Abstract 1734: In vivo immunomodulatory effects by uPAR-retargeted oncolytic Measles virus
Authors: Khatwani Natasha K. , Jing Yuqi , Chavez Valery , Merchan Jaime 
Published: August 2018

Abstract
Background: Oncolytic viruses offer an advantage over other treatment options, as they both induce cytotoxicity as well as immune modulation. Oncolytic measles virus (MV) is a safe and promising oncolytic viral vector that is being tested in early clinical trials for treatment of cancer. While the oncolytic activity of MV has been clearly defined, the virus' in vivo immunomodulatory effects have not been well established, as CD46 (the endogenous MV receptor) is expressed in human, but not murine cells. We have developed MV-m-uPA, a fully retargeted MV that can selectively target mouse tissues in a m-uPAR dependent manner. The goals of this study are to characterize the in vivo immunomodulatory effects of MV-m-UPA.
Methods: Immunocompetent Balb/c mice were injected subcutaneously with CT-26 tumors. When tumor growth reached 4-5 mm, mice were treated with either vehicle control or MV-m-UPA via tail vein (IV) or intratumor (IT) every other day for two doses. Tumors were resected and changes in the immune microenvironment were analyzed by flow cytometry at days 5 and 10 after treatment.
Results: IV and IT administration of MV-m-UPA induced differential, time-dependent changes of components of innate and adaptive immunity. At early time points (day 5), intravenous virus treatment was associated with increases in MDSCs and NK cells, while the opposite effects were observed after IT administration. Analysis of CD8+ T cell subpopulations showed that IV treatments led to a decrease in TIM3+/PD1+ (exhausted) CD8+ T cells, while TIM3-/PD1- CD8+ cells increased after IV administration. The opposite effect was observed after IT administration. While both CD4+ T helper and FOXP3+ CD4+ cells increased after IV treatments, no major changes occurred after IT treatments. Interestingly, while a significant decrease in TAM 2 cells was observed at days 5 and 10 in both groups, TAM 1 cells increased only in the IV group at day 10.
Conclusions: In summary, IV MV-m-uPA administration induces overall decreases in TAM 2 and MDSCs, while NK and TAM 1 cells increase, changes that may be associated with tumor control. On the other hand, FOXP3+ cells increase, which may be a mechanism of immune suppression after IV administration. IT administration is associated with a decrease in MDSCs, TAM 2, as well as a decrease in FOXP3+ CD4+ cells, while no significant changes were observed in TAM 1 cells. The above results demonstrate for the first time the dynamic changes that occur within the immune microenvironment upon administration an oncolytic measles virus in a fully immunocompetent cancer model. These findings may help better understand positive and negative changes as a result of MV infection and may lead to identification of rational combinations of viruses with selected immunotherapeutic agents.
Citation Format: Natasha K. Khatwani, Yuqi Jing, Valery Chavez, Jaime Merchan. In vivo immunomodulatory effects by uPAR-retargeted oncolytic Measles virus [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 1734.