Implantation of a neoantigen-targeted hydrogel vaccine prevents recurrence of pancreatic adenocarcinoma after incomplete resection

Tumor involvement of major vascular structures limits surgical options in pancreatic adenocarcinoma (PDAC), which in turn limits opportunities for cure. Despite advances in locoregional approaches, there is currently no role for incomplete resection. This study evaluated a gelatinized neoantigen-tar...

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Autores principales:	Daniel Delitto, Daniel J. Zabransky, Fangluo Chen, Elizabeth D. Thompson, Jacquelyn W. Zimmerman, Todd D. Armstrong, James M. Leatherman, Reecha Suri, Tamara Y. Lopez-Vidal, Amanda L. Huff, Melissa R. Lyman, Samantha R. Guinn, Marina Baretti, Luciane T. Kagohara, Won Jin Ho, Nilofer S. Azad, William R. Burns, Jin He, Christopher L. Wolfgang, Richard A. Burkhart, Lei Zheng, Mark Yarchoan, Neeha Zaidi, Elizabeth M. Jaffee
Formato:	article
Lenguaje:	EN
Publicado:	Taylor & Francis Group 2021
Materias:	pancreatic adenocarcinoma immunotherapy neoantigen vaccine hydrogel surgery Immunologic diseases. Allergy RC581-607 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/97094383247048c2ade5ce77d37edcab
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spelling	oai:doaj.org-article:97094383247048c2ade5ce77d37edcab2021-11-11T14:23:43ZImplantation of a neoantigen-targeted hydrogel vaccine prevents recurrence of pancreatic adenocarcinoma after incomplete resection2162-402X10.1080/2162402X.2021.2001159https://doaj.org/article/97094383247048c2ade5ce77d37edcab2021-01-01T00:00:00Zhttp://dx.doi.org/10.1080/2162402X.2021.2001159https://doaj.org/toc/2162-402XTumor involvement of major vascular structures limits surgical options in pancreatic adenocarcinoma (PDAC), which in turn limits opportunities for cure. Despite advances in locoregional approaches, there is currently no role for incomplete resection. This study evaluated a gelatinized neoantigen-targeted vaccine applied to a grossly positive resection margin in preventing local recurrence. Incomplete surgical resection was performed in mice bearing syngeneic flank Panc02 tumors, leaving a 1 mm rim adherent to the muscle bed. A previously validated vaccine consisting of neoantigen peptides, a stimulator of interferon genes (STING) agonist and AddaVaxTM (termed PancVax) was embedded in a hyaluronic acid hydrogel and applied to the tumor bed. Tumor remnants, regional lymph nodes, and spleens were analyzed using histology, flow cytometry, gene expression profiling, and ELISPOT assays. The immune microenvironment at the tumor margin after surgery alone was characterized by a transient influx of myeloid-derived suppressor cells (MDSCs), prolonged neutrophil influx, and near complete loss of cytotoxic T cells. Application of PancVax gel was associated with enhanced T cell activation in the draining lymph node and expansion of neoantigen-specific T cells in the spleen. Mice implanted with PancVax gel demonstrated no evidence of residual tumor at two weeks postoperatively and healed incisions at two months postoperatively without local recurrence. In summary, application of PancVax gel at a grossly positive tumor margin led to systemic expansion of neoantigen-specific T cells and effectively prevented local recurrence. These findings support further work into locoregional adjuncts to immune modulation in PDAC.Daniel DelittoDaniel J. ZabranskyFangluo ChenElizabeth D. ThompsonJacquelyn W. ZimmermanTodd D. ArmstrongJames M. LeathermanReecha SuriTamara Y. Lopez-VidalAmanda L. HuffMelissa R. LymanSamantha R. GuinnMarina BarettiLuciane T. KagoharaWon Jin HoNilofer S. AzadWilliam R. BurnsJin HeChristopher L. WolfgangRichard A. BurkhartLei ZhengMark YarchoanNeeha ZaidiElizabeth M. JaffeeTaylor & Francis Grouparticlepancreatic adenocarcinomaimmunotherapyneoantigenvaccinehydrogelsurgeryImmunologic diseases. AllergyRC581-607Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENOncoImmunology, Vol 10, Iss 1 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	pancreatic adenocarcinoma immunotherapy neoantigen vaccine hydrogel surgery Immunologic diseases. Allergy RC581-607 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	pancreatic adenocarcinoma immunotherapy neoantigen vaccine hydrogel surgery Immunologic diseases. Allergy RC581-607 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Daniel Delitto Daniel J. Zabransky Fangluo Chen Elizabeth D. Thompson Jacquelyn W. Zimmerman Todd D. Armstrong James M. Leatherman Reecha Suri Tamara Y. Lopez-Vidal Amanda L. Huff Melissa R. Lyman Samantha R. Guinn Marina Baretti Luciane T. Kagohara Won Jin Ho Nilofer S. Azad William R. Burns Jin He Christopher L. Wolfgang Richard A. Burkhart Lei Zheng Mark Yarchoan Neeha Zaidi Elizabeth M. Jaffee Implantation of a neoantigen-targeted hydrogel vaccine prevents recurrence of pancreatic adenocarcinoma after incomplete resection
description	Tumor involvement of major vascular structures limits surgical options in pancreatic adenocarcinoma (PDAC), which in turn limits opportunities for cure. Despite advances in locoregional approaches, there is currently no role for incomplete resection. This study evaluated a gelatinized neoantigen-targeted vaccine applied to a grossly positive resection margin in preventing local recurrence. Incomplete surgical resection was performed in mice bearing syngeneic flank Panc02 tumors, leaving a 1 mm rim adherent to the muscle bed. A previously validated vaccine consisting of neoantigen peptides, a stimulator of interferon genes (STING) agonist and AddaVaxTM (termed PancVax) was embedded in a hyaluronic acid hydrogel and applied to the tumor bed. Tumor remnants, regional lymph nodes, and spleens were analyzed using histology, flow cytometry, gene expression profiling, and ELISPOT assays. The immune microenvironment at the tumor margin after surgery alone was characterized by a transient influx of myeloid-derived suppressor cells (MDSCs), prolonged neutrophil influx, and near complete loss of cytotoxic T cells. Application of PancVax gel was associated with enhanced T cell activation in the draining lymph node and expansion of neoantigen-specific T cells in the spleen. Mice implanted with PancVax gel demonstrated no evidence of residual tumor at two weeks postoperatively and healed incisions at two months postoperatively without local recurrence. In summary, application of PancVax gel at a grossly positive tumor margin led to systemic expansion of neoantigen-specific T cells and effectively prevented local recurrence. These findings support further work into locoregional adjuncts to immune modulation in PDAC.
format	article
author	Daniel Delitto Daniel J. Zabransky Fangluo Chen Elizabeth D. Thompson Jacquelyn W. Zimmerman Todd D. Armstrong James M. Leatherman Reecha Suri Tamara Y. Lopez-Vidal Amanda L. Huff Melissa R. Lyman Samantha R. Guinn Marina Baretti Luciane T. Kagohara Won Jin Ho Nilofer S. Azad William R. Burns Jin He Christopher L. Wolfgang Richard A. Burkhart Lei Zheng Mark Yarchoan Neeha Zaidi Elizabeth M. Jaffee
author_facet	Daniel Delitto Daniel J. Zabransky Fangluo Chen Elizabeth D. Thompson Jacquelyn W. Zimmerman Todd D. Armstrong James M. Leatherman Reecha Suri Tamara Y. Lopez-Vidal Amanda L. Huff Melissa R. Lyman Samantha R. Guinn Marina Baretti Luciane T. Kagohara Won Jin Ho Nilofer S. Azad William R. Burns Jin He Christopher L. Wolfgang Richard A. Burkhart Lei Zheng Mark Yarchoan Neeha Zaidi Elizabeth M. Jaffee
author_sort	Daniel Delitto
title	Implantation of a neoantigen-targeted hydrogel vaccine prevents recurrence of pancreatic adenocarcinoma after incomplete resection
title_short	Implantation of a neoantigen-targeted hydrogel vaccine prevents recurrence of pancreatic adenocarcinoma after incomplete resection
title_full	Implantation of a neoantigen-targeted hydrogel vaccine prevents recurrence of pancreatic adenocarcinoma after incomplete resection
title_fullStr	Implantation of a neoantigen-targeted hydrogel vaccine prevents recurrence of pancreatic adenocarcinoma after incomplete resection
title_full_unstemmed	Implantation of a neoantigen-targeted hydrogel vaccine prevents recurrence of pancreatic adenocarcinoma after incomplete resection
title_sort	implantation of a neoantigen-targeted hydrogel vaccine prevents recurrence of pancreatic adenocarcinoma after incomplete resection
publisher	Taylor & Francis Group
publishDate	2021
url	https://doaj.org/article/97094383247048c2ade5ce77d37edcab
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Implantation of a neoantigen-targeted hydrogel vaccine prevents recurrence of pancreatic adenocarcinoma after incomplete resection

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