Oncolytic adenovirus expressing interferon alpha in a syngeneic Syrian hamster model for the treatment of pancreatic cancer.

BACKGROUND: The addition of interferon (IFN) alpha to adjuvant chemoradiotherapy regimens resulted in remarkable improvements in survival for pancreatic cancer patients. However, systemic toxicities and insufficient levels of IFN at the tumor sites have limited its widespread adoption in treatment schemes. We have previously developed an IFN-expressing conditionally replicative oncolytic adenovirus and demonstrated its therapeutic effects both in vitro and in vivo. Here, the same vectors were tested in a syngeneic and immunocompetent Syrian hamster model to better understand the roles of adenoviral replication and of the pleiotropic effects of IFN on pancreatic tumor growth suppression. METHODS: Oncolytic adenoviruses expressing human or hamster IFN were designed and generated. Viral vectors were tested in vitro to determine qualitative and quantitative cell viability, cyclooxygenase 2 (Cox2) promoter activity, and IFN production. For the in vivo studies, subcutaneous hamster pancreatic cancer tumors were treated with 1 intratumoral dose of virus. Similarly, 1 intraperitoneal dose of virus was used to prolong survival in a carcinomatosis model. RESULTS: All cell lines tested demonstrated Cox2 promoter activity. The oncolytic potential of a replication competent adenovirus expressing the IFN cytokine was clearly demonstrated. These viruses resulted in significant tumor growth suppression and survival increases compared with controls in a hamster model. CONCLUSION: The profound therapeutic potential of an IFN-expressing oncolytic adenovirus for the treatment of pancreatic cancer was demonstrated in a syngeneic Syrian hamster model. These results strongly suggest the potential application of our viruses as part of combination regimens with other therapeutics.

Neoadjuvant interferon-based chemoradiation for borderline resectable and locally advanced pancreas cancer: a Phase II pilot study.

OBJECTIVES: Neoadjuvant chemoradiotherapy (CRT) is a viable treatment strategy for patients with pancreatic cancer. This study was conducted to evaluate the Virginia Mason Protocol (5-fluorouracil, cisplatin, interferon-α and radiation) given in the neoadjuvant setting for the treatment of locally advanced pancreatic cancer. METHODS: A Phase II pilot study evaluating interferon-based neoadjuvant CRT in patients with locally advanced pancreatic cancer was performed. RESULTS: A total of 23 patients were enrolled. The mean age of the patients was 58.6 years. Of the 23 patients, seven (30.4%) completed all treatments. In the remaining 16 (69.6%) patients, treatment was interrupted as a result of toxicity. The most commonly reported effects of toxicity were leucopoenia/cytopoenia (n = 19, 82.6%) and gastrointestinal effects (n = 19, 82.6%). Surgical resection was successful in seven (30.4%) patients. Margins were negative in six (85.7%) of these seven patients. Positive lymph nodes were identified in three (42.9%) of seven patients. Overall survival was 11.5 months. Surgery provided improved survival (22.6 months) compared with CRT alone (8.8 months). Disease-free survival in resected patients was 17.2 months. CONCLUSIONS: Interferon-based neoadjuvant CRT may allow for resection of locally advanced pancreatic cancer, but with significant toxicity. In the absence of surgical resection, survival remains dismal.

Generation of a novel, cyclooxygenase-2-targeted, interferon-expressing, conditionally replicative adenovirus for pancreatic cancer therapy.

BACKGROUND: Oncolytic adenoviruses provide a promising alternative for cancer treatment. Recently, adjuvant interferon (IFN)-alfa has shown significant survival benefits for pancreatic cancer, yet was impeded by systemic toxicity. To circumvent these problems adenovirus with high-level targeted IFN-alfa expression can be generated. METHODS: Conditionally replicative adenoviruses (CRAds) with improved virulence and selectivity for pancreatic cancer were generated. The vectors were tested in vitro, in vivo, and in human pancreatic cancer and normal tissue specimens. RESULTS: Adenoviral death protein and fiber modifications significantly improved oncolysis. CRAds selectively replicated in vitro, in vivo and showed persistent spread in cancer xenografts. They showed high-level replication in human pancreatic cancer specimens, but not in normal tissues. Improved IFN-CRAd oncolytic efficiency was shown. CONCLUSIONS: Optimized cyclooxygenase-2 CRAds show highly favorable effects in vitro and in vivo. We report a pancreatic cancer-specific, highly virulent, IFN-expressing CRAd, and we believe that adenovirus-based IFN therapy offers a new treatment opportunity for pancreatic cancer patients.

Delivery of interferon alpha using a novel Cox2-controlled adenovirus for pancreatic cancer therapy.

BACKGROUND: Combination therapy with interferon alpha (IFN) is correlated with improved survival in patients with pancreatic ductal adenocarcinoma (PDAc) but frequently presents side effects. We designed a novel targeted adenovirus with replication restricted to cyclooxygenase 2 (Cox2)-overexpressing PDAcs and hypothesize that the locally delivered therapeutic gene IFN can augment oncolytic effects while minimizing systemic toxicity. METHODS: IFN-expressing vectors were tested in vitro with the use of 4 PDAc cell lines with cytocidal effect measured by crystal violet and colorimetrically and IFN production assayed by ELISA. Cox2 promoter activity was checked by a luciferase reporter assay. In vivo, subcutaneous tumor xenografts with 2 PDAc cell lines in nude mice were treated with a single intratumoral viral dose. RESULTS: All PDAc cell lines were Cox2-positive. Oncolysis from the novel Cox2-controlled virus was comparable or superior to Adwt, the wild-type virus without safety features. The absence of cytocidal effect in Cox2-negative cells with the novel virus indicated cancer specificity. In vivo, stronger tumor suppression from the novel virus was seen when compared with nonreplicating IFN-expressing vectors. CONCLUSION: We demonstrated the potent therapeutic effects of a novel tumor-specific conditionally replicative IFN-expressing adenovirus. With potential to locally deliver IFN and avoid systemic toxicity, this strategy may therefore expand the application of this robust and promising therapy.

Emergence of imatinib resistance associated with downregulation of c-kit expression in recurrent gastrointestinal stromal tumor (GIST): optimal timing of resection.

INTRODUCTION: Gastrointestinal stromal tumors (GISTs) are the most common gastrointestinal mesenchymal tumors. The activating mutation in the KIT (c-kit; CD117) proto-oncogene with subsequent tyrosine kinase activation plays a central role in the pathogenesis of GIST. Tyrosine kinase inhibitors are an integral part of GIST therapy. Initial response to neoadjuvant imatinib can be expected in up to 70% of the patients, thus offering an opportunity to surgically treat those with locally advanced primary or recurrent GIST. This favorable response to imatinib, however, is plagued with development of secondary resistance during the course of therapy. CASE DESCRIPTION: We herein report a case of recurrent locally advanced GIST in an elderly man, with excellent performance status, successfully managed with the integration of neoadjuvant targeted therapy and surgery. DISCUSSION: Continued monitoring by a multidisciplinary team, including a surgeon, is vital for the success of neoadjuvant imatinib therapy for unresectable primary or recurrent GIST in the context of emergence of secondary resistance. As such, surgeons should participate in managing imatinib-treated GIST, as resection may become a viable curative option. This case also highlights that major oncologic resections can be safely performed in older persons when their performance status and comorbidities are carefully considered.