Animal models of tumor immunity, immunotherapy and cancer vaccines

Abstract

Reliable animal models are critical for evaluating immunotherapies and for defining tumor immunology paradigms. Tumor immunologists are moving away from traditional transplantation tumor systems because they do not adequately model human malignancies. Transgenic mouse models in which tumors arise spontaneously have been developed for most cancers. The models use one of three technologies: tissue-specific promoters to drive expression of SV40 large T antigen or tissue-specific oncogenes; deletion of tumor suppressor genes by gene targeting; or, conditional deletion of tumor suppressor genes or activation of oncogenes via Cre-lox technology. Knockin mice expressing human tumor antigens and gene-targeted mice with deletions for immunologically relevant molecules have been integral to advancing knowledge of the tumor–host relationship. Although animal models are becoming more sophisticated, additional improvements are needed so that more realistic models can be developed.

Introduction

Animal models have played a critical role in establishing basic paradigms of tumor immunology because they provide an in vivo milieu that cannot be reproduced in vitro. As novel immunotherapies and cancer vaccines have been developed, animal models have also played an important role in pre-clinical testing for therapeutic efficacy. Historically, investigators have used transplantable tumor models, in which inbred animals are inoculated with tumor cells derived from the same genetic strain. The tumors were initially derived from spontaneously occurring malignancies or induced by chemicals or irradiation, and maintained either by in vivo or in vitro passage. As the tumor immunology field has moved towards developing cancer vaccines and other novel cancer immunotherapies, the same transplantable tumor models have been used to test therapeutic efficacy. Unfortunately, many of these tumor models are not good predictors for human clinical trials, as numerous therapies that look promising in experimental animals have turned out to be ineffective in patients. Although immunotherapy and cancer vaccine studies are moving away from using transplantable tumor models, they remain a mainstay for immunologists examining issues of basic tumor immunology. This review will briefly describe the pros and cons of transplantable tumor models and then focus on the recently developed transgenic mouse models in which tumors develop spontaneously. A brief overview of other mouse models that have been useful in defining basic principles of tumor immunology will also be discussed.