Abstract 4396: Combination of intratumoral regulated IL-12 gene delivery and systemic chemotherapy with Palifosfamide (IPM-Tris) enhances anti-tumor effects in breast cancer (4T1) model
Authors: Murugesan Selva , Fogler William , Valacer David , Youssoufian Hagop , Morgan Robert A. , Herberman Ronald , Connelly Shelia , Hart Susan E. , Bharathan Mini , Chan Timothy , Shakleya Diaa , Moreno Mario , Barrett John A. 
Published: August 2012

Abstract
A major obstacle for the development of effective immunotherapy is the ability of tumors to escape detection and/or destruction by the immune system. This study explored pairing a potent immunomodulatory cytokine (IL-12) with a bifunctional alkylating agent currently in Phase III clinical trials for soft tissue sarcoma (Palifosfamide, IPM-Tris). In this study intratumorally administered adenoviral vector, Ad-RTS-mIL-12, expressing IL-12 under the control of Rheoswitch Therapeutic System®, (RTS®), a novel inducible promoter system was used. Expression of IL-12 is regulated by oral administration of a small molecule activator ligand, INXN-1001 (AL). The in vitro transduction of the human fibrosarcoma cell line, HT1080, with Ad-RTS-hIL12 + AL at a MOI of 400 pfu, produced &gt;6000-fold induction of human IL-12 above background, while IPM-Tris (1-3 uM) was cytotoxic in a variety of cancer cell lines. The effect of Ad-RTS-mIL12 + AL in combination with IPM-Tris was evaluated in a subcutaneous 4T1 syngeneic BALB/c mouse mammary tumor model at low doses, which were chosen to have minimal effect on tumor growth rate. Indeed, IPM-Tris alone (40 - 120 mg/m2) had little effect on tumor growth rate (&lt; 30%) compared to vehicle. In contrast, a single intratumoral injection of Ad-RTS-mIL12 (1x1010 vp) and oral administration of AL (15, 30, 75 or 150 mg/m2) once daily for 5 days led to significant AL dose-related tumor growth inhibition (28, 29, 62, 59%, respectively; p&lt;0.05) with the Ad-RTS-mIL12 having no effect relative to control by Day 35. Combined treatment with Ad-RTS-mIL12 + AL (30 mg/m2) and IPM-Tris (40 or 120 mg/m*2 administered IP QD for 3 days) significantly inhibited tumor growth inhibition (∼71-90%, p&lt;0.001) and increased median survival rate by 8-14 days when compared to the single agents alone, without overt toxicity as assessed by change in body weight. These results indicate that local intratumoral immunotherapy combined with low dose chemotherapy with palifosfamide offers a distinct advantage over either therapeutic modality alone. These results are supportive of our hypothesis that cytotoxic agents at low doses may prime the immune system to enhance immunotherapy, which could potentially be translated into a safe clinical regimen for the treatment of metastatic breast cancer. Additional studies are ongoing to explore in depth the immunologic mechanism(s) that account for the more potent immunotherapeutic effects of IL-12 when combined with IPM-Tris.
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 4396. doi:1538-7445.AM2012-4396