TY - JOUR
T1 - Implantation of a neoantigen-targeted hydrogel vaccine prevents recurrence of pancreatic adenocarcinoma after incomplete resection
AU - Delitto, Daniel
AU - Zabransky, Daniel J.
AU - Chen, Fangluo
AU - Thompson, Elizabeth D.
AU - Zimmerman, Jacquelyn W.
AU - Armstrong, Todd D.
AU - Leatherman, James M.
AU - Suri, Reecha
AU - Lopez-Vidal, Tamara Y.
AU - Huff, Amanda L.
AU - Lyman, Melissa R.
AU - Guinn, Samantha R.
AU - Baretti, Marina
AU - Kagohara, Luciane T.
AU - Ho, Won Jin
AU - Azad, Nilofer S.
AU - Burns, William R.
AU - He, Jin
AU - Wolfgang, Christopher L.
AU - Burkhart, Richard A.
AU - Zheng, Lei
AU - Yarchoan, Mark
AU - Zaidi, Neeha
AU - Jaffee, Elizabeth M.
N1 - Funding Information:
The authors would like to acknowledge the National Cancer Institute (P01CA247886-01A1 to EMJ, R01CA197296-06 to EMJ and LZ, T32CA126607-11A1 to DD and LZ, K08CA248624-01A1 to NZ, K08CA248710-02 to RAB), the American Society of Clinical Oncology Young Investigator Award (WH), the American Association of Cancer Research Incyte Immuno-Oncology Research Fellowship (WH), the MacMillan Pathway to Independence Award (WH), the Skip Viragh Center for Pancreatic Cancer at Johns Hopkins University, the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins University and the Sidney Kimmel Comprehensive Cancer Center Immune Monitoring Core.
Funding Information:
This work was supported by the American Association for Cancer Research [Incyte Immuno-Oncology Research Fellowship]; American Society of Clinical Oncology [Young Investigator Award]; National Cancer Institute [R01CA197296]; National Cancer Institute [T32CA126607]; National Cancer Institute [K08CA248624]; National Cancer Institute [P01CA247886]; National Cancer Institute [K08CA248710]; National Cancer Institute [T32CA126607]; National Cancer Institute [R01CA197296]. The authors would like to acknowledge the National Cancer Institute (P01CA247886-01A1 to EMJ, R01CA197296-06 to EMJ and LZ, T32CA126607-11A1 to DD and LZ, K08CA248624-01A1 to NZ, K08CA248710-02 to RAB), the American Society of Clinical Oncology Young Investigator Award (WH), the American Association of Cancer Research Incyte Immuno-Oncology Research Fellowship (WH), the MacMillan Pathway to Independence Award (WH), the Skip Viragh Center for Pancreatic Cancer at Johns Hopkins University, the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins University and the Sidney Kimmel Comprehensive Cancer Center Immune Monitoring Core.
Publisher Copyright:
© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - Pancreatic adenocarcinoma
KW - hydrogel
KW - immunotherapy
KW - neoantigen
KW - surgery
KW - vaccine
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UR - http://www.scopus.com/inward/citedby.url?scp=85118948728&partnerID=8YFLogxK
U2 - 10.1080/2162402X.2021.2001159
DO - 10.1080/2162402X.2021.2001159
M3 - Article
C2 - 34777919
AN - SCOPUS:85118948728
SN - 2162-4011
VL - 10
JO - OncoImmunology
JF - OncoImmunology
IS - 1
M1 - 2001159
ER -