Faculty Bibliography

Our neoadjuvant clinical trial of a GM-CSF secreting allogeneic pancreas tumor vaccine (GVAX) revealed the development of tertiary lymphoid aggregates (TLAs) within the pancreatic ductal adenocarcinoma (PDA) tumor microenvironment 2 weeks after GVAX treatment. Microarray studies revealed that multiple components of the TGF-β pathway were suppressed in TLAs from patients who survived greater than 3 years and who demonstrated vaccine-enhanced mesothelin-specific T cell responses. We tested the hypothesis that combining GVAX with TGF-β inhibitors will improve the anti-tumor immune response of vaccine therapy. In a metastatic murine model of pancreatic cancer, combination therapy with GVAX vaccine and a TGF-β blocking antibody improved the cure rate of PDA-bearing mice. TGF-β blockade in combination with GVAX significantly increased the infiltration of effector CD8+ T lymphocytes, specifically anti-tumor-specific IFN-g producing CD8+ T cells, when compared to monotherapy controls (all p < 0.05). TGF-β blockade alone did not deplete T regulatory cells (Tregs), but when give in combination with GVAX, GVAX induced intratumoral Tregs were depleted. Therefore, our PDA preclinical model demonstrates a survival advantage in mice treated with an anti-TGF-β antibody combined with GVAX therapy and provides strong rational for testing this combinational therapy in clinical trials.

The majority of patients with curative resection of pancreatic ductal adenocarcinoma recur within 5 years of resection. However, the prognosis associated with different patterns of recurrence has not been well studied. A retrospective review of patients who underwent curative surgical resection of pancreatic cancer was performed. Of the 209 patients, 174 patients developed recurrent disease. Of these 174, 28(16.1%) had recurrent disease limited to lung metastases, 20(11.5%) had recurrence in the lung plus one or more other sites excluding the liver, 73(42.0%) had liver metastasis alone or liver metastasis with any other site except lung, 28(16.1%) local recurrence only, and 25(14.3%) peritoneal recurrence alone or together with local recurrence. Patients with recurrence limited to lung had a 8.5 months(Mo) median survival from recurrence to death, which was significantly better than the survival associated with recurrence in the liver(5.1Mo), in the peritoneum(2.3Mo) or locally(5.1Mo) in multivariable analyses. Among all groups, the time from surgery to the diagnosis of recurrence in patients who recurred in only in the lung was also the longest. However, 75% of patients were found to have indeterminate lung nodules on their surveillance CT scans prior to the diagnosis of recurrence in lung. This delayed diagnosis of lung recurrence may have a negative impact on survival after recurrence. In conclusion, pancreatic cancer with lung recurrence has a significantly better prognosis than recurrence in other sites. Further studies are needed to investigate how different diagnostic and treatment modalities affect the survival of this unique subpopulation of pancreatic cancer patients.

OBJECTIVE:Although pancreatic ductal adenocarcinoma is considered a rapidly progressive disease, mathematical models estimate that it takes many years for an initiating pancreatic cancer cell to grow into an advanced stage cancer. In order to estimate the time it takes for a pancreatic cancer to progress through different tumor, node, metastasis (TNM) stages, we compared the mean age of patients with pancreatic cancers of different sizes and stages. DESIGN/METHODS:Patient age, tumour size, stage and demographic information were analysed for 13,131 patients with pancreatic ductal adenocarcinoma entered into the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) database. Multiple linear regression models for age were generated, adjusting for patient ethnicity, gender, tumour location and neoplastic grades. RESULTS:African-American ethnicity and male gender were associated with an earlier age at diagnosis. Patients with stage I cancers (mean age 64.8 years) were on average 1.3 adjusted years younger at diagnosis than those with stage IV cancers (p=0.001). Among patients without distant metastases, those with T1 stage cancers were on average 1.06 and 1.19 adjusted years younger, respectively, than patients with T3 or T4 cancers (p=0.03 for both). Among patients with stage IIB cancers, those with T1/T2 cancers were 0.79 adjusted years younger than those with T3 cancers (p=0.06). There was no significant difference in the mean adjusted age of patients with stage IA versus stage IB cancers. CONCLUSIONS:These results are consistent with the hypothesis that once pancreatic ductal adenocarcinomas become detectable clinically progression from low-stage to advanced-stage disease is rapid.