**1. Introduction**

412 Advances in the Biology, Imaging and Therapies for Glioblastoma

Wouters BG, Sky AM, Skarsgard LD. (1996). Low dose hypersensitivity and increased

*Radiat Res*, 146, 399–413.

radioresistance in a panel of human tumor cell lines with different radiosensitivity.

Since many decades, medical doctors and researchers have been intrigued by the possible beneficial contribution of the immune system in the long-lasting combat against cancer. Both in the cellular and humoral immunity arms, powerful tools are available to target the cancer cell. Moreover, the gradual shift of a focus on aspecific reinforcement of the innate immune system towards a specifically activated adaptive immunity in order to reject cancer cells has dominated the field of the last 10 to 20 years(1). Restorative immunotherapy in which cytokine balances are restored or reset and aspecific adoptive immunotherapy using e.g. natural killer (NK) cells or lymphokine-activated killer (LAK) cells are classical representations of the first wave. Specific adoptive immunotherapy using ex vivo activated antitumor cytotoxic T cells and especially active specific immunotherapy ('cancer vaccines') are representative for the second wave. Thorough changes in the underlying basic immunology mechanism guide these novel approaches. To date, only the different variants of cancer vaccines are able to induce an immunological memory, as such being the only approach potentially protecting the patients for future cancer re-challenges(2). A perceived low rate of classical objective responses, restricted to volume changes of a measurable tumor burden, has been the principal body of criticism against these therapies.

Several new insights however, especially focusing on changes in the micro-environment of the tumors, are only starting to be unraveled. Without any doubt, they're already now revealing much more than the previous tips of the curtains. Nowadays, converging evidence is being gained in a rapid way, for the need to move towards a third wave of immunotherapy approaches, those of the multimodal integrated immunotherapy paradigms, considering all the relevant players in the complex field of tumor immunology.
