Introduction: Brain cancer treatment has seen little improvement in outcome, calling for innovative intraoperative treatment post-resection. We discovered that patient derived adipose mesenchymal stem cells (hMSCs) engineered with our novel PBAE-Nanoparticles (NP) carrying BMP4, migrate specifically toward brain tumor initiating cells (BTICs), due to their inherent tumor-tropic and migratory properties, while sparing healthy cells. Our method enables the creation of “off-the-shelf” personalized therapy using autologous hMSCs-BMP4 as a therapeutic system that targets residual GBM cells post-resection; these cells are known to be the main culprits of relapse and metastasis.

Methods: We tested the hypothesis that hMSCs, transfected with NP-BMP4, specifically target residual tumor cells, enabling “off-the-shelf” therapy for diseases that require early intraoperative intervention, such as GBM. Therapeutic efficacy of hMSCs-BMP4 was examined through: 1) bioavailability and safety: by optimizing in vitro expansion, examining stemness and assessing efficiency of in vivo transplantation. 2) Clinical efficacy: we examined hMSC toxicity, proliferation, migration and BMP4-gene delivery to brain cancer in a PDX GBM mouse model.

Results: Primary hMSCs (obtained from our patients; n=51) migrated toward BTICs and delivered BMP4 via our lyophilized biodegradable NPs with hMSC transfection efficiency >60%- higher than the leading commercial reagent in the market (LIPOFECTAMINE). hMSCs remained multipotent, retained stemness and didn’t undergo oncogenic transformation (p<.001). In addition, migration toward BTICs increased 37% and hMSCs that delivered BMP4 caused >80% residual GBM cell death by day 9.

Conclusions: This is a novel intraoperative treatment that is both safe, autologous, biodegradable- selectively targeting BTICs while sparing healthy tissue. “Trojan Horses” are effective for both operable, inoperable, primary and metastatic tumors serving as personalized treatment based on a patients' genetic needs. This study demonstrates rapid ex vivo expansion, autologous acquisition, tropism and hypoimmunogenicity: all are factors permitting hMSC transplantation across major histocompatibility barriers and enabling the creation of “off-the-shelf” intraoperative personalized brain cancer therapy.

Patient Care: This study identifies mesenchymal stem cells from adipose tissue as potential "off-the-shelf" delivery vehicles, termed "trojan horses" for the treatment of brain cancer- mesenchymal stem cells possess tumor-tropic capabilities that would serve as autologous delivery vehicles using nanoparticles to deliver therapeutic agents/genes to brain tumor initiating cells. This is a novel intraoperative treatment that is both safe, autologous, biodegradable and efficient in selectively targeting cancer cells while sparing healthy tissue. This treatment would be effective for both operable, inoperable, primary and metastatic tumors and could serve as personalized treatment based on a patients' genetic needs.

Learning Objectives: By the conclusion of the study & presentation, participants will be able to 1)understand the importance of targeting residual cancer cells left behind after resection 2) using a nanomedicine based approach to bypass the regulatory hurdles of viral-gene delivery 3)exploring intraoperative therapy for the treatment of GBM 4) Using autologous stem cells to enhance biosafety and bioavailability to deliver therapy to residual cells left behind, implicated in cancer relapse and metastasis

References: -Li, Qian et al. “Mesenchymal Stem Cells from Human Fat Engineered to Secrete BMP4 Are Non-Oncogenic, Suppress Brain Cancer, and Prolong Survival.” Clinical cancer research?: an official journal of the American Association for Cancer Research 20.9 (2014): 2375–2387. PMC. Web. 12 Feb. 2016 -Tzeng, S. Y. et al. Non-viral gene delivery nanoparticles based on poly(beta-amino esters) for treatment of glioblastoma. Biomaterials 32, 5402-5410, doi:10.1016/j.biomaterials.2011.04.016 (2011).