Msc Loaded Oncolytic Virus And Expressing Immunomodulators Have Therapeutic Efficacy In Advanced Melanomas.

Abstract Patients with advanced melanoma have a high propensity to metastasize to the brain and numerous investigational treatments with targeted agents have shown modest response in melanoma brain metastatic patients. Therefore, there is an urgent need to develop innovative therapies for such tumors. Oncolytic herpes simplex virus (oHSV) that selectively replicate in tumor cells and illicit an antitumor effect via oncolysis and production of neoantigens is among the recently approved promising therapies for primary melanoma patients. However, virus neutralization, and inefficient extravasation are the major barriers to the effective systemic delivery of oHSV to target metastatic tumor lesions in the brain. We have previously shown that mesenchymal stem cells (MSC) armed with different oHSV variants (MSC-oHSV) home to metastatic tumor lesions and have therapeutic benefits in melanoma brain metastases (MBM) models. To enhance therapeutic efficacy for metastasis melanoma, we investigated the novel combined therapy using MSC loaded with oHSV and simultaneously MSC releasing GM-CSF. Based on our TCGA data indicating significant loss of PTEN expression in late-stage metastatic melanoma, we tested MSC based therapeutics in PTEN mutant mouse melanomas. We show that MSC loaded oHSV effectively kills PTEN mutant syngeneic tumor cells in vitro. Next, we established MSC secreting GM-CSF and tested the abscopal effects as well as the antitumor efficacy in combination with MSC-oHSV in PTEN mutant syngeneic bilateral subcutaneous tumor model. The combined MSC based therapy showed significant therapeutic effects at both the treated and untreated site compared to control therapies. Interestingly, when these mice after combination therapy were re-challenged with mouse melanoma cells injected into brain, all mice remained tumor free. The combined MSC therapy induced effector memory CD8 and central memory CD8 cells in spleen and there was no toxicity in major organs post-therapy. In conclusion, our data indicate that combined MSC-oHSV/GM-CSF therapy is a promising novel therapy for advanced melanomas. Citation Format: Nobuhiko Kanaya, Maria Lopez Vazquez, Arnaldo J. Franco Torres, Yohei Kitamura, Genevieve M. Boland, Khalid Shah. MSC loaded oncolytic virus and expressing immunomodulators have therapeutic efficacy in advanced melanomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 77.