**Acknowledgements**

of PVSRIPO was well-tolerated and revealed a promising efficacy, as well as provided a survival advantage when compared to historical control group of patients that was also analyzed [51]. Reovirus is a double-stranded RNA virus that is isolated from the respiratory and gastrointestinal tracts of humans. The safety of intratumoral administration in a doseescalation of this genetically unmodified OV was also assessed in a phase I trial in patients with recurrent GBM that received prior radiotherapy with or without chemotherapy [68]. More information about a phase I trial of reolysin, a genetically engineered reovirus, is

The use of OVs has been shown through some CTs as a harmless strategy with promising results; however, no OV has yet been approved by the FDA for GBM [58]. On the other hand, their therapeutic efficacy needs to be thoroughly assessed and proven with convincing clinical success in advanced phase trials. This task is hampered by the high genetic heterogeneity of GBM, and the ability of BBB to inhibit migration of OVs to the tumor site, thus compromis-

The current, first line, GBM standard therapy has not provided the necessary and expected improvements in overall patient survival rates. Immunotherapy is being explored as an alternative strategy, revealing to be a promising field, associated with good outcomes and fewer

The advances in technology, as well as in scientific knowledge regarding gene expression and signaling pathways analysis, have provided data to translate into new perspectives on personalized therapeutic approaches. In this context, immunotherapy has gained importance insofar as the identification of specific biomarkers in each patient could be useful for prognosis of personal immune responses. Several immunotherapeutic CTs are currently ongoing for GBM, predominantly using vaccines, and the preliminary results attained so far yielded satisfactory clinical responses associated with antitumor activity. However, some challenges have been reported, which are associated to finding therapeutic agents capable to penetrate the BBB, the identification of suitable, specific and immunogenic tumor antigens and appropriate pre- and post-therapeutic markers in order to develop immune-targeted agents. Other limitations comprise the reduced number of GBM patients skilled to incorporate particular clinical studies, and the insufficient understanding of the immune system as well as the GBM microenvironment. Given the molecular heterogeneity and immunosuppression that so well depict the GBM, combinatorial therapies targeting multiple pathways now become a need and so they have already been explored. A variety of regimens have been equated, combining immunotherapeutic strategies (vaccines, cell therapies, multiple checkpoint inhibitors, and antibodies) along with molecules targeting either tumor cells or their microenvironment, as well the current standard therapy. Consequently, more advanced CTs need to be underway to deeply explore the fundamental insights of these therapies. In addition, the discovery of new targets and mechanisms is essential in order to help widespread this field of research, and develop optimized thera-

depicted in **Table 2**.

78 Biopharmaceuticals

**4. Conclusions**

adverse events.

peutic strategies for GBM.

ing the success of the treatment [6].

This paper was supported by the Fundação para a Ciência e a Tecnologia (FCT), Portuguese Agency for Scientific Research, through: the project no. 016648 (Ref. POCI-01-0145- FEDER-016648), the project PEst-UID/NEU/04539/2013, and COMPETE (Ref. POCI-01-0145- FEDER-007440) - Centre for Neurosciences and Cell Biology (CNC); the projects PEst-OE/ QUI/UI0313/2014 and POCI-01-0145-FEDER-007630 - Coimbra Chemistry Centre; and the project UID/QUI/50006/2013 - LAQV/REQUIMTE.
