Abstract 4647: Tie2-expressing monocytes (TEMs) as potential biomarkers of angiopoietin-Tie2 (Ang/Tie2) directed therapies: correlative analysis of a phase I study of AMG386 + temsirolimus (T).
Authors: Cescon David W. , Bedard Philippe L. , Chow Sue , Chen Helen , Razak Albiruni , Wizemann Monika , Siu Lillian L. , Hedley David 
Published: August 2014

Abstract
Background: The Ang/Tie2 pathway plays a critical role in tumor angiogenesis, and several agents targeting this axis are in development. Tie2 is expressed by monocytes (M), and TEMs may be angiogenic mediators. Thymidine phosphorylase (TP), an angiogenic enzyme, is increased in TEMs upon Tie2 stimulation. We used flow cytometry to evaluate TEMs in a phase I study of AMG386 (Ang1/2 peptibody) + T in patients (pts) with solid tumors.
Methods: Peripheral blood was collected from healthy volunteers and pts with advanced cancer (n=10 each) for assay development. For phase I study pts (n=5 to date), blood was collected on Cycle 1 Day 1 (D1), D3 and D8. Extracellular Tie2 staining was performed after hypotonic red blood cell lysis. TP staining followed formaldehyde fixation and Triton X-100 permeabilization. M and lymphocytes (L) were gated with CD45 and CD33. Median fluorescence intensities (MFI) were measured and normalized by calculating a M/L ratio. Tumor response was assessed every 2 cycles.
Results: Tie2 staining was present on all M (absent in other leukocytes) in healthy controls and cancer pts, with no discrete Tie2+/- populations. Tie2 and TP M/L were similar between these 2 groups. Tie2, TP and response data from the first 5 pts receiving AMG386 + T are presented. Preliminary results reveal an association between change in TP D1 to D3 and tumor response. TP M/L decreased in all pts with tumor shrinkage (mean -18%), but increased (+6%) in the pt with tumor growth. No consistent association between Tie2 M/L and response was observed.
Conclusions: Measurement of Tie2 and TP in circulating M is feasible. No discrete Tie2+ M population is identifiable. Tie2 and TP staining are similar in cancer pts and healthy volunteers. Preliminary analyses reveal an association between an initial reduction in TP and tumor shrinkage in pts receiving AMG386+T. Enrolment continues and additional data will be presented.
Tie2, TP and tumor response in the first 5 pts receiving AMG386+T Patient 1 2 3 4 5 Tie2 M/L D1 2.63 2.53 6.56 5.07 9.85 D3 2.58 2.41 6.07 4.94 13.87 D8 3.33 2.61 5.11 7.85 7.95 Tie2% Change D1 to D3 −2.1% -4.9% -7.5% -2.5% 40.7% TP M/L D1 7.41 5.49 8.98 6.59 5.43 D3 6.70 5.83 8.11 5.21 3.81 D8 11.07 9.21 9.19 5.70 5.63 TP% Change D1 to D3 -9.6% 6.2% -9.6% -20.8% -30.0% Best response in target lesions (% change) -25% 14% -31% -14% -7% This study is supported by the National Cancer Institute Grant # U01-CA-132123
Citation Format: David W. Cescon, Philippe L. Bedard, Sue Chow, Helen Chen, Albiruni Razak, Monika Wizemann, Lillian L. Siu, David Hedley. Tie2-expressing monocytes (TEMs) as potential biomarkers of angiopoietin-Tie2 (Ang/Tie2) directed therapies: correlative analysis of a phase I study of AMG386 + temsirolimus (T). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4647. doi:10.1158/1538-7445.AM2013-4647