AdΔ24 and the p53‐expressing variant AdΔ24‐p53 achieve potent anti‐tumor activity in glioma when combined with radiotherapy

Abstract

Exogenous p53 expression does not appear to increase the synergistic interaction of CRAds combined with radiotherapy. These results however do indicate that radiotherapy provides the time frame in which AdDelta24 and AdDelta24-p53 can eradicate established tumors that would otherwise escape treatment, and establishes the need to combine these modalities to form an effective anti-cancer treatment.

Double E1B 19 kDa- and E1B 55 kDa-deleted oncolytic adenovirus in combination with radiotherapy elicits an enhanced anti-tumor effect

“…To show any additive or synergistic effects of combination therapy in vivo, we selected a dose of Ad that was fivefold lower than the effective dose in the single-agent treatment experiments. After they reached 80-100 mm 3 in volume, subcutaneously implanted C33A tumors were randomized and treated with PBS (phosphate-buffered saline), AdÀDE1B55 or AdÀDE1B19/55 alone, or in combination with radiation (10 Gy). Local tumor irradiation was preceded by three sequential injections of oncolytic Ads 24 h before.…”

“…When tumor size reached about 80-100 mm 3 , the animals were randomized and treated by direct injection with PBS, AdÀDE1B55 or AdÀDE1B19/55 at a dose of 1 Â 10 8 PFU on days 0, 2 and 4. For the combination group, the animals were treated locally with a single application of radiation (10 Gy) on the right thigh on day 5 using a clinical linear accelerator (Varian Co., Milpitas, CA, USA).…”

“…1 In recent years, a therapeutic regimen combining radiation with oncolytic Ad has shown some promise in controlling tumor cell growth. [2][3][4] An E1B 55 kDa-deleted oncolytic Ad, dl1520 (ONYX-015), has been shown to potentiate radiation therapy, 5 leading to several pre-clinical studies examining the value of combining these two modalities. [6][7][8][9] Intra-arterial injections of dl1520, in conjunction with total body irradiation (5 Gy), result in enhanced anti-tumor efficacy in p53 functional human malignant glioma xenograft models.…”

Targeting glioblastoma with oncolytic adenovirus delta 24

“…Treatment to glioma with Ad-Δ24 or its derivatives has been observed to enhance when combined with TRAIL, [16] adenovirus expressing p53, [22] temozolomide, [23] radiation [24] and topoisomerase I inhibitor irinotecan. [25] Autophagic induced cell death and induction of apoptosis are well-characterized results of Ad-Δ24 infection giving the erratum for combination treatments.…”

Viruses, gene therapy and stem cells for the treatment of human glioma

“…45 In vivo, combination therapy of radiotherapy with either Delta-24 or AdDelta24-p53 significantly increased the number of mice showing tumor regression (100%) and long-term survival (50%), but no differences between the two viruses were noted, suggesting that exogenous p53 expression did not increase the synergistic interaction of conditionally replicative adenoviruses with radiotherapy. 46 Other modifications of the Delta-24, included addition of the herpes simplex virus type 1 thymidine kinase-green fluorescent protein fusion gene (TK-GFP) encompassing CRAd (Ad5Delta24TK-GFP), that could efficiently penetrate into tumors and cause oncolysis. 47 An oncolytic herpes simplex virus that expressed human tissue inhibitor of metalloproteinases 3 or firefly luciferase showed enhanced antitumor efficacy through multiple mechanisms, including direct cytotoxicity, elevated virus titer and reduced tumor neovascularization.…”