Optimizing patient derived mesenchymal stem cells as virus carriers for a phase I clinical trial in ovarian cancer.
BACKGROUND
Mesenchymal stem cells (MSC) can serve as carriers to deliver oncolytic measles virus (MV) to ovarian tumors. In preparation for a clinical trial to use MSC as MV carriers, we obtained cells from ovarian cancer patients and evaluated feasibility and safety of this approach.


METHODS
MSC from adipose tissues of healthy donors (hMSC) and nine ovarian cancer patients (ovMSC) were characterized for susceptibility to virus infection and tumor homing abilities.


RESULTS
Adipose tissue (range 0.16-3.96 grams) from newly diagnosed and recurrent ovarian cancer patients yielded about 7.41×106 cells at passage 1 (range 4-9 days). Phenotype and doubling times of MSC were similar between ovarian patients and healthy controls. The time to harvest of 3.0×108 cells (clinical dose) could be achieved by day 14 (range, 9-17 days). Two of nine samples tested had an abnormal karyotype represented by trisomy 20. Despite receiving up to 1.6×109 MSC/kg, no tumors were seen in SCID beige mice and MSC did not promote the growth of SKOV3 human ovarian cancer cells in mice. The ovMSC migrated towards primary ovarian cancer samples in chemotaxis assays and to ovarian tumors in athymic mice. Using non-invasive SPECT-CT imaging, we saw rapid co-localization, within 5-8 minutes of intraperitoneal administration of MV infected MSC to the ovarian tumors. Importantly, MSC can be pre-infected with MV, stored in liquid nitrogen and thawed on the day of infusion into mice without loss of activity. MV infected MSC, but not virus alone, significantly prolonged the survival of measles immune ovarian cancer bearing animals.


CONCLUSIONS
These studies confirmed the feasibility of using patient derived MSC as carriers for oncolytic MV therapy. We propose an approach where MSC from ovarian cancer patients will be expanded, frozen and validated to ensure compliance with the release criteria. On the treatment day, the cells will be thawed, washed, mixed with virus, briefly centrifuged and incubated for 2 hours with virus prior to infusion of the virus/MSC cocktail into patients.
Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Emily K
EK
Mader
Greg
G
Butler
Sean C
SC
Dowdy
Andrea
A
Mariani
Keith L
KL
Knutson
Mark J
MJ
Federspiel
Stephen J
SJ
Russell
Evanthia
E
Galanis
Allan B
AB
Dietz
Kah-Whye
KW
Peng
D000818:Animals; D016022:Case-Control Studies; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007621:Karyotyping; D008459:Measles virus / Q000502:physiology*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000821:virology; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D050130:Oncolytic Virotherapy; D010051:Ovarian Neoplasms / Q000235:genetics / Q000628:therapy*; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed