An Oncolytic Virus Expressing IL15/IL15Rα Combined with Off-the-Shelf EGFR-CAR NK Cells Targets Glioblastoma

Abstract

IL15 is a pleiotropic cytokine with multiple roles that improve immune responses to tumor cells. Oncolytic viruses (OV) specifically lyse tumors and activate immune responses. Systemic administration of IL15 or its complex with the IL15Rα and chimeric antigen receptor (CAR) natural killer (NK) cells are currently being tested in the clinic. Here, we generated a herpes simplex 1–based OV-expressing human IL15/IL15Rα sushi domain fusion protein (named OV-IL15C), as well as off-the-shelf EGFR-CAR NK cells, and studied their monotherapy and combination efficacy in vitro and in multiple glioblastoma (GBM) mouse models. In vitro, soluble IL15/IL15Rα complex was secreted from OV-IL15C–infected GBM cells, which promoted GBM cytotoxicity and improved survival of NK and CD8+ T cells. Frozen, readily available off-the-shelf EGFR-CAR NK cells showed enhanced killing of tumor cells compared with empty vector–transduced NK cells. In vivo, OV-IL15C significantly inhibited tumor growth and prolonged survival of GBM-bearing mice in the presence of CD8+ T cells compared with parental OV. OV-IL15C plus EGFR-CAR NK cells synergistically suppressed tumor growth and significantly improved survival compared with either monotherapy, correlating with increased intracranial infiltration and activation of NK and CD8+ T cells and elevated persistence of CAR NK cells in an immunocompetent model. Collectively, OV-IL15C and off-the-shelf EGFR-CAR NK cells represent promising therapeutic strategies for GBM treatment to improve the clinical management of this devastating disease. Significance: The combination of an oncolytic virus expressing the IL15/IL15Rα complex and frozen, ready-to-use EGFR-CAR NK cells elicits strong antitumor responses in glioblastoma.

Engineering CAR-NK cells to secrete IL-15 sustains their anti-AML functionality but is associated with systemic toxicities

“…Our observation of unexpected toxicity begs for expanded study of novel ways to stimulate CAR-NK-cell cytokine receptor pathways while circumventing systemic cytokine delivery. Localization of IL-15 with membrane tethering 55 or targeted delivery through the use of oncolytic viruses 56 are alternative therapeutic strategies. Controllable cytokine expression using engineered inducible systems and safety switches also holds promise.…”

An oncolytic virus expressing a full-length antibody enhances antitumor innate immune response to glioblastoma

“…oHSV has proven to be relatively safe and has shown some activity in treating GBM 3 . In our previous studies, we found that oHSV treatment dramatically increased the intratumoral infiltration of immune cells [4][5][6][7][8][9] . However, tumor cells have evolved to engage the immune checkpoints, e.g., CD47 and PD-L1, and down-modulate the immune cells, thereby evading the antitumor immune response 10,11 .…”

In Situ Cancer Vaccination and Immunovirotherapy Using Oncolytic HSV

“…However, OV-IL15C, expressing an IL-15 super agonist (human IL-15/IL-15Rα complex), from OV-Q1 (HSV-1 γ34.5 and ICP6 deleted; rHsvQ1) was more effective at extending survival in a CT2A syngeneic mouse GBM model than OV-Q1, and this was associated with increased in NK and T cell infiltration [27]. The combination with intratumoral injection of human EGFR-CAR NK cells further significantly extended the survival of mice with CT2A-hEGFR brain tumors [27], representing a promising therapeutic strategy.…”