Abstract 75: A phase I trial of mesenchymal stem cells transfected with a plasmid secreting interferon beta in advanced ovarian cancer
Authors: Andreeff Michael , Marini Frank C. , Westin Shannon N. , Coleman Robert L. , Thall Peter F. , Aljahdami Vivian , Qazilbash Muzaffar H. , Rezvani Katy , Timmons Melissa , Heese Lauren , Wang Rui-Yu , Champlin Richard E. , Shpall Elizabeth J. , Olson Amanda 
Published: August 2018

Abstract
Background: Standard treatment for ovarian cancer with a platinum and taxane is effective initially but associated with significant relapse. Our group was first to demonstrate genetically modified MSC preferentially engraft and secrete gene products such as interferon beta (IFNB) at tumor sites, resulting in complete responses in animal models (Studeny M et al. Cancer Res 2002;62:3603; JNCI 2004;96:1593).
Methods: We conducted a single-center phase 1 trial to evaluate the safety, feasibility tumor response of mesenchymal stem cells transfected with plasmid secreting IFNB administered via intraperitoneal infusion (IPI) for women with advanced refractory epithelial ovarian cancer. We electroporated MSC derived from male donors with a plasmid vector containing the IFNB gene (MSC-IFNB). MSC-IFNB were then administered on an outpatient basis via IPI. Pretreatment biopsy, peritoneal fluid sample, blood draw, and a CT were performed at enrollment.
Results: Three patients were enrolled at dose level 1 (105 MSC/kg) and received 4 weekly IPI of MSC-IFNB between 6-10/2016. After the 4th dose we performed a restaging CT and a biopsy, which was examined by FISH for the presence of male Y-chromosome positive MSCs, for production of IFNB assessed by multispectral multiplexed IHC, presence of injected MSCs, changes in immune cell phenotypes, and tumor cell death. We demonstrated detectable production of IFNB in the serum of patient 1, and at week 4 detection of IFNB in the peritoneal fluid, suggesting injected MSC-IFNB produce IFNB locally. We performed multispectral analysis to identify and quantitate the constituents of the ovarian tumor microenvironment in pre- and post-treatment biopsy specimens. We focused on ovarian tumor cells (CK3/5+,AE1+), as well as stromal cells (αSMA+), and IFNB. We observed in all 3 patients colocalization of IFNB (red) with αSMA-(green,) suggesting MSC homing and production of IFNB at tumor stroma interface. To confirm the presence of injected MSC (derived from male donors), we then analyzed the pre- and post-treatment tumor biopsies for presence of the “XY” chromosome by FISH. We identified “XY” chromosomes MSC only in the post-tumor biopsy, suggesting incorporation of injected MSC at the tumor site. There were no infusion- or MSC-related adverse events and 1 patient had stable disease on CT scan at 4 months after treatment.
Conclusion: We demonstrate, for the first time, proof of principle that MSC-IFNB home to and are incorporated into tumors and locally produce beta-interferon after IP injection in patients with ovarian cancer. We anticipate increased responses at higher MSC dose levels and envision MSC-IFNB may be used in combination with immunotherapies and chemotherapy, as we have shown in animal models that MSC-IFNB modulate the immune phenoptype of the tumor, recruit FOXp3 immune cells, and facilitate long-term control of tumor growth and metastases.
Citation Format: Michael Andreeff, Frank C. Marini, Shannon N. Westin, Robert L. Coleman, Peter F. Thall, Vivian Aljahdami, Muzaffar H. Qazilbash, Katy Rezvani, Melissa Timmons, Lauren Heese, Rui-Yu Wang, Richard E. Champlin, Elizabeth J. Shpall, Amanda Olson. A phase I trial of mesenchymal stem cells transfected with a plasmid secreting interferon beta in advanced ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 75.