Radiotherapy Enhances Antitumor Effect of Anti-CD137 Therapy in a Mouse Glioma Model

Abstract

Previously, we reported that peripheral vaccination of mice with modified autologous tumor cells secreting granulocyte-macrophage colony-stimulating factor (GM-CSF) combined with ionizing radiation to the whole brain cured 50% of mice using a syngeneic, intracranial model of murine high-grade glioma. Here, we tested the combination of radiotherapy (4 Gy × 2) with an immunotherapeutic approach using an anti-CD137 antibody directed to the co-stimulatory molecule CD137. The CD137 antibody has shown promise in generating effective antitumor responses in several animal models and has demonstrated a favorable toxicity profile in the clinic. The combination of radiation and anti-CD137 therapy resulted in complete tumor eradication and prolonged survival in six of nine (67%) mice with established brain tumors (P = 0.0009). Five of six (83%) long-term survivors in the combination group demonstrated antitumor immunity by rejecting challenge tumors. Antitumor immunity was associated with an increased number of tumor-infiltrating lymphocytes (TILs) in brain tumors and increased tumor-specific production of γ IFN. In view of the finding that radiation enhanced the antitumor effect of anti-CD137 therapy, this approach should be studied further for clinical translation.

Tumor-secreted SDF-1 promotes glioma invasiveness and TAM tropism toward hypoxia in a murine astrocytoma model

“…21 (see Supplemental Methods). Before the kill, the animals were anesthetized and then perfused transcardially with PBS followed by 4% paraformaldehyde.…”

Radiation Immune Modulation Therapy of Glioma

“…Nemunaitis, et al 2006a; J. J. Nemunaitis, et al 2006b;Newcomb, et al 2010; B. R. R. Persson, et al 2010;Salford, et al 2006;.…”

“…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.…”

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

“…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).…”