Abstract 2512: PF-04605412 induces cytokine activation and marginalization of NK cells and macrophages in patients with solid tumor
Authors: Borghaei Hossein , Satmpino Corrado Gallo , Li Chunze , Alpaugh Katherine 
Published: August 2012

Introduction: Integrin Δ5α1 is a fibronectin receptor involved in cell adhesion, proliferation, and survival expressed by cancer cells in addition to tumor-associated macrophages, fibroblasts, and endothelial cells. PF-04605412 is a fully human IgG1 mAb against integrin α1Δ5, with enhanced FcαRIII binding capacity, currently in Phase 1. Pre-clinical studies indicate this antibody has anti-angiogenic properties and is capable of inducing antibody dependent cellular cytotoxicity. We report on correlative biological studies designed to understand the underlying mechanisms for infusion reactions which occurred to some patients during the dose escalation. Methods: This sub-study includes 9 patients (5 female, 4 males; median age 58, ECOG PS 0-1) who received doses of PF-04605412 from 7.5 mg to 34 mg as 2 hrs infusion. Cytokine-like infusion reactions was observed at the first dose level (7.5 mg). To mitigate symptoms, subsequent patients were pre-medicated and the infusion time was extended to two hours. An extensive cytokine panel was assessed at time points corresponding to pharmacokinetic (PK) analysis. Circulating monocytes (CD14+/CD16+) and NK (CD56+/CD16+) cells were evaluated by flow cytometry. Cell-bound PF-04605412 was detected using Fab’2 anti-human antibody. PK analysis has been conducted in four patients to date (7.5 mg (n=3) and 11.25 mg (n=1). Results: Infusion reactions with premedications were mild and included chills, fever, rigors and hypotension (grades 1-2). A decline in white blood cell subsets occurred at the onset of fevers and chills, independent of the dose administered, and normalized within 24 hours post infusion. Activation of cell populations was evident by an increase in percentage of cells expressing CD16 at 24 hour post infusion compared to baseline. Persistent (up to 24 hours) in vivo cell-bound PF-04605412 was observed with the Fab’2 anti-human antibody in all patients. Cmax values for the 7.5 mg and 11.25 mg doses were 671 ng/mL and 933 ng/mL, respectively. PF-04605412 serum concentrations were below quantitation limit 24 hours post infusion at these two doses. Pro inflammatory mediators such as IL 6, IL 8, and TNF alpha typically increased within 1-1.5 hours post infusion and normalized over 10-24 hours. Marked increases were seen in several patients with the first infusion while this was reduced with subsequent doses. There was not a direct relationship between adverse events and the magnitude of cytokine increase. Conclusions: PF-04605412 leads to robust cellular activation and cytokine induction resulting from Fc- FcαRIII engagement of effector cells. Biopsies of metastatic sites pre- and post- treatment will be examined for evidence of effector cell accumulation at the tumor site and will be presented at the meeting.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2512. doi:1538-7445.AM2012-2512