**6. Acknowledgement**

376 Advances in the Biology, Imaging and Therapies for Glioblastoma

metastasis. This immune response, however, is abrogated by conventional fractionated RT or adjuvant chemotherapy (Lee, et al. 2009). So far only preclinical studies of hypofractionated radiation therapy in combination with immune therapy have been performed. The results are however encouraging and clinical trials using this therapeutic regime is urgently needed for both primary and recurrent glioma (Newcomb, et al. 2006; B. R. R.

Henke et al. (2010) found that retreatment of recurrent high-grade glioma with hypofractionated radiation therapy with 20 Gy given over 1 week seems to be feasible even after a previous complete course of radiotherapy (Henke, et al. 2009). Thus it should be feasible to consider hypo-fractionated radiotherapy with about 8 Gy in one or two fractions to

**4.3 Treatment of newly diagnosed glioma with fractionated radiotherapy combined** 

An autologous formalin-fixed tumor vaccine (AFTV) has been prepared from formalinfixed and/or paraffin-embedded glioma tumor tissue obtained upon surgery and premixed with original adjuvant materials. In a clinical pilot study, AFTV inoculations of 12 patients took place at least 4 weeks after prior primary conventional glioma treatments were concluded. Of these 12 patients, four responded to the AFTV therapy: one showed a complete response, one showed a partial response, two showed minor responses, and one had stabilization of disease. The median survival period was about 11 months from the initiation of the AFTV treatment. But three of these patients survived for 20 months or more after AFTV inoculation (Ishikawa, et al. 2007). In a subsequent phase I/IIa clinical trial, the AFTV was inoculated in 24 patients with newly diagnosed glioblastoma multiforme, in combination with conventional fractionated radiotherapy. The treatment protocol in that study included aggressive tumor resection, fractionated radiotherapy, 2 Gy per fraction, up to a total dose of 60 Gy, and 3 concomitant courses of AFTV administered with an interval of one week during the last 3 weeks of irradiation. The median duration of overall survival was 21.4 months (95% CI 13.8–31.3 months). The actuarial 2-year survival rate was 40%. These results demonstrate that vaccine treatment in combination with fractionated radiotherapy may be effective in patients with newly diagnosed glioblastoma (Muragaki, et al. 2011). Since the previous pilot study with AFTV therapy only, also has shown a good response, the outcome of the phase I/IIa clinical trial might have been even better if it has been combined with hypo-fractionated radiation

Many pre-clinical models have proven that one or two radiotherapy fractions with a total absorbed dose in the range of 5 - 16 Gy in combination with immune therapy result in enhanced therapeutic response to glioma. This finding opens for the possibility of clinical testing of new challenging therapeutic regimes for glioma, based on a combination of immune-therapy and hypo-fractionated radiotherapy. A regime of one or two radiation sessions with a total radiation target dose in the order of 8 Gy in combination with clinically proven immunotherapy seem so be adequate (De Vleeschouwer, et al. 2008; Gulley, et al. 2005; J. Nemunaitis, et al. 2006a; J. J. Nemunaitis, et al. 2006b; Newcomb, et al. 2010; B. R. R.

Persson, et al. 2002; B. R. R. Persson, et al. 2010; B. R. R. Persson, et al. 2008).

recurrent glioma in combination with immune therapy.

therapy as described in the previous paragraph 4.3.

Persson, et al. 2010; Salford, et al. 2006; Salford, et al. 2004).

**5. Summary and conclusion** 

**with vaccination therapy** 

This chapter is dedicated to emeritus professor Leif G. Salford who spent his career as neuro-surgeon to fight against the "*guerrilla cells*" of glioma. He initiated the Brain Immuno Gene Tumour Therapy project "BRIGTT" with support of Märit and Hans Rausing Charitable Foundation. Berta Kamprad's foundation of cancer and the Faculty of Medicine at Lund University are gratefully acknowledged for their support in publishing this chapter.
