112 - Human mesenchymal stromal cells administered after radiotherapy and surgery in a soft tissue sarcoma mouse xenograft model do not promote local recurrence or metastasis

Abstract

Mesenchymal stromal cells (MSCs) are promising candidates for tissue regeneration. We are investigating the potential of MSCs to overcome the morbidity of delayed wound healing after standard of care surgery and involved field irradiation for soft tissue sarcomas (STS). We previously showed that MSCs facilitate the healing of irradiated deep and superficial wounds in a rat model. We next assessed the safety of MSCs in the setting of residual cancer. We studied the effect of MSCs on proliferation, recurrence and metastasis of human STS in vitro and in vivo in a NOD/SCID/γc null mouse xenograft model. We isolated primary human STS cells and gene marked available permanent STS lines that we co-cultured or co-injected with or without MSCs. Tumor cell proliferation and growth were evaluated by flow cytometry and bioluminescence imaging, respectively. We demonstrated that MSCs do not affect the proliferation of STS lines in vitro and in vivo. In vitro proliferation assayed by CFSE showed that doubling times of fibrosarcoma and primary undifferentiated sarcoma (PUS) lines were comparable with and without MSCs (22 hr vs. 23 hr, p = 0.7 and 25 hr vs. 26 hr, p = 0.5, resp). No difference in bioluminescence emission was observed for fibrosarcoma or PUS co-cultured with and without MSCs for 7 days (4.8 × 107 p/s/cm2/sr vs. 5.9 × 107 p/s/cm2/sr p = 0.7 and 5.3 × 105 p/s/cm2/sr vs. 5.9 × 105 p/s/cm2/sr p = 0.6, resp.), and the in vivo co-injection model also confirmed no direct proliferative potential of MSCs on either fibrosarcoma or PUS (1.2 × 109 p/s/cm2/sr vs. 9.7 × 108 p/s/cm2/sr p = 0.4, and 3.6 × 108 p/s/cm2/sr vs. 3.9 × 108 p/s/cm2/sr p = 0.9, respectively). Administration of MSCs after radiotherapy and surgical removal in the pre-established fibrosarcoma xenograft model had no effect on local recurrence (4.1 × 108 p/s/cm2/sr vs. 5.9 × 108 p/s/cm2/sr, p = 0.4) or metastasis (2.0 × 1011 p/s vs. 2.7 × 1011 p/s, p = 0.36) of the tumor compared with control animals. Both MSC treated and control groups showed metastatic tumor nodules in axillary lymph nodes, liver and kidney to the same extent 3 weeks after surgery. Our preclinical data showed that MSCs did not stimulate tumor cells and suggest that an early phase clinical trial to assess safety and determine preliminary evidence of efficacy with MSCs after standard of care therapy for STS is warranted.