title: Synergy between chemotherapeutic agents and CTLA-4 blockade in preclinical tumor models.
abstract: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) binding agent, has proven to be an effective monotherapy for metastatic melanoma and has shown antitumor activity in trials when administered with other therapeutic agents. We hypothesized that the combination of ipilimumab with chemotherapeutic agents, such as ixabepilone, paclitaxel, etoposide, and gemcitabine, may produce therapeutic synergy based on distinct but complementary mechanisms of action for each drug and unique cellular targets. This concept was investigated using a mouse homolog of ipilimumab in preclinical murine tumor models, including SA1N fibrosarcoma, EMT-6 mammary carcinoma, M109 lung carcinoma, and CT-26 colon carcinoma. Results of CTLA-4 blockade in combination with one of various chemotherapeutic agents demonstrate that synergy occurs in settings where either agent alone was not effective in inducing tumor regression. Furthermore, when combined with CTLA-4 blockade, ixabepilone, etoposide, and gemcitabine elicited prolonged antitumor effects in some murine models with induction of a memory immune response. Future investigations are warranted to determine which specific chemo-immunotherapy combinations, if any, will produce synergistic antitumor effects in the clinical setting.
authors.affiliation: Bristol-Myers Squibb Company, PO Box 4000, Princeton, NJ 08543, USA. maria.jurekunkel@bms.com
authors.forename: Maria
authors.initials: M
authors.lastname: Jure-Kunkel
authors.forename: Gregg
authors.initials: G
authors.lastname: Masters
authors.forename: Emel
authors.initials: E
authors.lastname: Girit
authors.forename: Gennaro
authors.initials: G
authors.lastname: Dito
authors.forename: Francis
authors.initials: F
authors.lastname: Lee
authors.forename: John T
authors.initials: JT
authors.lastname: Hunt
authors.forename: Rachel
authors.initials: R
authors.lastname: Humphrey
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D034261:Epothilones / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D000074324:Ipilimumab; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology; D000093542:Gemcitabine
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D034261:Epothilones; D000074324:Ipilimumab; D003841:Deoxycytidine; D005047:Etoposide; C430592:ixabepilone; D000093542:Gemcitabine