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

• Published in: Molecular cancer therapeutics 2021-10, Vol.20 (12), p.2457-2468
• Main Authors: Markov, Spas Dimitrov, Caffrey, Thomas C., O’Connell, Kelly A., Grunkemeyer, James A., Shin, Simon, Hanson, Ryan, Patil, Prathamesh P., Shukla, Surendra K., Gonzalez, Daisy, Crawford, Ayrianne J., Vance, Krysten E., Huang, Ying, Eberle, Kirsten C., Radhakrishnan, Prakash, Grandgenett, Paul M., Singh, Pankaj K., Madiyalakan, Ragupathy, Daniels-Wells, Tracy R., Penichet, Manuel L., Nicodemus, Christopher F., Poole, Jill A., Jaffee, Elizabeth M., Hollingsworth, Michael A., Mehla, Kamiya
• Format: Article
• Language: English
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-21-0368

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 antibody’s potential against pancreatic cancer. Our study demonstrates the notable expression of FcεRI (receptor for IgE antibody) in tumors from PDAC patients. Our study showed that administration with a limited amount 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 anti-tumor response that is dependent on NK and CD8 T cells in pancreatic tumor-bearing mice. Subsequently, our study showed that IgE antibody’s antigen specificity plays a vital role in executing the anti-tumor response as non-specific 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.