An Experimental Vaccine Expressing Wild‐Type p53 Induces Protective Immunity against Glioblastoma Cells with High Levels of Endogenous p53

Blaszczyk-Thurin, Magdalena; Ertl, I. O.; Ertl, Hildegund C. J.

doi:10.1046/j.1365-3083.2002.01119.x

Cited by 12 publications

(10 citation statements)

References 54 publications

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“…Thus at best, RAD50-derived epitopes are only weakly and inconsistently expressed. A similar inconcistency between lack of killing of tumor cells in vitro and protection against tumor take was reported recently after immunization with wild-type p53 expressing vaccinia virus [15]. Protection in this latter work was shown to involve both CD4, CD8 and NK cell responses.…”

Section: Discussionsupporting

confidence: 77%

Tumor–associated antigens identified by mRNA expression profiling as tumor rejection epitopes

Andersen

Rühwald

Thorn

et al. 2003

J Immune Based Ther Vaccines

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Thirteen H-2 b -binding peptides derived from six potentially overexpressed proteins in p53 -/-thymoma (SM7) cells were studied for immunogenecity and vaccine-induced prevention of tumor growth in mice inoculated with SM7 tumor cells. Six of the peptides generated specific CTL responses after immunization, but only two of these peptides (RAD 23-31 and RAD 24-31 ) were capable of generating a weak vaccination-induced protection against adoptive tumor growth. SM7 inoculated mice treated with a blocking antibody against the inhibitory T cell signal transducing molecule CTLA4 appeared to delay tumor take, suggesting that SM7 thymoma cells are recognized by the adaptive immune system of the host. However, prophylactic vaccination with RAD 23-31 and RAD 24-31 peptides combined with anti-CTLA4 Ab treatment and did not improve tumor resistance. Our data would indicate that vaccination with immunogenic peptides derived from potentially overexpressed tumor proteins, as identified by mRNA expression profiling of p53 -/-thymoma cells, at best results in a weak tumor protection thus questioning this way of detection of new tumor rejection epitopes.

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Section: Discussionsupporting

confidence: 77%

Tumor–associated antigens identified by mRNA expression profiling as tumor rejection epitopes

Andersen

Rühwald

Thorn

et al. 2003

J Immune Based Ther Vaccines

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“…U87MG cells had wild-type p53, 26,27 whereas U251MG and GL261 cells had mutated p53. 26,28 These cell lines were selected on the basis of COX-2 expression screening by immunoblotting. The p53 and COX-2 expression levels of each cell line are shown in Supplementary Fig.…”

Section: Cell Lines and Normoxic And Hypoxic Cell Culture Conditionsmentioning

confidence: 99%

Celecoxib enhances radiosensitivity of hypoxic glioblastoma cells through endoplasmic reticulum stress

et al. 2013

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Background. Refractoriness of glioblastoma multiforme (GBM) largely depends on its radioresistance. We investigated the radiosensitizing effects of celecoxib on GBM cell lines under both normoxic and hypoxic conditions. Methods. Two human GBM cell lines, U87MG and U251MG, and a mouse GBM cell line, GL261, were treated with celecoxib or g-irradiation either alone or in combination under normoxic and hypoxic conditions. Radiosensitizing effects were analyzed by clonogenic survival assays and cell growth assays and by assessing apoptosis and autophagy. Expression of apoptosis-, autophagy-, and endoplasmic reticulum (ER) stressrelated genes was analyzed by immunoblotting. Results. Celecoxib significantly enhanced the radiosensitivity of GBM cells under both normoxic and hypoxic conditions. In addition, combined treatment with celecoxib and g-irradiation induced marked autophagy, particularly in hypoxic cells. The mechanism underlying the radiosensitizing effect of celecoxib was determined to be ER stress loading on GBM cells. Conclusion. Celecoxib enhances the radiosensitivity of GBM cells by a mechanism that is different from cyclooxygenase-2 inhibition. Our results indicate that celecoxib may be a promising radiosensitizing drug for clinical use in patients with GBM. Keywords:autophagy, celecoxib, ER stress, glioblastoma, hypoxia, radiosensitivity. G lioblastoma multiforme (GBM) is the most frequently occurring malignant tumor of the central nervous system. 1 Despite standard carecomprising maximum surgical resection, 60 Gy of conventional radiotherapy, and chemotherapy with temozolomide (TMZ), the median survival time among patients with GBM is 1 year. 2The molecular mechanisms underlying the initiation and progression of GBM reported to date fall into 2 categories: (i) primary GBM with increased epidermal growth factor receptor (EGFR) expression and mutation of the phosphatase and tensin homolog and (ii) secondary GBM that is transformed from benign glioma types with stepwise mutations in the p53 and retinoblastoma genes. It is known that these genetic alterations in GBM are significantly associated with clinical prognosis.1 It has also been reported that methylation of O6-methylguanine-DNA methyltransferase increases the susceptibility of GBM tumor cells to alkylating agents, such as TMZ, 3 and mutation in the isocitrate dehydrogenase 1 gene was recently reported to significantly affect the prognosis in patients with GBM. 4 On the basis of these findings, therapy that targets these specific molecules could be a promising approach for controlling GBM. One possible target is cyclooxygenase-2 (COX-2) because a positive association has been reported among the levels of COX-2, EGFR/EGFRvIII, and activated signal transducer and activator of transcription 3 (STAT3).5 COX-2 expression was reportedly increased in human GBM and was negatively correlated with clinical outcomes in patients. 6 Celecoxib, a nonsteroidal anti-inflammatory drug (NSAID), selectively inhibits This drug is used clinically both for patients with ...

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“…Using an immunization strategy in mice, it has been possible to generate wtp53-specific CTL that can lyse murine p53-overexpressing tumor cells (11,12). In addition, some immunotherapy approaches in the murine model have been successful at preventing the outgrowth of p53-overexpressing tumors (13)(14)(15)(16)(17). Treatment of established p53-overexpressing tumors in mice has required intratumoral immunization with ALVAC/p53 (18), infusion of epitope-specific CTL (12,19), infusion of epitope-pulsed or adenovirus-infected dendritic cells (DC) (11,20), or infusion of mutant p53 epitope with IL-12 (21).…”

mentioning

confidence: 99%

CTLA-4 Blockade Enhances the Therapeutic Effect of an Attenuated Poxvirus Vaccine Targeting p53 in an Established Murine Tumor Model

Espenschied¹,

Lamont²,

Longmate

et al. 2003

The Journal of Immunology

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p53 is overexpressed by half of all cancers, and is an attractive target for a vaccine approach to immunotherapy. p53 overexpression is frequently the result of point mutations, which leaves the majority of the protein in its wild-type form. Therefore, the majority of p53 sequence is wild type, making it a self-protein for which tolerance plays a role in limiting immune responses. To overcome tolerance to p53, we have expressed wild-type murine p53 in the nonpathogenic attenuated poxvirus, modified vaccinia virus Ankara (recombinant modified vaccinia virus Ankara expressing wild-type murine p53 (rMVAp53)). Mice immunized with rMVAp53 vaccine developed vigorous p53-specific CTL responses. rMVAp53 vaccine was evaluated for its ability to inhibit the outgrowth of the syngeneic murine sarcoma Meth A, which overexpresses mutant p53. Mice were inoculated with a lethal dose (5 × 105 cells injected s.c.) of Meth A tumor cells and vaccinated by i.p. injection 3 days later with 5 × 107 PFU of rMVAp53. The majority of mice remained tumor free and resistant to rechallenge with Meth A tumor cells. We wished to determine whether rMVAp53 immunization could effect the rejection of an established, palpable Meth A tumor. In subsequent experiments, mice were injected with 106 Meth A tumor cells, and treated 6 days later with anti-CTLA-4 Ab (9H10) and rMVAp53. The majority of treated mice had complete tumor regression along with lasting tumor immunity. In vivo Ab depletion confirmed that the antitumor effect was primarily CD8 and to a lesser extent CD4 dependent. These experiments demonstrate the potential of a novel cell-free vaccine targeting p53 in malignancy.

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An Experimental Vaccine Expressing Wild‐Type p53 Induces Protective Immunity against Glioblastoma Cells with High Levels of Endogenous p53

Cited by 12 publications

References 54 publications

Tumor–associated antigens identified by mRNA expression profiling as tumor rejection epitopes

Tumor–associated antigens identified by mRNA expression profiling as tumor rejection epitopes

Celecoxib enhances radiosensitivity of hypoxic glioblastoma cells through endoplasmic reticulum stress

CTLA-4 Blockade Enhances the Therapeutic Effect of an Attenuated Poxvirus Vaccine Targeting p53 in an Established Murine Tumor Model

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