Abstract 1538: Enhanced antitumor effects of intratumoral (IT) hu14.18-IL2 immunocytokine (IC) compared to intravenous (IV) hu14.18-IL2 are distinguished by increased activated tumor infiltrating lymphocytes (TILs) and IC retention
Authors: Yang Richard K. , Kalogriopoulos Nicholas A. , Rakhmilevich Alexander L. , Ranheim Erik A. , Seo Songwon , Kim KyungMann , Alderson Kory L. , Gan Jacek , Reisfeld Ralph A. , Gillies Stephen D. , Hank Jacquelyn A. , Sondel Paul M. 
Published: August 2012

Abstract
Introduction: Hu14.18-IL2 (APN301, Apeiron Biologics) is an immunocytokine (IC) consisting of human IL2 linked to each IgG heavy chain of the hu14.18 mAb, which recognizes the GD2 disialoganglioside. Phase 2 clinical trials of IV hu14.18-IL2 IC in neuroblastoma and melanoma are underway, with activity already demonstrated in neuroblastoma. We have previously shown that intratumoral IC treatment (IT-IC) results in enhanced anti-tumor activity in mouse models. These studies were designed to determine the mechanisms involved in the enhanced activity and to provide justification for future clinical testing of localized IT administration of this and other immunocytokines. Methods: We characterize tumor growth, survival outcomes, histology and phenotype of tumor infiltrating lymphocytes (TILs) by flow cytometry of IT-hu.14.18-IL2 treatment of A/J mice bearing subcutaneous NXS2 neuroblastomas. Looking at these parameters, IT-IC treated mice are compared to IV-IC treated, IT PBS treated and untreated mice. Data: Mice receiving IT-IC show significant increases [by immunohistochemistry (IHC) and by flow cytometry] of NKp46+ Natural Killer (NK) cells and CD8a+ cytotoxic T cells in TIL populations compared to control tumor-bearing mice. Improved survival and inhibition of tumor growth are observed in mice receiving IT-IC vs. untreated mice or mice receiving IV-IC. Comparisons within treatment groups, or independent of treatment groups, show that the number of NK or CD8 T cells in the tumor correlates inversely with change in tumor size. Analyses by IHC and flow-cytometry show greater IC detection in tumor after IT-IC vs. IV-IC. Moreover, IT-IC results in improved IC retention in tumors and increased NKG2D effector receptors on intratumoral NKG2A/C/E cells and on CD8 T cells when compared to control mice or mice receiving IV-IC. The augmented NKG2D seen in TILs was not seen in spleen cells, supporting the localized nature of the intratumoral changes induced by this treatment. Conclusions: In this murine neuroblastoma model, enhanced antitumor effects of IT hu14.18-IL2 compared to IV hu14.18-IL2 are distinguished by increased activated TILs and IC retention, improved survival and inhibition of tumor growth. These observations suggest that localized administration of immunocytokines in human patients may show analogous advantages over IV administration. In accordance, we have designed a phase I/II clinical trial protocol investigating the maximum tolerated dose (MTD) and efficacy endpoints of intratumorally administered hu14.18-IL2 in stage III/IV melanoma patients with recurrent or refractory disease, and are working towards approval for its activation. Supported by R01-CA-32685-27.
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 1538. doi:1538-7445.AM2012-1538