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Dendritic Cell Vaccines for Gliomas 93 standard external beam radiation therapy and then administration of DC vaccinations. The recurrent patients had undergone radiation therapy and/or chemotherapy previously before presenting with recurrent tumor and then underwent surgical resection before administration of DC vaccines. After DC vaccination for all 12 GBM patients, overall survival was 100% at six months, 75% at one year, and 50% at 2 years with two long-term survivors ( 4 years). Median time to progression was 15.5 months and median overall survival was 23.4 months. For those five patients with ongoing progressive disease and bulky tumor, median overall survival was 11.7 months. For the seven patients with either gross stable disease or no measurable residual disease at baseline, overall survival was 18 to over 58 months. This resulted in an overall median survival benefit of 35.8 months after DC vaccination when compared to control population who had a median overall survival of 18.3 months. Postvaccination using conventional CTL assays, six patients were found to have peripheral tumor-specific CTL activity. These patients did not have peripheral CTL activity prior to vaccination. Those who developed systemic antitumor cytotoxicity had longer survival time compared to those patients who did not. All of the patients who had stable/minimal residual disease at baseline generated a positive CTL response (100%), whereas those with active progressive disease at baseline did not produce statistically significant cell-mediated CTL responses (0%), suggesting that those with active tumor progression/ recurrence may have an impaired ability to mount an effective cellular antitumor immune response. Eight patients who developed tumor progression on follow-up MRI postvaccine therapy underwent repeat surgical resection or biopsy. A robust infiltration of CD3 þ tumor-infiltrating lymphocytes (TIL), not present in tissue samples taken prior to DC vaccination, was found in four of the eight patients who survived >30 months. However, those patients who died within one year (3 patients) demonstrated no significant infiltration, demonstrating that accumulation of tumor-specific T cells locally within tumors is associated with positive clinical responses. CD8 þ /CD45RO þ memory T cells with lesser number of CD4 þ helper T cells were the majority of TILs identified. Liau and colleagues also found that patients who had minimal tumor burden prevaccination (4 of 4) demonstrated evidence of increased TIL, whereas those with progressive disease prevaccination (3 of 3) showed no detectable increase in TIL. The authors suggest that clinical benefit from DC vaccination may be limited by active tumor recurrence and/or bulky residual tumor, which can negatively influence T lymphocytes’ ability to accumulate within the local tumor microenvironment. This study also looked at expression of TGF-b2 and IL-10 using reverse transcription-PCR and immunohistochemistry in the tumor tissue to demonstrate whether secretion of immunosuppressive cytokines by the tumors affected local accumulation of T cells. They found that those patients with detectable TIL had lower quantitative expression of TGF-b2 and had a longer survival (>30 months) than those with higher quantitative expression of TGF-b2. The authors suggest that a high expression of TGF-b2 may decrease the
94 Luptrawan et al. ability of TIL to accumulate within CNS gliomas to mount a clinical relevant local antitumor immune response in brain cancer patients. MALIGNANT GLIOMAS AND CHEMORESISTANCE Despite recent advances in surgery, chemotherapy, and radiation therapy, the increases in median survival in patients with GBM remain modest. With bestknown treatment, the median survival for GBM is currently increased to just two to three months. A major reason for this modest response to therapy is chemotherapy resistance by malignant tumor cells. Resistance to chemotherapy can be due to either an innate property of malignant tumor cells or their ability to acquire resistance during drug treatment. Over the past decade, researchers have begun to pave the road to understanding the molecular mechanisms by which brain tumor cells develop a drug-resistant phenotype with much success (53). Fas antigen (FasA) and Fas ligand has been shown to participate in cytotoxicity mediated by T lymphocytes and NK cells. By using the combination of anti-Fas Ab and various drugs, Wakahara and his colleagues in 1997 demonstrated the ability to overcome drug resistance in ovarian cancer (54). In animal models, efficient elimination of both intrinsically resistant myeloma cells and acquired multiple drug-resistant (MDR) tumor cells was shown with granulocytemacrophage colony-stimulating factor (GM-CSF)- and IL-12-expressing tumor cell vaccines (55). Drug-resistant tumors are probably more readily lysed by MHC-restricted, tumor-associated CTLs as some drug-resistant tumor cells expressed significant higher HLA class I–surface antigens and TAP mRNA than drug-sensitive cells (56,57). Extensive investigations of intracellular vaccinations targeting molecules related to drug resistance have been performed (58). Through collective evidence, immunotherapy is demonstrating to be an effective approach in overcoming a major treatment barrier in cancer treatment—drug resistance with chemotherapy. Many cancer immunotherapy trials are limited in demonstrating an effective antitumor immune response. However, newer DC-based therapy approaches have demonstrated some success. Liu and his colleagues demonstrated for the first time that targeting of tumor-associated antigen TRP-2 by DC vaccination significantly increased chemotherapeutic sensitivity. Immunotherapy not only induces T-cell cytotoxicity as is well established, but can also make tumors more sensitive to drug therapy (59). SENSITIZATION TO CHEMOTHERAPY OF GLIOMA CELLS AFTER DC THERAPY It was demonstrated by Fisk in 1998 that by eliminating tumor cells expressing higher levels of MHC class I and relevant tumor antigens by co-culturing tumor cells with CTLs, CTL-resistant tumor cells exhibited increased drug sensitivity (57). Liu and colleagues recently found that significant drug resistance to carboplatin and temozolomide compared to wild-type U-373 (W-U373) resulted
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Translational Medicine Series 6 Can
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TRANSLATIONAL MEDICINE SERIES 1. Pr
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Informa Healthcare USA, Inc. 52 Van
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Preface Throughout the last 20 year
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Preface vii Table 1 A Diverse Techn
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Preface . . . . v Contributors . .
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Contributors Pedro Alves Ludwig Ins
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1 Factoring in Antigen Processing i
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206 Index Antigenic peptides degrad
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208 Index Chromogens, enzymatic act
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212 Index Langerhans cells, 133, 13
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Oncology and Immunology about the b
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