Systemic treatment of xenografts with vaccinia virus GLV-1h68 reveals the immunologic facet of oncolytic therapy

Andrea Worschech,Nanhai Chen,Francesco M Marincola,Ena Wang,Vladia Monsurró,Yong A Yu,Viktoria Raab,Marianna Sabatino,Qian Zhang,Zoltan Pos,David F Stroncek,Hui Liu,Alessandro Monaco,Aladar A Szalay,Stephanie Weibel,R Mark Buller

doi:10.1186/1471-2164-10-301

Abstract

BackgroundGLV-1h68 is an attenuated recombinant vaccinia virus (VACV) that selectively colonizes established human xenografts inducing their complete regression.ResultsHere, we explored xenograft/VACV/host interactions in vivo adopting organism-specific expression arrays and tumor cell/VACV in vitro comparing VACV replication patterns. There were no clear-cut differences in vitro among responding and non-responding tumors, however, tumor rejection was associated in vivo with activation of interferon-stimulated genes (ISGs) and innate immune host's effector functions (IEFs) correlating with VACV colonization of the xenografts. These signatures precisely reproduce those observed in humans during immune-mediated tissue-specific destruction (TSD) that causes tumor or allograft rejection, autoimmunity or clearance of pathogens. We recently defined these common pathways in the "immunologic constant of rejection" hypothesis (ICR).ConclusionThis study provides the first prospective validation of a universal mechanism associated with TSD. Thus, xenograft infection by oncolytic VACV, beyond offering a promising therapy of established cancers, may represent a reliable pre-clinical model to test therapeutic strategies aimed at modulating the central pathways leading to TSD; this information may lead to the identification of principles that could refine the treatment of cancer and chronic infection by immune stimulation or autoimmunity and allograft rejection through immune tolerance.

Highlights

GLV-1h68 is an attenuated recombinant vaccinia virus (VACV) that selectively colonizes established human xenografts inducing their complete regression
This exercise leads to the formulation of the "immunologic constant of rejection" (ICR) hypothesis: "immune-mediated tissue specific destruction (TSD) follows a common final pathway independent of the originating cause and the disease context" [2]. 4 axioms were proposed at the basis of the immunologic constant of rejection" hypothesis (ICR): i) tissue-specific destruction (TSD) does not necessarily occur because of non-self recognition and occurs against self or quasi-self; ii) the requirements for the induction of a cognate immune response differ from those necessary for the activation of an effector one; iii) the prompts leading to TSD vary in distinct pathologic states, the effector immune response converges into a single mechanism; and iv) adaptive immunity participates as a tissue-specific trigger, but it is not always sufficient or necessary
Xenograft infection by oncolytic VACV offers a promising therapy of established cancer, it needs to be taken into account that the presence of adaptive immunity might change what is expected, perhaps inducing suppressive T cell responses that could abrogate the therapeutic effect of the virus in natural conditions

Summary

Introduction

GLV-1h68 is an attenuated recombinant vaccinia virus (VACV) that selectively colonizes established human xenografts inducing their complete regression. We applied inductive reasoning [1] to identify immunologic signatures associated with tumor rejection, clearance of pathogen, acute allograft rejection or autoimmunity This exercise leads to the formulation of the "immunologic constant of rejection" (ICR) hypothesis: "immune-mediated tissue specific destruction (TSD) follows a common final pathway independent of the originating cause and the disease context" [2]. We selected a promising pre-clinical endeavor where the systemic administration of oncolytic VACV induces xenograft regression in immune deficient mice through an, at least in part, immunologically-mediated mechanism. The ability to replicate within tumors and to leave non malignant tissues virus-free makes GLV-1h68 systemic administration a promising pre-clinical tool capable of safely eradicating pancreatic cancer [14], malignant pleural mesothelioma [15], breast carcinoma GI101A xenografts [13] and anaplastic thyroid cancer [16]

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