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Oncolytic viruses expressing MATEs facilitate target-independent T-cell activation in tumors

ABSTRACT: Oncolytic viruses (OV) expressing bispecific T-cell engagers (BiTEs) are promising tools for tumor immunotherapy but the range of target tumors is limited. To facilitate effective T-cell stimulation with broad-range applicability, we established membrane-associated T-cell engagers (MATEs) harboring the protein transduction domain of the HIV-Tat protein to achieve non-selective binding to target cells. In vitro, MATEs effectively activated murine T-cells and improved killing of MC38 colon carcinoma cells. Similarly, humanized MATEs activated T-cells in PBMCs from human donors. In MC38-tumors in mice, MATE-expression by the oncolytic adenovirus Ad5/11 facilitated intratumoral T-cell activation, reduced tumor growth and prolonged survival accompanied by infiltration of tumor-directed CD8+ T-cells and improved CD8/CD4 T-cell ratio. Absence of early T-cell activation in tumor draining lymph nodes suggest the safe applicability of this strategy. Furthermore, MATE-expression by Ad5/11 was capable of breaking resistance to αPD-1 checkpoint therapy thereby promoting T-cell/tumor cell proximity and clustering of CD8+ and CD4+ T cells. In summary, we demonstrated that MATE expressing OVs are powerful T-cell activating tools suitable for local immunotherapy of a broad range of tumors.

SUBMITTER: Malin Peter

PROVIDER: S-SCDT-10_1038-S44321-024-00187-Y | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:Medulloblastoma is the most common type of pediatric brain tumor. Although numerous factors influence patient survival rates, more than 30% of all cases will ultimately be refractory to conventional therapies. Current standards of care are also associated with significant morbidities, giving impetus for the development of new treatments. We have previously shown that oncolytic measles virotherapy is effective against medulloblastoma, leading to significant prolongation of survival and even cures in mouse xenograft models of localized and metastatic disease. Because medulloblastomas are known to be highly vascularized tumors, we reasoned that the addition of angiogenesis inhibitors could further enhance the efficacy of oncolytic measles virotherapy. Toward this end, we have engineered an oncolytic measles virus that express a fusion protein of endostatin and angiostatin, two endogenous and potent inhibitors of angiogenesis.Oncolytic measles viruses encoding human and mouse variants of a secretable endostatin/angiostatin fusion protein were designed and rescued according to established protocols. These viruses, known as MV-hE:A and MV-mE:A respectively, were then evaluated for their anti-angiogenic potential and efficacy against medulloblastoma cell lines and orthotopic mouse models of localized disease.Medulloblastoma cells infected by MV-E:A readily secrete endostatin and angiostatin prior to lysis. The inclusion of the endostatin/angiostatin gene did not negatively impact the measles virus' cytotoxicity against medulloblastoma cells or alter its growth kinetics. Conditioned media obtained from these infected cells was capable of inhibiting multiple angiogenic factors in vitro, significantly reducing endothelial cell tube formation, viability and migration compared to conditioned media derived from cells infected by a control measles virus. Mice that were given a single intratumoral injection of MV-E:A likewise showed reduced numbers of tumor-associated blood vessels and a trend for increased survival compared to mice treated with the control virus.These data suggest that oncolytic measles viruses encoding anti-angiogenic proteins may have therapeutic benefit against medulloblastoma and support ongoing efforts to target angiogenesis in medulloblastoma.

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Oncolytic viruses expressing MATEs facilitate target-independent T-cell activation in tumors

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