TY - JOUR
T1 - IgE-based therapeutic combination enhances antitumor response in preclinical models of pancreatic cancer
AU - Markov, Spas Dimitrov
AU - Caffrey, Thomas C.
AU - O'Connell, Kelly A.
AU - Grunkemeyer, James A.
AU - Shin, Simon
AU - Hanson, Ryan
AU - Patil, Prathamesh P.
AU - Shukla, Surendra K.
AU - Gonzalez, Daisy
AU - Crawford, Ayrianne J.
AU - Vance, Krysten E.
AU - Huang, Ying
AU - Eberle, Kirsten C.
AU - Radhakrishnan, Prakash
AU - Grandgenett, Paul M.
AU - Singh, Pankaj K.
AU - Madiyalakan, Ragupathy
AU - Daniels-Wells, Tracy R.
AU - Penichet, Manuel L.
AU - Nicodemus, Christopher F.
AU - Poole, Jill A.
AU - Jaffee, Elizabeth M.
AU - Hollingsworth, Michael A.
AU - Mehla, Kamiya
N1 - Funding Information:
J.A. Grunkemeyer reports grants from NIH during the conduct of the study. P.K. Singh reports grants from NIH/NCI during the conduct of the study. R. Madiyalakan reports other support from OncoQuest Inc. during the conduct of the study; also has a patent for OncoQuest Inc pending and issued. M.L. Penichet reports grants from NIH/NCI during the conduct of the study. J.A. Poole reports grants from NIEHS and NIOSH during the conduct of the study; other support from Astra Zeneca and Takeda; and personal fees from AgriSafety outside the submitted work. E.M. Jaffee reports other support from Abmeta; personal fees from Genocea, Achilles, DragonFly, CSTONE, Candel Therapeutics, Adaptive Biotech, Lustgarten, PICI, NextCure, and Stimit; grants from BMS and Genentech outside the submitted work. M.A. Hollingsworth has ownership of Oncocare Therapeutics stock. K. Mehla reports grants from Onco-Quest Inc. during the conduct of the study; also has a patent 63237634 pending. No disclosures were reported by the other authors.
Funding Information:
We would like to thank the University of Nebraska Medical Center Rapid Autopsy Pancreatic Program and the patients who generously donated their samples. We would also like to thank Jonathan Pester for his help in the pilot animal experiments. Besides, we would like to thank Camila G. Pacheco and Amy J. Nelson for their technical help in the animal studies. K. Mehla was supported by NCI-SPORE P50 CA127297 Career Development Award. This study was also funded in part by the support of grants from the NIH grant under the project numbers R01CA163649, R01CA210439, and R01CA216853 to P.K. Singh, and R01CA181115 to M.P. the Specialized Programs for Research Excellence (SPORE, NCI) under the project number 2P50 CA127297 to M.A. Hollingsworth and P.K. Singh, NCI Research Specialist award (5R50CA211462) to P.M. Grandgenett and the Pancreatic cancer detection consortium U01CA210240 to M.A. Hollingsworth. This work was also supported by grants from the National Institute of Environmental Health Sciences (R01ES019325) and National Institute for Occupational Safety and Health (U54OH010162) to J.A. Poole. This study was also funded in part by the support of award from OncoQuest Pharmaceuticals Inc.
Funding Information:
K. Mehla was supported by NCI-SPORE P50 CA127297 Career Development Award. This study was also funded in part by the support of grants from the NIH grant under the project numbers R01CA163649, R01CA210439, and R01CA216853 to P.K. Singh, and R01CA181115 to M.P. the Specialized Programs for Research Excellence (SPORE, NCI) under the project number 2P50 CA127297 to M.A. Hollingsworth and
Publisher Copyright:
© 2021 American Association for Cancer Research
PY - 2021/12
Y1 - 2021/12
N2 - Pancreatic ductal adenocarcinoma (PDAC) represents 3% of all cancer cases and 7% of all cancer deaths in the United States. Late diagnosis and inadequate response to standard chemotherapies contribute to an unfavorable prognosis and an overall 5-year survival rate of less than 10% in PDAC. Despite recent advances in tumor immunology, tumor-induced immunosuppression attenuates the immunotherapy response in PDAC. To date, studies have focused on IgG-based therapeutic strategies in PDAC. With the recent interest in IgE-based therapies in multiple solid tumors, we explored the MUC1-targeted IgE potential against pancreatic cancer. Our study demonstrates the notable expression of FceRI (receptor for IgE antibody) in tumors from PDAC patients. Our study showed that administration of MUC1 targeted-IgE (mouse/human chimeric anti-MUC1.IgE) antibody at intermittent levels in combination with checkpoint inhibitor (anti-PD-L1) and TLR3 agonist (PolyICLC) induces a robust antitumor response that is dependent on NK and CD8 T cells in pancreatic tumor-bearing mice. Subsequently, our study showed that the antigen specificity of the IgE antibody plays a vital role in executing the antitumor response as nonspecific IgE, induced by ovalbumin (OVA), failed to restrict tumor growth in pancreatic tumor-bearing mice. Utilizing the OVA-induced allergic asthma-PDAC model, we demonstrate that allergic phenotype induced by OVA cannot restrain pancreatic tumor growth in orthotopic tumor-bearing mice. Together, our data demonstrate the novel tumor protective benefits of tumor antigen-specific IgE-based therapeutics in a preclinical model of pancreatic cancer, which can open new avenues for future clinical interventions.
AB - Pancreatic ductal adenocarcinoma (PDAC) represents 3% of all cancer cases and 7% of all cancer deaths in the United States. Late diagnosis and inadequate response to standard chemotherapies contribute to an unfavorable prognosis and an overall 5-year survival rate of less than 10% in PDAC. Despite recent advances in tumor immunology, tumor-induced immunosuppression attenuates the immunotherapy response in PDAC. To date, studies have focused on IgG-based therapeutic strategies in PDAC. With the recent interest in IgE-based therapies in multiple solid tumors, we explored the MUC1-targeted IgE potential against pancreatic cancer. Our study demonstrates the notable expression of FceRI (receptor for IgE antibody) in tumors from PDAC patients. Our study showed that administration of MUC1 targeted-IgE (mouse/human chimeric anti-MUC1.IgE) antibody at intermittent levels in combination with checkpoint inhibitor (anti-PD-L1) and TLR3 agonist (PolyICLC) induces a robust antitumor response that is dependent on NK and CD8 T cells in pancreatic tumor-bearing mice. Subsequently, our study showed that the antigen specificity of the IgE antibody plays a vital role in executing the antitumor response as nonspecific IgE, induced by ovalbumin (OVA), failed to restrict tumor growth in pancreatic tumor-bearing mice. Utilizing the OVA-induced allergic asthma-PDAC model, we demonstrate that allergic phenotype induced by OVA cannot restrain pancreatic tumor growth in orthotopic tumor-bearing mice. Together, our data demonstrate the novel tumor protective benefits of tumor antigen-specific IgE-based therapeutics in a preclinical model of pancreatic cancer, which can open new avenues for future clinical interventions.
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U2 - 10.1158/1535-7163.MCT-21-0368
DO - 10.1158/1535-7163.MCT-21-0368
M3 - Article
C2 - 34625505
AN - SCOPUS:85121137610
SN - 1535-7163
VL - 20
SP - 2457
EP - 2468
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 12
ER -