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.

• Authors: 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
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 20 Issue 12 Pg. 2457-2468 (12 2021) ISSN: 1538-8514 [Electronic] United States
• PMID: 34625505 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• Immunoglobulin E

Topics

• Adenocarcinoma (drug therapy)
• Animals
• Carcinoma, Pancreatic Ductal (drug therapy)
• Humans
• Immunoglobulin E (pharmacology, therapeutic use)
• Mice