Combination of mAb-AR20.5, anti-PD-L1 and PolyICLC inhibits tumor progression and prolongs survival of MUC1.Tg mice challenged with pancreatic tumors

• DOI: 10.1007/s00262-017-2095-7
• Publication Date: 2017-12-04T13:38:49Z
• Authors: Kamiya Mehla; Jarrod Tremayne; James A. Grunkemeyer; Kelly A. O’Connell; Maria M. Steele; Thomas C. Caffrey; Xinyi Zhu; Fang Yu; Pankaj K. Singh; Birgit C. Schultes; Ragupathy Madiyal...; Christopher F. Ni...; Michael A. Hollin...
• Keywords: Cytotoxicity, Immunologic; Antimetabolites, Antineoplastic; Immunity, Cellular; Mucin-1; Antibodies, Monoclonal; Mice, Transgenic; Deoxycytidine; Xenograft Model Antitumor Assays; Gemcitabine; B7-H1 Antigen; 3. Good health; Pancreatic Neoplasms; Survival Rate; Mice; 03 medical and health sciences; Poly I-C; 0302 clinical medicine; Carboxymethylcellulose Sodium; Tumor Cells, Cultured; Animals; Humans; Polylysine

A substantial body of evidence suggests the existence of MUC1-specific antibodies and cytotoxic T cell activities in pancreatic cancer patients. However, tumor-induced immunosuppression renders these responses ineffective. The current study explores a novel therapeutic combination wherein tumor-bearing hosts can be immunologically primed with their own antigen, through opsonization with a tumor antigen-targeted antibody, mAb-AR20.5. We evaluated the efficacy of immunization with this antibody in combination with PolyICLC and anti-PD-L1. The therapeutic combination of mAb-AR20.5 + anti-PD-L1 + PolyICLC induced rejection of human MUC1 expressing tumors and provided a long-lasting, MUC1-specific cellular immune response, which could be adoptively transferred and shown to provide protection against tumor challenge in human MUC1 transgenic (MUC.Tg) mice. Furthermore, antibody depletion studies revealed that CD8 cells were effectors for the MUC1-specific immune response generated by the mAb-AR20.5 + anti-PD-L1 + PolyICLC combination. Multichromatic flow cytometry data analysis demonstrated a significant increase over time in circulating, activated CD8 T cells, CD3+CD4-CD8-(DN) T cells, and mature dendritic cells in mAb-AR20.5 + anti-PD-L1 + PolyICLC combination-treated, tumor-bearing mice, as compared to saline-treated control counterparts. Our study provides a proof of principle that an effective and long-lasting anti-tumor cellular immunity can be achieved in pancreatic tumor-bearing hosts against their own antigen (MUC1), which can be further potentiated using a vaccine adjuvant and an immune checkpoint inhibitor.