Optimizing patient derived mesenchymal stem cells as virus carriers for a phase I clinical trial in ovarian cancer
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Published on: June 4, 2017
Emily K Mader1, Greg Butler, Sean C Dowdy
1Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA.
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.
Insights
Patient-derived mesenchymal stem cells (MSC) effectively deliver oncolytic measles virus (MV) to ovarian tumors. This approach is feasible and safe for ovarian cancer therapy, showing prolonged survival in preclinical models.
Area of Science:
- Oncology
- Stem Cell Biology
- Virology
Background:
- Mesenchymal stem cells (MSC) show potential as carriers for oncolytic measles virus (MV) delivery to ovarian tumors.
- Preparation for clinical trials necessitates evaluating the feasibility and safety of using patient-derived MSC for MV delivery.
Purpose of the Study:
- To assess the feasibility and safety of utilizing mesenchymal stem cells (MSC) from ovarian cancer patients as carriers for oncolytic measles virus (MV) therapy.
- To characterize patient-derived MSC for virus susceptibility and tumor homing capabilities.
Main Methods:
- Mesenchymal stem cells (MSC) were isolated from adipose tissue of healthy donors (hMSC) and nine ovarian cancer patients (ovMSC).
- Characterization included virus susceptibility, tumor homing assays, karyotype analysis, and in vivo studies in mice.
- Pre-infection, storage, and thawing of MV-infected MSC were evaluated for activity retention.
Main Results:
- Patient-derived MSC (ovMSC) were successfully harvested and expanded, meeting clinical dose requirements within 14 days.
- ovMSC exhibited tumor homing abilities and rapid co-localization with ovarian tumors after intraperitoneal administration of MV-infected MSC.
- MV-infected MSC significantly prolonged survival in preclinical ovarian cancer models, demonstrating therapeutic efficacy.
Conclusions:
- Using patient-derived MSC as carriers for oncolytic MV therapy is feasible and safe.
- A proposed clinical approach involves expanding, freezing, and validating patient MSC for on-demand treatment preparation.
- This strategy offers a promising avenue for ovarian cancer treatment using oncolytic virotherapy.
