Background The addition of interferon alpha (IFN) 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 IFN’s pleiotropic effects 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, Cox2 promoter activity, and IFN production. For the in vivo studies, subcutaneous hamster pancreatic cancer tumors were treated with one intratumoral dose of virus. Similarly, one 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 to controls in a hamster model. Conclusions 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.

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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.

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.

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.

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266 Background: Neoadjuvant chemoradiotherapy (CRT) is a viable treatment strategy for patients with locally advanced pancreas cancer. We evaluated 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: We performed a phase II pilot study treating patients with locally advanced pancreas cancer, including borderline resectable and initially non-resectable cases. Patients with evidence of metastases, previous chemotherapy, ECOG performance status >1, or inadequate hematologic, renal or hepatic function were excluded. Results: We enrolled 23 patients between 1/2005 and 10/2010. Mean age at enrollment was 58.6 years. Males made up 73.4% of the cohort. Of 23 patients, 7 (30.4%) completed all treatments. The remaining 16 (69.6%) patients did not receive all scheduled treatments due to severe side effects (n=7, 30.4%), progressive disease (n=3, 13%), alternative treatment (n=3, 13%), patient withdrawal (n=1, 4.3%), other disease (n=1, 4.3%), and death on study (n=1, 4.3%). Hospitalization was required due to toxicity for 47.8% (n=11) of patients. The most commonly reported grade 3 or 4 toxicities were leucopenia/cytopenia (n=19, 82.6%) and gastrointestinal (n=19, 82.6%). Other toxicities were much less common (fatigue, weight loss, pain, skin rash, all n<3). Tumor regression was not seen in any patient. Surgical resection was ultimately successful in 7 (30.4%) cases. Surgical margins were negative in 6 of 7 cases (85.7%). The mean lymph node count was 11. Positive lymph nodes were identified in 3 of 7 cases (42.8%). Overall survival for all patients was 11.5 months. Surgical resection provided significantly improved survival (22.6 months) compared to CRT alone (8.8 months). Disease free survival in resected patients was 17.2 months. Conclusions: Aggressive neoadjuvant CRT with immunotherapy may allow for resection of initially non-resectable, locally advanced pancreas cancer, but with significant toxicity. Overall survival was similar to other, less toxic regimens. In the absence of surgical resection, survival remains dismal.

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