*3.1. H-1PV + Ionizing Radiation*

We have previously shown that radiotherapy, one of the conventional first-line treatments in glioblastoma patients, sensitizes low-passage glioma cultures to H-1PV oncolysis. Pre-irradiation increases the susceptibility of these cells to virus infection. Interestingly,

H-1PV achieves killing both radiation-sensitive and resistant glioma cells [53]. Apart from triggering enhanced tumor cytolysis, the irradiation followed by H-1PV treatment holds, in addition, the potential—although not yet validated in animal models—of acting as combinatorial immunotherapy. Indeed, although irradiation was long regarded as a local anticancer therapy, the first reports on radiotherapy interactions with the host immune system can be traced back to the 1970s of the last century. In 1979, Slone et al. were the first to report that the radiation dose required to control 50% of mouse fibrosarcomas was twice as high in immunocompromised animals as in immunocompetent hosts [54]. Furthermore, tumor regression at sites distant to radiation fields, the so-called abscopal effect, has been systematically observed [55]. Radiation-triggered immunomodulation encompasses, among other effects, ICD induction, T and NK cell activation and MDSC suppression. These observations prompted the development of various combination therapy regimens based on radiation and other immunomodulating agents [56,57], including OVs (e.g., adeno-, herpes simplex-, measles- and vaccinia-viruses) against glioma [58].
