Gene-mediated cytotoxic immunotherapy as adjuvant to surgery or chemoradiation for pancreatic adenocarcinoma

• DOI: 10.1007/s00262-015-1679-3
• Publication Date: 2015-03-20T10:08:12Z
• Authors: Laura K. Aguilar; Lawrence A. Shirley; Vincent M. Chung; Christopher L. Marsh; Jon Walker; Walter Coyle; Howard Marx; Tanios Bekaii-Saab; Gregory B. Lesinski; Benjamin Swanson; Daniel Sanchez; Andrea G. Manzanera; Estuardo Aguilar-...; Mark Bloomston
• Keywords: Adult; Male; Dose-Response Relationship, Drug; Genetic Vectors; Acyclovir; Chemoradiotherapy; Genetic Therapy; Adenocarcinoma; Middle Aged; Combined Modality Therapy; Immunohistochemistry; Thymidine Kinase; Adenoviridae; 3. Good health; Pancreatic Neoplasms; 03 medical and health sciences; 0302 clinical medicine; Valacyclovir; Humans; Female; Immunotherapy; Neoplasm Recurrence, Local; Aged

While surgical resection of pancreatic adenocarcinoma provides the only chance of cure, long-term survival remains poor. Immunotherapy may improve outcomes, especially as adjuvant to local therapies. Gene-mediated cytotoxic immunotherapy (GMCI) generates a systemic anti-tumor response through local delivery of an adenoviral vector expressing the HSV-tk gene (aglatimagene besadenovec, AdV-tk) followed by anti-herpetic prodrug. GMCI has demonstrated synergy with standard of care (SOC) in other tumor types. This is the first application in pancreatic cancer.Four dose levels (3 × 10(10) to 1 × 10(12) vector particles) were evaluated as adjuvant to surgery for resectable disease (Arm A) or to 5-FU chemoradiation for locally advanced disease (Arm B). Each patient received two cycles of AdV-tk + prodrug.Twenty-four patients completed therapy, 12 per arm, with no dose-limiting toxicities. All Arm A patients were explored, eight were resected, one was locally advanced and three had distant metastases. CD8(+) T cell infiltration increased an average of 22-fold (range sixfold to 75-fold) compared with baseline (p = 0.0021). PD-L1 expression increased in 5/7 samples analyzed. One node-positive resected patient is alive >66 months without recurrence. Arm B RECIST response rate was 25 % with a median OS of 12 months and 1-year survival of 50 %. Patient-reported quality of life showed no evidence of deterioration.AdV-tk can be safely combined with pancreatic cancer SOC without added toxicity. Response and survival compare favorably to expected outcomes and immune activity increased. These results support further evaluation of GMCI with more modern chemoradiation and surgery as well as PD-1/PD-L1 inhibitors in pancreatic cancer.