BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Authors: Mark W Kieran; Liliana Goumnerova; Peter Manley; Susan N Chi; Karen J Marcus; Andrea G Manzanera; Maria Lucia Silva Polanco; Brian W Guzik; Estuardo Aguilar-Cordova; C Marcela Diaz-Montero; Arthur J DiPatri; Tadanori Tomita; Rishi Lulla; Lianne Greenspan; Laura K Aguilar; Stewart Goldman Journal: Neuro Oncol Date: 2019-03-18 Impact factor: 12.300
Authors: Charu Aggarwal; Andrew R Haas; Susan Metzger; Laura K Aguilar; Estuardo Aguilar-Cordova; Andrea G Manzanera; Gregoria Gómez-Hernández; Sharyn I Katz; Evan W Alley; Tracey L Evans; Joshua M Bauml; Roger B Cohen; Corey J Langer; Steven M Albelda; Daniel H Sterman Journal: Mol Ther Date: 2018-02-21 Impact factor: 11.454
Authors: Maria-Carmela Speranza; Carmela Passaro; Franz Ricklefs; Kazue Kasai; Sarah R Klein; Hiroshi Nakashima; Johanna K Kaufmann; Abdul-Kareem Ahmed; Michal O Nowicki; Prisca Obi; Agnieszka Bronisz; Estuardo Aguilar-Cordova; Laura K Aguilar; Brian W Guzik; Xandra Breakefield; Ralph Weissleder; Gordon J Freeman; David A Reardon; Patrick Y Wen; E Antonio Chiocca; Sean E Lawler Journal: Neuro Oncol Date: 2018-01-22 Impact factor: 12.300
Authors: Lee A Wheeler; Andrea G Manzanera; Susan D Bell; Robert Cavaliere; John M McGregor; John C Grecula; Herbert B Newton; Simon S Lo; Behnam Badie; Jana Portnow; Bin S Teh; Todd W Trask; David S Baskin; Pamela Z New; Laura K Aguilar; Estuardo Aguilar-Cordova; E Antonio Chiocca Journal: Neuro Oncol Date: 2016-02-02 Impact factor: 12.300