Abstract
Oncolytic myxoma virus (MYXV) is being developed as a novel virotherapeutic against human brain cancer and has promising activity against human brain tumor models in immunocompromised hosts. Because an intact immune system could reduce its efficacy, the purpose of this study was to evaluate the oncolytic potential of MYXV in immunocompetent racine glioma models. Here, we report that MYXV infects and kills all racine cell glioma lines and that its effects are enhanced by rapamycin. Intratumoral administration of MYXV with rapamycin improved viral replication in the tumor and significantly prolonged host survival. Similarly, coadministration via a method of convection-enhanced delivery (CED) enhanced viral replication and efficacy in vivo. Mechanisms by which rapamycin improved MYXV oncolysis included an inhibition of type I IFN production in vitro and a reduction of intratumoral infiltration of CD68(+) microglia/macrophages and CD163(+) macrophages in vivo. Our findings define a method to improve MYXV efficacy against gliomas by rapamycin coadministration, which acts to promote immune responses engaged by viral delivery.
Highlights
The current management of patients with malignant gliomas uses a combination of surgery, radiation, and chemotherapy [1] but is unsatisfactory because patients survive for only a year on average
We found that compared with dead virus (DV)-treated animals, myxoma virus (MYXV) delivered via convection-enhanced delivery (CED) significantly improved survival (P = 0.0045, log-rank test; Fig. 5A) and this was further increased when MYXV was delivered by CED in combination with rapamycin (P < 0.0007; Fig. 5A), with 50% of the animals subsisting as “long-term” survivors (>45 days)
We found that the presence of either IFNα (50 units/mL) or IFNβ (100 units/mL) was able to limit MYXV (0.1 multiplicities of infection (MOI)) infection as assessed by green fluorescent protein (GFP) expression 48 hours after infection (Fig. 6A; Supplementary Fig. S5C), a limitation that was reversed by the presence of rapamycin (20 nmol/L; Fig. 6A; Supplementary Fig. S5C)
Summary
The current management of patients with malignant gliomas uses a combination of surgery, radiation, and chemotherapy [1] but is unsatisfactory because patients survive for only a year on average. Oncolytic viruses have been evaluated against malignant gliomas in preclinical models [2,3,4,5,6,7] and in clinical trials [8,9,10,11,12]. We discovered that myxoma virus (MYXV) was oncolytic for several human cancers [5, 13,14,15,16]. It is promising for human therapy because its genome has been sequenced, it is simple to engineer, its natural tropism is highly restricted to European rabbits (Oryctolagus cuniculus), and there is no acquired viral immunity in humans [17]. Despite its extremely narrow host tropism in nature, MYXV infects many human
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