Abstract 5024: mDX400, the murine analog against the anti-PD1 antibody MK-347 is active in immunocompetent, autochthonous murine models of melanoma and breast cancer
Authors: Darr David , Clark Kelly S. , Phillips Joseph H. , Pinheiro Elaine , Sriram Venkataraman , Xiong Jessie , Jordan Jamie , Sharpless Norman E. , Perou Charles , Moschos Stergios 
Published: May 2015

Abstract
Although effective therapies exist for BRAF-mutant metastatic melanomas (MM) and ER+/PR+/HER2+ breast cancers, fewer options are available for the more aggressive triple negative breast cancers (TNBC) and Ras-mutant MM. Immune infiltration is frequently observed in patient subsets with MM or TNBC. An anti-tumor host immune response may be restrained by the expression of immune checkpoint proteins, such as the programmed death 1 (PD1) protein. We evaluated mDX400, a murine version of the anti-PD-1 antibody MK-3475 that is currently in human clinical trials, in genetically engineered murine models (GEMMs) of melanoma and breast cancer (BC). PD1 antibody was used alone and in combination. Models studied were for basal-like, TNBC (C3TAg), Claudin-Low breast cancer p53null, luminal BC (MMTV-Her2/Neu), RAS-driven melanoma (Tyr-H-Ras and null for Ink4a/Arf (TRIA)) and BRaf-mutant, Pten-deficient melanoma (BRaf/Pten). Mice were housed, treated, and evaluated in the UNC Lineberger Comprehensive Cancer Center Mouse Phase I Unit (MP1U). mDX400 and isotype antibody (10mg/kg IP qw) were supplied by Merck & Co., Inc. Murine cohorts were assessed weekly and therapeutic intervention began once tumors reached 40-64mm3. TNBC models were treated with Carboplatin (C, 50mg/kg IP qwk) in combination with mDX400. mDX400 was administered as a single agent in Melanoma GEMMs. Endpoints were maximal response at ≥21 days and median overall survival (OS). In the C3TAg BC model, mDX400 did not exhibit single-agent activity, but substantial synergy was observed in combination with C [partial response (PR) or CR in 12 of 15 vs. 0 of 19 in non-treated animals, Fisher's exact p=0.006 or vs. C alone 5 of 13 animals, p=0.05] and prolonged OS (41 vs. 28 days in NT, log-rank p=0.006 or C only 28 days, p=0.006) in the C3TAg model. Treatment with single-agent mDX400 induced a marked response in the RAS-driven TRIA melanoma model that is resistant to multiple systemic treatments. mDX400-treated TRIA mice enjoyed an almost tripling of OS [median 56 vs. 21 days, p=0.006]. BRaf/Pten melanomas did not respond to mDX400. Likewise mDX400 plus C provided no benefit to the p53null or MMTV-Her2/Neu BC GEMMs vs. C alone. Our data show differential response of PD-1 antibody therapies to various melanoma and BC models, the latter in combination with C. The responsiveness of a RAS-driven melanoma model to mDX400 is consistent with earlier reports about the clinical benefit of patients with NRAS-mutant melanoma to Ipilimumab, and the lack of PD-L1 expression and immune infiltrates of PTEN-deficient melanomas. At the meeting we will report expression of PD-L1 and other immune checkpoint proteins by cancer cells. The basis whereby carboplatin potentiates the activity of anti-PD1 in TNBC is an area of ongoing study.
Citation Format: David Darr, Kelly S. Clark, Joseph H. Phillips, Elaine Pinheiro, Venkataraman Sriram, Jessie Xiong, Jamie Jordan, Norman E. Sharpless, Charles Perou, Stergios Moschos. mDX400, the murine analog against the anti-PD1 antibody MK-347 is active in immunocompetent, autochthonous murine models of melanoma and breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5024. doi:10.1158/1538-7445.AM2014-5024