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• W1995891130 abstract "Purpose/Objective: The high invasiveness of glioma cells into surrounding brain is largely responsible for the mortality associated with this tumor. Presently, no therapy can effectively target invading glioma cells, but immunotherapy is being actively investigated. Peripheral vaccination with irradiated glioma cells modified to secrete GM-CSF has been shown in experimental models to induce anti-tumor T cells capable of preventing or controlling early stage growth of intracranial tumors (Cancer Gene Ther 1997 Nov-Dec 4:345–352). However, anti-tumor T cells are less effective against well-established gliomas. In order to study in vivo invading glioma cells at the cellular and molecular level, we have developed green fluorescent protein (GFP)-tagged GL261 glioma cells. Employing this poorly immunogenic mouse model we recently reported that invading glioma cells selectively down-regulate expression of Major Histocompatibility Complex (MHC) class I molecules (Lab Invest 2005 Mar 85:328–341). This implies that invading glioma cells are less susceptible to recognition and killing by T cells. Notably, we found that irradiation in vitro significantly up-regulated MHC class I molecules on GL261 cells. The aim of the present study is to test in vivo whether whole brain radiation therapy (WBRT) can be combined with peripheral vaccination to improve the therapeutic efficacy of this immunotherapeutic approach against a well-established glioma. Materials/Methods: C57BL/6 mice were injected on day 0 with 105 GL261 glioma cells, stereotactically in the brain. On Day 12, when tumors are approximately 4 ± 1 mm3 in volume, mice were randomly assigned to 4 groups of 5 animals each: 1) no treatment; 2) WBRT; 3) vaccination (VAC); 4) WBRT + VAC. RT was delivered to the whole brain, with mice under anesthesia, in two consecutive 4 Gy fractions, on Days 12 and 14. On Day 14, animals in groups 3 and 4 were vaccinated with irradiated (25 Gy) GL261 glioma cells transduced to secrete GM-CSF, by s.c. injection in the inguinal region (2.5 × 106 cells/side). Mice were followed for survival. Survival differences were analyzed by Kaplan-Meier survival curves using the Logrank test. Results: The control mice showed a mean survival of 33±7 days compared with 45±21 days in the VAC group and 55±24 days in the WBRT group. In the RT + VAC group, only one mouse developed a tumor requiring sacrifice at Day 50. On Day 75 post implantation, surviving mice (4/5 in WBRT + VAC, 1/5 in VAC, and 1/5 in WBRT groups) were challenged s.c. with GL261 glioma cells (2 × 106) in the left hind leg together with 5 näıve mice. All näıve mice developed palpable tumors within 3 weeks, whereas all of the challenged mice remain tumor-free one month after challenge, indicating the presence of a long-lived anti-tumor immune response. Conclusions: These results indicate that WBRT can be successfully combined with peripheral VAC in mice with established glioma. Importantly, whereas VAC by itself had a limited therapeutic impact, in combination with WBRT it led to long-term tumor-free survival. Irradiation may synergize with immunotherapy by delaying tumor growth, but also by enhancing the susceptibility of invading glioma cells to anti-tumor T cells. Further studies are ongoing to determine whether RT-induced MHC class I up-regulation on invading glioma cells plays a role in improving tumor cell killing by the anti-tumor T-cells. Results of these studies may have important clinical implications, since analysis of primary tumor specimens from patients has shown down-regulation of MHC expression on invading glioma cells, similar to the findings in the experimental model." @default.
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• W1995891130 date "2005-10-01" @default.
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• W1995891130 title "The Combination of Ionizing Radiation and Peripheral Vaccination Produces Long-Term Survival of Mice Bearing Invasive GL261 Glioma" @default.
• W1995891130 doi "https://doi.org/10.1016/j.ijrobp.2005.07.294" @default.
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