Ali A Maawy1, Yukihiko Hiroshima2, Yong Zhang3, Miguel Garcia-Guzman4, George A Luiken5, Hisataka Kobayashi6, Robert M Hoffman7, Michael Bouvet8. 1. Department of Surgery, University of California San Diego, San Diego, California. 2. Department of Surgery, University of California San Diego, San Diego, California; AntiCancer, Inc, San Diego, California; Department of Surgery, Yokohama City University, Yokohama City, Japan. 3. AntiCancer, Inc, San Diego, California. 4. Aspyrian Therapeutics, San Diego, California. 5. OncoFluor, Inc, San Diego, California. 6. National Institutes of Health, Bethesda, Maryland. 7. Department of Surgery, University of California San Diego, San Diego, California; AntiCancer, Inc, San Diego, California. 8. Department of Surgery, University of California San Diego, San Diego, California; Department of Surgery, VA Healthcare System, San Diego, California. Electronic address: mbouvet@ucsd.edu.
Abstract
BACKGROUND: Photoimmunotherapy (PIT) is based on the use of a monoclonal antibody specific to cancer epitopes conjugated to a photosensitizer near-infrared phthalocyanine dye (IR700). In this study, PIT with IR700 conjugated to anti-carcinoembryonic antigen (CEA) was used as an adjunct to surgery in orthotopically-implanted human pancreatic cancer in a nude mouse model to eliminate microscopic disease in the post-surgical tumor bed and prevent local as well as metastatic recurrence. MATERIALS AND METHODS: Athymic nude mice were orthotopically implanted with the human pancreatic cancer cell line BxPC3 expressing green fluorescent protein. After tumor engraftment, the mice were divided into two groups as follows: bright light surgery (BLS) + anti-CEA-IR700 + 690 nm laser (PIT); and BLS only. Anti-CEA-IR700 (100 μg) was administered to the treatment group via tail-vein injection 24 h before therapy. Tumors were resected, and the surgical bed was treated with intraoperative phototherapy at an intensity of 150 mW/cm(2) for 30 min. Mice were imaged noninvasively for 8 wk using an OV-100 small animal fluorescence imager. RESULTS: BLS + PIT reduced local recurrence to 1/7 mice from 7/7 mice with BLS-only (P = 0.001) and metastatic recurrence to 2/7 mice compared with 6/7 mice with BLS-only (P = 0.03). Local tumor growth continued at a rapid rate after BLS-only compared with BLS + PIT where almost no local growth occurred. There was a significant difference in tumor size between mice in the BLS + PIT (2.14 mm(2), 95% confidence interval [CI] [-2.06 to 6.34] and BLS-only groups (115.2 mm(2), 95% CI [88.8-141.6]) at 6 wk after surgery (P < 0.001). There was also a significant difference in tumor weight between the BLS + PIT group (6.65 mg, 95% CI [-6.35 to 19.65] and BLS-only group (1100 mg, 95% CI [794-1406] at 8 wk after surgery (P < 0.001). CONCLUSIONS: PIT holds promise in the treatment of pancreatic cancer and may serve as a useful adjunct to surgery in the eradication of microscopic residual disease that can lead to both local and metastatic recurrence. Further studies are warranted to investigate the potential toxicities of PIT, especially with regard to anastomoses, such as those involved in pancreaticoduodenectomy.
BACKGROUND: Photoimmunotherapy (PIT) is based on the use of a monoclonal antibody specific to cancer epitopes conjugated to a photosensitizer near-infrared phthalocyanine dye (IR700). In this study, PIT with IR700 conjugated to anti-carcinoembryonic antigen (CEA) was used as an adjunct to surgery in orthotopically-implanted humanpancreatic cancer in a nude mouse model to eliminate microscopic disease in the post-surgical tumor bed and prevent local as well as metastatic recurrence. MATERIALS AND METHODS: Athymic nude mice were orthotopically implanted with the humanpancreatic cancer cell line BxPC3 expressing green fluorescent protein. After tumor engraftment, the mice were divided into two groups as follows: bright light surgery (BLS) + anti-CEA-IR700 + 690 nm laser (PIT); and BLS only. Anti-CEA-IR700 (100 μg) was administered to the treatment group via tail-vein injection 24 h before therapy. Tumors were resected, and the surgical bed was treated with intraoperative phototherapy at an intensity of 150 mW/cm(2) for 30 min. Mice were imaged noninvasively for 8 wk using an OV-100 small animal fluorescence imager. RESULTS: BLS + PIT reduced local recurrence to 1/7 mice from 7/7 mice with BLS-only (P = 0.001) and metastatic recurrence to 2/7 mice compared with 6/7 mice with BLS-only (P = 0.03). Local tumor growth continued at a rapid rate after BLS-only compared with BLS + PIT where almost no local growth occurred. There was a significant difference in tumor size between mice in the BLS + PIT (2.14 mm(2), 95% confidence interval [CI] [-2.06 to 6.34] and BLS-only groups (115.2 mm(2), 95% CI [88.8-141.6]) at 6 wk after surgery (P < 0.001). There was also a significant difference in tumor weight between the BLS + PIT group (6.65 mg, 95% CI [-6.35 to 19.65] and BLS-only group (1100 mg, 95% CI [794-1406] at 8 wk after surgery (P < 0.001). CONCLUSIONS: PIT holds promise in the treatment of pancreatic cancer and may serve as a useful adjunct to surgery in the eradication of microscopic residual disease that can lead to both local and metastatic recurrence. Further studies are warranted to investigate the potential toxicities of PIT, especially with regard to anastomoses, such as those involved in pancreaticoduodenectomy.
Authors: Hop S Tran Cao; Sharmeela Kaushal; Cristina A Metildi; Rhiana S Menen; Claudia Lee; Cynthia S Snyder; Karen Messer; Minya Pu; George A Luiken; Mark A Talamini; Robert M Hoffman; Michael Bouvet Journal: Hepatogastroenterology Date: 2012-09
Authors: Michael Bouvet; Jinwei Wang; Stephanie R Nardin; Rounak Nassirpour; Meng Yang; Eugene Baranov; Ping Jiang; A R Moossa; Robert M Hoffman Journal: Cancer Res Date: 2002-03-01 Impact factor: 12.701
Authors: Cristina A Metildi; Sharmeela Kaushal; Claudia Lee; Chanae R Hardamon; Cynthia S Snyder; George A Luiken; Mark A Talamini; Robert M Hoffman; Michael Bouvet Journal: J Am Coll Surg Date: 2012-04-27 Impact factor: 6.113
Authors: Sharmeela Kaushal; Michele K McElroy; George A Luiken; Mark A Talamini; A R Moossa; Robert M Hoffman; Michael Bouvet Journal: J Gastrointest Surg Date: 2008-07-30 Impact factor: 3.452
Authors: Cristina A Metildi; Sharmeela Kaushal; George A Luiken; Mark A Talamini; Robert M Hoffman; Michael Bouvet Journal: J Surg Oncol Date: 2013-11-19 Impact factor: 3.454
Authors: Ali A Maawy; Yukihiko Hiroshima; Yong Zhang; George A Luiken; Robert M Hoffman; Michael Bouvet Journal: PLoS One Date: 2014-05-23 Impact factor: 3.240
Authors: Elmire Hartmans; Matthijs D Linssen; Claire Sikkens; Afra Levens; Max J H Witjes; Gooitzen M van Dam; Wouter B Nagengast Journal: Oncotarget Date: 2017-05-02
Authors: Ancély F Dos Santos; Letícia F Terra; Rosangela A M Wailemann; Talita C Oliveira; Vinícius de Morais Gomes; Marcela Franco Mineiro; Flávia Carla Meotti; Alexandre Bruni-Cardoso; Maurício S Baptista; Leticia Labriola Journal: BMC Cancer Date: 2017-03-15 Impact factor: 4.430
Authors: Adrian Rosenberg; Fuyuki Inagaki; Takuya Kato; Ryuhei Okada; Hiroaki Wakiyama; Aki Furusawa; Peter L Choyke; Hisataka Kobayashi Journal: Cancer Med Date: 2020-06-24 Impact factor: 4.452
Authors: Hannah M Hollandsworth; Siamak Amirfakhri; Filemoni Filemoni; Justin Molnar; Robert M Hoffman; Paul Yazaki; Michael Bouvet Journal: PLoS One Date: 2020-06-18 Impact factor: 3.240
Authors: Ancély F Dos Santos; Alex Inague; Gabriel S Arini; Letícia F Terra; Rosangela A M Wailemann; André C Pimentel; Marcos Y Yoshinaga; Ricardo R Silva; Divinomar Severino; Daria Raquel Q de Almeida; Vinícius M Gomes; Alexandre Bruni-Cardoso; Walter R Terra; Sayuri Miyamoto; Maurício S Baptista; Leticia Labriola Journal: Cell Death Dis Date: 2020-12-14 Impact factor: 8.469