724. Phase I Study of Replication-Competent Adenovirus-Mediated Suicide Gene Therapy in Combination with Conformal Radiotherapy for the Treatment of Intermediate- to High-Risk Prostate Cancer: Two Year Efficacy Results

Freytag, Svend O.; Kim, Jae Ho; Stricker, Hans; Pegg, Jan; Brown, Stephen L.; Lü, Mei

doi:10.1016/j.ymthe.2006.08.804

Cited by 110 publications

(154 citation statements)

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“…18 In humans, inflammation of the prostate due to expression of viral antigens and radiation followed by removal of necrotic tissue may contribute to a reduction of tumor burden. 19 In addition, CG7870 may also augment the antitumor activity of radiation. Malignant tumors that express adenoviral proteins may become more sensitive to treatment with DNA-damaging agents such as radiation in vivo.…”

Section: Discussionmentioning

confidence: 99%

Oncolytic adenovirus CG7870 in combination with radiation demonstrates synergistic enhancements of antitumor efficacy without loss of specificity

Dilley

Reddy

et al. 2005

Cancer Gene Ther

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Conditionally replicating adenoviruses that selectively replicate in tumor cells, but not in normal cells, are being explored as virotherapeutic agents for cancer. A prostate-specific oncolytic adenovirus, CG7870 is currently being evaluated in phase 1/2 clinical trials for the treatment of prostate cancer. To decrease the effective dose and further increase the therapeutic efficacy of CG7870, the combination of virotherapy with radiation therapy was explored in this study. CG7870 is an oncolytic adenovirus in which tumor-specific promoters are driving the expression of E1A and E1B proteins. The effects of combined treatment with CG7870 and radiation on cultured cells were determined in cytotoxicity and virus yield assays. The antitumor efficacy of CG7870 (1 Â 10 7 particles/mm 3 of tumor), 10 Gy of local radiation or both was evaluated in established subcutaneous LNCaP xenografts in nude mice. In vitro, the dual agent treatment resulted in synergistically enhanced potency at suboptimal doses of radiation and virus. Virus yield in irradiated cells increased relative to yield in nonirradiated cells without compromising the specificity of the vector for its target cell types. In vivo, CG7870 treatment alone suppressed tumor growth and extended tumor nonprogression time. The average tumor-volume of the groups treated with CG7870 only and radiation only was 121 and 126% of baseline, respectively, 39 days after treatment. The average tumor-volume of the combination group was 34% of baseline 39 days after a single dose of treatment. No significant body weight loss was observed in any treatment group. There was a significant drop in serum level of prostate-specific antigen (PSA) in the combination group compared to the group treated with either agent alone. In mice treated with CG7870 only or radiation only, serum PSA levels changed to 26 and 383% of baseline, respectively, by study day 46. In contrast, PSA levels in mice treated with CG7870 plus radiation decreased to less than 11% of baseline by study day 46. Histological analysis of tumor sections collected from the combination group revealed enhanced necrosis and more apoptotic cells. Combination of CG7870 with radiotherapy significantly increased antitumor efficacy compared to either agent alone. These results suggest that CG7870 in combination with radiation has improved antitumor efficacy at lower doses and with no additional side effects.

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Section: Discussionmentioning

confidence: 99%

Oncolytic adenovirus CG7870 in combination with radiation demonstrates synergistic enhancements of antitumor efficacy without loss of specificity

Dilley

Reddy

et al. 2005

Cancer Gene Ther

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“…Overexpression of the death protein, expression of TRAIL or deletion of the E1b-19kD gene, all have been shown to improve viral spread and efficacy of replicating adenoviruses in vitro and in vivo. 20,35,43,52,53 Various suicide genes [54][55][56][57][58] or TNF-a [59][60][61] have also been expressed with replication-competent vectors to improve cell killing, although with mixed results.…”

Section: Discussionmentioning

confidence: 99%

Modification of the p53 transgene of a replication-competent adenovirus prevents mdm2- and E1b-55kD-mediated degradation of p53

et al. 2006

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Clinical efficacy of adenovirus-mediated cancer gene therapy has been limited thus far. To improve its oncolytic effect, a replication-competent adenoviral vector was previously constructed to express high levels of p53 at a late time point in the viral life cycle. p53 expression from this vector improved tumor cell killing and viral spread in vitro. However, p53 function is antagonized by cellular mdm2 and adenoviral E1b-55kD, both of which are known to bind to and inactivate p53. Therefore, a new vector (Adp53W23S) that expresses a modified p53 transgene, which does not bind to E1b-55kD and mdm2, was constructed. The modified p53 protein was demonstrated to have a substantially prolonged half-life, and its localization was predominantly nuclear. Viral replication was unaffected by expression of the modified p53 and cancer cell killing was improved in vitro. However, in a xenograft model, efficacy was not significantly different from control virus. In conclusion, expression of a degradation-resistant p53 transgene late in the life cycle of a replication-competent adenovirus improves p53 stability and cancer cell killing in vitro. However, other factors, such as the adenoviral E1b-19kD and E1a proteins, which oppose p53 function, and limitations to viral spread need to be addressed to further improve in vivo efficacy.

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“…The CD/5-FC system is a powerful eradication system, [12][13][14] especially when CD from yeast rather than from Escherichia coli is used, 15 and it has entered clinical trials. 16,17 If appropriate culture conditions are provided, CD can also function as a positive selection system in vitro. 18,19 When de novo pyrimidine synthesis is blocked by N-(phosphonacetyl)-Laspartate (PALA), CD-bearing cells are rescued from PALA-induced cell death if cytosine and also inosine are given to drive the pyrimidine salvage pathway.…”

Section: Introductionmentioning

confidence: 99%

Enriching suicide gene bearing tumor cells for an increased bystander effect

et al. 2006

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The success of cancer gene therapies requiring in vivo gene transfer is severely hampered by the low efficacy of gene transfer, which has been difficult to improve. We therefore established a novel strategy to increase the share of transduced cells post gene transfer. We hypothesized that in vivo selection of tumor cells transduced with a suicide gene effectively enriches these cells within a tumor, thus allowing for an increased bystander effect after the prodrug is given, leading to enhanced eradication of tumor cells. We reasoned that in vivo enrichment should be achieved by exploiting the metabolism of the suicide gene product. For this 'enrichment-eradication' strategy we chose a fusion gene of cytosine deaminase and uracil phosphoribosyl transferase. Positive selection (enrichment) was to be achieved by concurrently giving N-(phosphonacetyl)-L-aspartate, an inhibitor of pyrimidine de novo synthesis, which leads to pyrimidine depletion-mediated death of non-transduced cells, and cytosine, to rescue fusion gene expressing cells via the pyrimidine salvage pathway. Negative selection (eradication) was to be induced by giving the prodrug 5-fluorocytosine. Indeed, murine NXS2 neuroblastoma cells transduced with the fusion gene were effectively enriched in vitro, leading to a near-complete bystander effect. In vivo enrichment-eradication of NXS2 cells led to decreased tumor growth. This proof-of-principle study shows that enrichment-eradication may compensate the effects of low in vivo gene transfer efficacy, a major obstacle in cancer gene therapy.

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724. Phase I Study of Replication-Competent Adenovirus-Mediated Suicide Gene Therapy in Combination with Conformal Radiotherapy for the Treatment of Intermediate- to High-Risk Prostate Cancer: Two Year Efficacy Results

Cited by 110 publications

References 0 publications

Oncolytic adenovirus CG7870 in combination with radiation demonstrates synergistic enhancements of antitumor efficacy without loss of specificity

Oncolytic adenovirus CG7870 in combination with radiation demonstrates synergistic enhancements of antitumor efficacy without loss of specificity

Modification of the p53 transgene of a replication-competent adenovirus prevents mdm2- and E1b-55kD-mediated degradation of p53

Enriching suicide gene bearing tumor cells for an increased bystander effect

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