**3.3.2 Combination of radiation therapy and vaccination of mice with glioma**

In a study of combining radiation therapy and vaccination, mice with intracerebrally established invasive GL261 glioma were treated with two fraction of radiation therapy (2x4 Gy) to the whole brain, peripheral vaccination with cells transfected to secrete granulocytemacrophage colony-stimulating factor GM-CSF and their combination (Newcomb, et al. 2006).

Less than 10% increase in survival time was observed in mice given radiation therapy or vaccination alone. But by combining radiation therapy and vaccination a highly significant increase in the survival time, with about 40-80%, was observed. The surviving animals showed acquired antitumor immunity by rejecting challenge tumours (Newcomb, et al. 2006). These results are in good agreement with the results of (75 %) long term survivals and acquired antitumor immunity in N29 rats treated with the combination of radiation and immune therapy with cells secreting IFN (B. R. R. Persson, et al. 2010).

#### **3.3.3 Combination of radiation therapy and anti-CD137 antibodies in treatment of mice with glioma**

The immune response induced by CD137 monoclonal antibodies (BMS-469492, Bristol-Meyer Squibb) directed to the co-stimulatory molecule CD137 has shown to generate effective antitumor responses in several animal models and in clinical trials (Ascierto, et al. 2010; Mazzolini, et al. 2007; Nam, et al. 2005).

Treatment of murine lung (M109) and breast (EMT6) carcinoma with CD137 monoclonal antibodies BMS-469492 generate tumour growth retardation of 3 days in M109 tumours and of 12.5 days in EMT6 tumours. In combination with radiation therapy, however, the tumour responses were enhanced in both tumour models (Shi & Siemann 2006).

A recent study in mice with intracerebrally established invasive GL261glioma applied the combination of radiotherapy with anti-CD137 antibody directed to the co-stimulatory molecule CD137 (Newcomb, et al. 2010). The mice were treated with two fractions (2x4 Gy) radiation therapy to the whole brain. Non-specific rat IgG or anti-CD137 mAb was administered either alone or in combinations with RT.


Table 5. Median survival time of rats, with 9 animals in each group, after the different types of treatments (Newcomb, et al. 2010).

The results summarized in Table 5 show that the combination of radiation (4 Gy2) with anti-CD137 therapy resulted in complete tumour eradication and prolonged survival in six of nine (67%) mice with established brain tumours (p < 0.001). Five of the six long-term survivors in the combination group demonstrated acquired antitumor immunity by

In a study of combining radiation therapy and vaccination, mice with intracerebrally established invasive GL261 glioma were treated with two fraction of radiation therapy (2x4 Gy) to the whole brain, peripheral vaccination with cells transfected to secrete granulocytemacrophage colony-stimulating factor GM-CSF and their combination (Newcomb, et al.

Less than 10% increase in survival time was observed in mice given radiation therapy or vaccination alone. But by combining radiation therapy and vaccination a highly significant increase in the survival time, with about 40-80%, was observed. The surviving animals showed acquired antitumor immunity by rejecting challenge tumours (Newcomb, et al. 2006). These results are in good agreement with the results of (75 %) long term survivals and acquired antitumor immunity in N29 rats treated with the combination of radiation and

**3.3.3 Combination of radiation therapy and anti-CD137 antibodies in treatment of mice** 

The immune response induced by CD137 monoclonal antibodies (BMS-469492, Bristol-Meyer Squibb) directed to the co-stimulatory molecule CD137 has shown to generate effective antitumor responses in several animal models and in clinical trials (Ascierto, et al.

Treatment of murine lung (M109) and breast (EMT6) carcinoma with CD137 monoclonal antibodies BMS-469492 generate tumour growth retardation of 3 days in M109 tumours and of 12.5 days in EMT6 tumours. In combination with radiation therapy, however, the tumour

A recent study in mice with intracerebrally established invasive GL261glioma applied the combination of radiotherapy with anti-CD137 antibody directed to the co-stimulatory molecule CD137 (Newcomb, et al. 2010). The mice were treated with two fractions (2x4 Gy) radiation therapy to the whole brain. Non-specific rat IgG or anti-CD137 mAb was

days

Table 5. Median survival time of rats, with 9 animals in each group, after the different types

The results summarized in Table 5 show that the combination of radiation (4 Gy2) with anti-CD137 therapy resulted in complete tumour eradication and prolonged survival in six of nine (67%) mice with established brain tumours (p < 0.001). Five of the six long-term survivors in the combination group demonstrated acquired antitumor immunity by

IgG 31 0 anti-CD137 42 0 RT (4Gy2) alone No data No data IgG + RT (4Gy2) 37 2 anti-CD137 + RT (4Gy2) 114 6

Number of > 120 days survivals out of 9 rats

**3.3.2 Combination of radiation therapy and vaccination of mice with glioma** 

immune therapy with cells secreting IFN (B. R. R. Persson, et al. 2010).

responses were enhanced in both tumour models (Shi & Siemann 2006).

2010; Mazzolini, et al. 2007; Nam, et al. 2005).

administered either alone or in combinations with RT.

of treatments (Newcomb, et al. 2010).

Type of treatment Median survival time

2006).

**with glioma** 

rejecting challenge tumours. Antitumor immunity was associated with an increased number of tumour-infiltrating lymphocytes (TILs) in brain tumours and increased tumour-specific production of IFN. Since anti-CD137 therapy is already used in clinical trials it was suggested to be studied further in combination with local hypo-fractionated (2x4 Gy) radiation therapy for clinical translation (Newcomb, et al. 2010).
