Unlocking the promise of oncolytic virotherapy in glioma: combination with chemotherapy to enhance efficacy

Abstract

Malignant glioma is a relentless burden to both patients and clinicians, and calls for innovation to overcome the limitations in current management. Glioma therapy using viruses has been investigated to accentuate the nature of a virus, killing a host tumor cell during its replication. As virus mediated approaches progress with promising therapeutic advantages, combination therapy with chemotherapy and oncolytic viruses has emerged as a more synergistic and possibly efficacious therapy. Here, we will review malignant glioma as well as prior experience with oncolytic viruses, chemotherapy and combination of the two, examining how the combination can be optimized in the future.

Figure 1. Immunological and genetic effects of chemotherapy

(A) Effects of the chemotherapeutic agents temozolomide, cyclophosphamide, cisplatin and 5-FU on the local tumor environment. Depletion of Tregs and MDSCs allows infiltration of CD4+ and CD8+ effector T cells. (B) Cytotoxic effects of chemotherapeutic agents. TMZ and CPA induce intra- and interstrand DNA cross-links. Etoposide allows for accumulation of double stranded DNA breaks. Rapamycin and other inhibitors of the PI3K/Akt/mTOR pathway decrease DNA replication and cell proliferation. 5-FU inhibits thymidylate synthase and uracil is incorporated into DNA instead of thymidine, inhibiting DNA synthesis. 5-FU: 5-Fluorouracil; CPA: Cyclophosphamide; MDSC: Myeloid derived suppressor cells; mTOR: Mammalian target of rapamycin; PI3K: Phosphatidylinositol 3-kinase; TMZ: Temozolomide.