IgE-based therapeutic combination enhances antitumor response in preclinical models of pancreatic cancer

Spas Dimitrov Markov; Thomas C. Caffrey; Kelly A. O'Connell; James A. Grunkemeyer; Simon Shin; Ryan Hanson; Prathamesh P. Patil; Surendra K. Shukla; Daisy Gonzalez; Ayrianne J. Crawford; Krysten E. Vance; Ying Huang; Kirsten C. Eberle; Prakash Radhakrishnan; Paul M. Grandgenett; Pankaj K. Singh; Ragupathy Madiyalakan; Tracy R. Daniels-Wells; Manuel L. Penichet; Christopher F. Nicodemus; Jill A. Poole; Elizabeth M. Jaffee; Michael A. Hollingsworth; Kamiya Mehla

doi:10.1158/1535-7163.MCT-21-0368

IgE-based therapeutic combination enhances antitumor response in preclinical models of pancreatic cancer

Spas Dimitrov Markov
, Thomas C. Caffrey
, Kelly A. O'Connell
, James A. Grunkemeyer
, Simon Shin
, Ryan Hanson
, Prathamesh P. Patil
, Surendra K. Shukla
, Daisy Gonzalez
, Ayrianne J. Crawford
, Krysten E. Vance
, Ying Huang
, Kirsten C. Eberle
, Prakash Radhakrishnan
, Paul M. Grandgenett
, Pankaj K. Singh
, Ragupathy Madiyalakan
, Tracy R. Daniels-Wells
, Manuel L. Penichet
, Christopher F. Nicodemus

Jill A. Poole, Elizabeth M. Jaffee, Michael A. Hollingsworth, Kamiya Mehla

Physiology

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	2457-2468
Number of pages	12
Journal	Molecular Cancer Therapeutics
Volume	20
Issue number	12
DOIs	https://doi.org/10.1158/1535-7163.MCT-21-0368
State	Published - Dec 2021

Bibliographical note

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Publisher link

10.1158/1535-7163.MCT-21-0368

Find It

Find It at U of M Libraries

Cite this

Markov, S. D., Caffrey, T. C., O'Connell, K. A., Grunkemeyer, J. A., Shin, S., Hanson, R., Patil, P. P., Shukla, S. K., Gonzalez, D., Crawford, A. J., Vance, K. E., Huang, Y., Eberle, K. C., Radhakrishnan, P., Grandgenett, P. M., Singh, P. K., Madiyalakan, R., Daniels-Wells, T. R., Penichet, M. L., ... Mehla, K. (2021). IgE-based therapeutic combination enhances antitumor response in preclinical models of pancreatic cancer. Molecular Cancer Therapeutics, 20(12), 2457-2468. https://doi.org/10.1158/1535-7163.MCT-21-0368

Markov, SD, Caffrey, TC, O'Connell, KA, Grunkemeyer, JA, Shin, S, Hanson, R, Patil, PP, Shukla, SK, Gonzalez, D, Crawford, AJ, Vance, KE, Huang, Y, Eberle, KC, Radhakrishnan, P, Grandgenett, PM, Singh, PK, Madiyalakan, R, Daniels-Wells, TR, Penichet, ML, Nicodemus, CF, Poole, JA, Jaffee, EM, Hollingsworth, MA & Mehla, K 2021, 'IgE-based therapeutic combination enhances antitumor response in preclinical models of pancreatic cancer', Molecular Cancer Therapeutics, vol. 20, no. 12, pp. 2457-2468. https://doi.org/10.1158/1535-7163.MCT-21-0368

@article{25bebfbf6b2b4965b354bf88b91aece1,

title = "IgE-based therapeutic combination enhances antitumor response in preclinical models of pancreatic cancer",

abstract = "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.",

author = "Markov, \{Spas Dimitrov\} and Caffrey, \{Thomas C.\} and O'Connell, \{Kelly A.\} and Grunkemeyer, \{James A.\} and Simon Shin and Ryan Hanson and Patil, \{Prathamesh P.\} and Shukla, \{Surendra K.\} and Daisy Gonzalez and Crawford, \{Ayrianne J.\} and Vance, \{Krysten E.\} and Ying Huang and Eberle, \{Kirsten C.\} and Prakash Radhakrishnan and Grandgenett, \{Paul M.\} and Singh, \{Pankaj K.\} and Ragupathy Madiyalakan and Daniels-Wells, \{Tracy R.\} and Penichet, \{Manuel L.\} and Nicodemus, \{Christopher F.\} and Poole, \{Jill A.\} and Jaffee, \{Elizabeth M.\} and Hollingsworth, \{Michael A.\} and Kamiya Mehla",

note = "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: {\textcopyright} 2021 American Association for Cancer Research",

year = "2021",

month = dec,

doi = "10.1158/1535-7163.MCT-21-0368",

language = "English (US)",

volume = "20",

pages = "2457--2468",

journal = "Molecular Cancer Therapeutics",

issn = "1535-7163",

publisher = "American Association for Cancer Research Inc.",

number = "12",

}

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.

UR - https://www.scopus.com/pages/publications/85121137610

UR - https://www.scopus.com/pages/publications/85121137610#tab=citedBy

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 -

IgE-based therapeutic combination enhances antitumor response in preclinical models of pancreatic cancer

Abstract

Bibliographical note

UN SDGs

Publisher link

Find It

Other files and links

Fingerprint

Cite this