Tailored cancer immunotherapy using combinations of chemotherapy and a mixture of antibodies against EGF-receptor ligands

• Published in: Proceedings of the National Academy of Sciences - PNAS 2010-07, Vol.107 (28), p.12559-12563
• Main Authors: Lindzen, Moshit, Lavi, Sara, Leitner, Orith, Yarden, Yosef, Sela, Michael
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Antibodies - pharmacology; Antibodies - therapeutic use; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Antibody Specificity - drug effects; Biological Sciences; Cancer; Cell growth; Cell Line, Tumor; Cell lines; Cell Proliferation - drug effects; Cells; Chemotherapy; Deoxycytidine - analogs & derivatives; Female; Heparin-binding EGF-like Growth Factor; Humans; Immunotherapy; Intercellular Signaling Peptides and Proteins - pharmacology; Intercellular Signaling Peptides and Proteins - therapeutic use; Ligands; Mice; Mice, Inbred BALB C; Mice, Nude; Molecules; Neoplasms - drug therapy; Pancreatic cancer; Pancreatic neoplasms; Pancreatic Neoplasms - drug therapy; Receptor, Epidermal Growth Factor - immunology; Receptor, Epidermal Growth Factor - metabolism; Receptor, Epidermal Growth Factor - therapeutic use; Receptors; Rodents; T cell receptors; Transforming Growth Factor alpha - metabolism; Transforming Growth Factor alpha - pharmacology; Transforming Growth Factor alpha - therapeutic use; Tumor cell line; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1006218107

Growth factors are implicated in several processes essential for cancer progression. Specifically, growth factors that bind to ErbB family receptors have been implicated in cell proliferation and in resistance of solid tumors to chemotherapy. We quantified ligand secretion by several human cancer cell lines, and generated mAbs against two ligands, namely TGF-α and heparin-binding EGF-like growth factor. These growth factors are frequently secreted by pancreatic tumor cell lines, including BxPC3 cells. The monoclonal antibodies were tested for their antigen specificity and ability to inhibit growth of BxPC3 cells in vitro. Combining the two antibodies resulted in enhanced inhibition of BxPC3 cell growth, both in vitro and in tumor-bearing animals. Hence, we combined the two antibodies with gemcitabine, an effective chemotherapeutic drug commonly used to treat pancreatic cancer patients. Because treatment with a combination of two monoclonal antibodies enhanced the ability of chemotherapy to inhibit BxPC3 tumors in mice, we propose a general cancer therapeutic strategy that entails profiling the repertoire of growth factors secreted by a tumor, and combining with chemotherapy several antibodies capable of blocking autocrine ligands.