Replication-competent Adenovirus-mediated Suicide Gene Therapy with Radiation in a Preclinical Model of Pancreatic Cancer

Abstract

In preparation for a Phase I trial, we evaluated the efficacy and toxicity of replication-competent adenovirus-mediated suicide gene therapy in combination with radiation in a preclinical model of pancreatic cancer. Human MiaPaCa-2 and PANC-1 pancreatic adenocarcinoma cells were found to be sensitive to the oncolytic effects of the Ad5-yCD/mutTK(SR39)rep-ADP adenovirus and also to the cytotoxic effects of the yeast cytosine deaminase (yCD) and herpes simplex virus thymidine kinase (HSV-1 TK(SR39)) genes in vitro. Combining Ad5-yCD/mutTK(SR39)rep-ADP-mediated suicide gene therapy with radiation significantly increased tumor control beyond that of either modality alone. Injection of Ad5-yCD/mutTK(SR39)rep-ADP in the dog pancreas at doses (10(12) virus particle (vp)) to be used in humans resulted in mild pancreatitis but not peritonitis or hepatotoxicity. Following administration of 9-(4-[(18)F]-fluoro-3-hydroxymethylbutyl)guanine ([(18)F]-FHBG), a positron-emitting substrate of HSV-1 TK, Ad5-yCD/mutTK(SR39)rep-ADP activity could be monitored non-invasively by positron emission tomography (PET). [(18)F]-FHBG uptake was readily detected in the pancreas but not in other major abdominal organs, indicating that little of the injected adenovirus disseminates to collateral tissues. These results demonstrate that Ad5-yCD/mutTK(SR39)rep-ADP-mediated suicide gene therapy has the potential to augment the effectiveness of pancreatic radiotherapy without resulting in excessive toxicity. Hence they provide the scientific basis for an ongoing Phase I trial in pancreatic cancer.

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

“…[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. 5 Moreover, Freytag et al 4 have shown that oncolytic Ad-mediated suicide gene therapy augments the effectiveness of pancreatic radiotherapy without resulting in significant toxicity. Enhanced antitumor efficacy has also been shown in combination studies using Ad5ÀD24RGD (Rb-binding mutant oncolytic Ad with an RGD (arginyl-glycyl-aspartic acid) motif in the HI-loop), CV706 (PSA (prostate-stimulating antigen)-selective oncolytic Ad) and Ad5-CD/TKrep Ads (oncolytic Ad containing a cytosine deaminase and herpes simplex virus thymidine kinase fusion gene).…”

“…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.…”

Novel oncolytic adenovirus sensitizes renal cell carcinoma cells to radiotherapy via mitochondrial apoptotic cell death

“…An E1B 55 kDa-deleted conditionally replicated adenovirus, ONYX-015, has been observed to potentiate radiation therapy, resulting in several pre-clinical studies analyzing the value of combining the two treatments (12). Several specific types of oncolytic adenovirus administered in combination with radiotherapy have been observed to exhibit greater antitumor effects than treatment with either therapy alone (13)(14)(15).…”

Imaging Virus-Associated Cancer

“…In another study Freytag et al [47] explored the efficacy and toxicity of using a secondgeneration adenovirus (Ad5-yCD/mutTKsr39rep-ADP) for combining replication-competent adenovirus-mediated suicide gene therapy with radiation therapy in an experimental dog model of pancreatic cancer. The authors demonstrated the feasibility of monitoring HSV1-sr39tk gene expression using [ 18 F]FHBG during the therapeutic trial.…”

“…Noninvasive and quantitative imaging of transgene expression using either wild type or mutant HSV1-tk-based reporter gene systems has been evaluated in preclinical models for monitoring adenoviral gene delivery [47], oncolytic herpesvirus therapy [48], adoptive cellbased therapies [49], and antitumor immune response [50], to name a few. The use of a reporter gene strategy is particularly useful to determine the spatiotemporal distribution and magnitude of expression of transgene expression to direct gene therapy in vivo.…”