Interferon signaling predicts response to oncolytic virotherapy

Lassa-VSV chimeric virus targets and destroys human and mouse ovarian cancer by direct oncolytic action and by initiating an anti-tumor response

“…This is the primary initial receptor for the LASV-VSV viral glycoprotein (Jae et al, 2013), and robust receptor expression could potentially lead to enhanced viral uptake and infection. Another critical mechanism of selective action is that a large number of human cancers lack a normal interferon-mediated innate immune response to viral infections, allowing viral propagation, whereas normal cells are better equipped to resist virus infection (Stojdl et al, 2000;Kurokawa et al, 2018;Kurokawa and Galanis, 2019). CD44 expression is correlated with chemotherapeutic resistance and enhanced migration and metastasis of ovarian cancer (Chen et al, 2018); in time-lapse studies LASV-VSV showed good infection and cytolytic destruction of both CD44 + and CD44 − ovarian cancer cells.…”

Collateral Lethal Effects of Complementary Oncolytic Viruses

“… 4 Mounting evidence, however, indicates that there is considerable heterogeneity of innate antiviral immune defenses within and between tumor types. 5 As we and others have demonstrated, many tumor cell lines, as well as primary human tumors, mount robust innate antiviral immune responses. Additionally, although many cell lines prove highly susceptible to oncolytic viruses in culture, growth within a tumor microenvironment populated by stromal elements can lead to the induction of a constitutive antiviral state in tumor cells that are IFN responsive, preventing a spreading oncolytic infection.…”

Combining Oncolytic Viruses and Small Molecule Therapeutics: Mutual Benefits

“…The selectivity of various oncolytic viruses largely depends on defects in the tumor cell’s innate ability to fend off viral infections [ 35 ]. However, the initial assumption that an impaired interferon (IFN) response is a common feature shared by many tumors [ 36 ] may not reflect the clinical reality of solid cancers’ heterogeneity [ 37 ]. Some tumors, such as pancreas cancer, may even display an upregulated antiviral state leading to primary resistance [ 38 ].…”

“…However, in light of missing systematic assessments of a large range of tumor types, general conclusions as to what cancer types are more antivirally active and which are not remain to be drawn. Although most viruses have evolved to express proteins that counter antiviral measures [ 41 ], engineering of many oncolytic viruses were aimed at abolishing exactly those viral counter measures, generating OVs with a heightened IFN sensitivity [ 37 ]. Cornerstones of the antiviral innate immune response are type I (and to a lesser extend type III) interferons [ 42 ].…”