The Combination of Ionizing Radiation and Peripheral Vaccination Produces Long-term Survival of Mice Bearing Established Invasive GL261 Gliomas

Abstract

Purpose: High-grade glioma treatment includes ionizing radiation therapy. The high invasiveness of glioma cells precludes their eradication and is responsible for the dismal prognosis. Recently, we reported the down-regulation of MHC class I (MHC-I) products in invading tumor cells in human and mouse GL261gliomas. Here, we tested the hypothesis that whole-brain radiotherapy (WBRT) up-regulates MHC-I expression on GL261 tumors and enhances the effectiveness of immunotherapy. Experimental Design: MHC-I molecule expression on GL261 cells was analyzed in vitro and in vivo by flow cytometry and immunohistochemistry, respectively. To test the response of established GL261gliomas to treatment, mice with measurable (at CT imaging) brain tumors were randomly assigned to four groups receiving (a) no treatment, (b) WBRT in two fractions of 4 Gy, (c) vaccination with irradiated GL261cells secreting granulocyte-macrophage colony-stimulating factor, or (d) WBRTand vaccination. Endpoints were tumor response and survival. Results: An ionizing radiation dose of 4 Gy maximally up-regulated MHC-I molecules on GL261 cells in vitro. In vivo,WBRT induced the expression of the h2-microglobulin light chain subunit of the MHC class I complex on glioma cells invading normal brain and increased CD4+ and CD8+ Tcell infiltration. However, the survival advantage obtained with WBRTor vaccination alone was minimal. In contrast,WBRT in combination with vaccination increased long-term survival to 40% to 80%, compared with 0% to 10% in the other groups (P < 0.002). Surviving animals showed antitumor immunity by rejecting challenge tumors. Conclusion: Ionizing radiation can be successfully combined with peripheral vaccination for the treatment of established high-grade gliomas.

Radiation Immune Modulation Therapy of Glioma

“…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).…”

“…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.…”

“…Currently, there is a growing interest in combining radiation with other kinds of therapy, of which some are immunotherapy, to treat a broad range of malignancies (Chakraborty, et al 2004;Gulley, et al 2005;Sharp, et al 2007). There is also an ongoing pre-clinical search for methods to enhance the therapeutic response of malignant glioma by combining immunotherapy with single fraction or hypo-fractionated radiation therapy (Demaria, et al 2005a;Graf, et al 2002;Lumniczky, et al 2002;Newcomb, et al 2006; B. R. R. ; B. R. R. Persson, et al 2003; B. R. R. Persson, et al 2010; B. R. R. Persson, et al 2008). The clinical trials using this approach, however, are still very sparse.…”

Pathological Changes After Autologous Formalin-Fixed Tumor Vaccine Therapy Combined With Temozolomide for Glioblastoma -Three Case Reports-

“…10) Only RT increased CD4 ＋ and CD8 ＋ T cell infiltration. 13) These points should be resolved in further AFTV/TMZ studies, using immunohistochemical staining and cytotoxic T lymphocyte assay against already identified glioma-specific antigens. The immunohistochemical staining of MGMT showed positive staining in all 3 cases, suggesting relative resistance of the tumor cells to TMZ treatment.…”

“…24) RT can enhance immune response to tumors and so the combination of immunotherapy and RT is promising. 2,5,13) Recently, we closed a Phase IIa study of RT combined with AFTV (RT/AFTV) for the treatment of patients with initially diagnosed primary GBM (since September 2005, …”