*3.2. H-1PV + Tumor Angiogenesis Inhibitors (Bevacizumab)*

Another promising approach is the combination of H-1PV with bevacizumab (Avastin®). This co-treatment was evaluated in a series of compassionate virus uses in recurrent glioblastoma patients. Bevacizumab is an anti-VEGF-A monoclonal antibody available in Europe since 2005 for the treatment of breast, lung, kidney, colon, ovarian and endometrial carcinomas. In 2009, bevacizumab was approved by the Food and Drug Administration (FDA) for application in glioblastoma patients [59]. While achieving a steroid-sparing effect and alleviation of edema, bevacizumab monotherapy has, however, not demonstrated significant survival benefits [60]. On the other hand, scientists and clinicians have gathered an extensive—and yet to grow—knowledge of bevacizumab's mode of action. In particular, bevacizumab was found to exert immunomodulating activity by counteracting VEGF-induced negative effects on DC maturation, antigen presentation and lymphocytic trafficking [61]. These bevacizumab properties, together with the ParvOryx01 trial experience showing H-1PV treatment-associated immunogenic changes in glioblastoma TME, have opened up prospects for novel anti-glioma combinatorial immunotherapy development, i.e., H-1PV + bevacizumab (Figure 3). A compassionate use proof-of-concept program was conducted in five GBM patients, who developed a second or third recurrence after being treated in the ParvOryx01 trial. The patients underwent tumor resection, followed by local H-1PV administration and bevacizumab. The mean survival after treatment was extended to 15.4 months. Moreover, in three out of the five patients, striking remission of the recurrence was observed, providing first clinical hints of synergistic glioblastoma suppression through parvoviro-immunotherapy [62].
