety and feasibility of allogeneic MSC infusion before removal of the prostate establishes that MSCs do not home to primary tumor sites in sufficient levels to warrant further development as a cell‐based therapeutic delivery strategy [5].

See below for the highlights from this new trial:

  • MSCs derived from healthy donors and ex vivo expansion employed standard protocols 
  • Enrolled prostate cancer patients received a single intravenous infusion 4–6 days before planned prostate removal
    • Three patients received one million cells per kilogram
    • A subsequent four patients received two million cells per kilogram
  • The trial noted no dose‐limiting and all patients underwent prostate removal surgery without delay
    • Therefore, the authors indicate the safety of MSCs infusions in prostate cancer patients
  • Pathologic assessments revealed around 70% tumor involvement in prostate cores from four patients, with benign tissue present in others
  • Unfortunately, the authors failed to detect MSCs in any of the patients upon quantification of MSC accumulation within foci of primary prostate cancer tissue
    • Assessments employed an extremely sensitive digital BEAMing (beads, emulsion, amplification, magnetics) PCR-based method and sequencing SNPs within the HLA‐A locus for MSC detection
    • Therefore, the authors terminated the study early due to futility

While the authors establish that MSCs do not home to primary prostate cancer tumors in detectable numbers and are thus unlikely to home to prostate cancer metastases (the intended eventual application of this strategy), they note the existence of approaches that may enhance homing efficiency, such as genetic engineering, cell surface modifications, or preconditioning regimens, and allow their application as vehicles for prostate cancer treatment strategies.

For more on this new study, see a Letter to the Editor from Raj et al. [6] and the reply to the letter from Brennen et al.  [7] for some further interesting thoughts on this new article!

For yet more on MSC-based therapies and new treatment strategies for prostate cancer, stay tuned to the Stem Cells Portal.

References

  1. Williams SA, Merchant RF, Garrett-Mayer E, et al., A prostate-specific antigen-activated channel-forming toxin as therapy for prostatic disease. Journal of the National Cancer Institute 2007;99:376-85.
  2. Levy O, Brennen WN, Han E, et al., A prodrug-doped cellular Trojan Horse for the potential treatment of prostate cancer. Biomaterials 2016;91:140-150.
  3. Denmeade SR, Sokoll LJ, Chan DW, et al., Concentration of enzymatically active prostate-specific antigen (PSA) in the extracellular fluid of primary human prostate cancers and human prostate cancer xenograft models. The Prostate 2001;48:1-6.
  4. Brennen WN, Chen S, Denmeade SR, et al., Quantification of Mesenchymal Stem Cells (MSCs) at sites of human prostate cancer. Oncotarget 2013;4:106-17.
  5. Schweizer MT, Wang H, Bivalacqua TJ, et al., A Phase I Study to Assess the Safety and Cancer-Homing Ability of Allogeneic Bone Marrow-Derived Mesenchymal Stem Cells in Men with Localized Prostate Cancer. STEM CELLS Translational Medicine 2019;8:441-449.
  6. Raj AT, Kheur S, Bhonde R, et al., Use of Bone Marrow-Derived Mesenchymal Stem Cells in Prostate Cancer Could Increase the Risk of Cancer Progression. STEM CELLS Translational Medicine 2019; In Press.
  7. Brennen WN, Schweizer MT, Wang H, et al., In Reply to the Letter to the Editor from Raj et al.: Clinical Evidence Indicates Allogeneic Mesenchymal Stem Cells Do Not Pose a Significant Risk for Cancer Progression in the Context of Cell-Based Drug Delivery. STEM CELLS Translational Medicine 2019; In Press.