There is an unmet need for developing Immuno-oncology preclinical animal models that recapitulate tumor microenvironment to reliably test antitumor drugs. A widely used preclinical model is syngeneic tumor cells in which murine tumor cell lines are grown and expanded in vitro and subsequently injected into an immunocompetent host to generate a de novo tumor growth. The advantages of this model are the ease of use, reproducibility, and ease of manipulation to study specific tumor cells or resistance to immunotherapy. The disadvantages of this model are lack of heterogeneity that defines cancer- this makes finding effective immunotherapy difficult, and as both tumor and immune cells are of murine origin, certain drugs may not recognize the mouse ortholog of their human target.
New advances in the last two decades have led to the development of genetically engineered mouse models for anti-tumor therapies. These pre-clinical models are created using tissue-specific promoters to drive expression of an oncogene (e.g. Kras or MYC) or a recombinase enzyme (e.g. PTEN) to drive deletion of tumor suppressors. This model offers gradual development of tumor in its microenvironment that is physiologically relevant recapitulating oncogenesis steps and is critical for the evaluation of anti-tumor agents. This model has some limitations such as penetrance through the tissue and latency, but these issues can be overcome if multiple oncogenes or tumor suppressors are targeted. Another challenge with this model is the issue of cross-reactivity between the murine and human cells when designing immunotherapeutic vaccines using this preclinical model- to make sure to use antigens or surface markers that are present only on human immune cells (e.g. human MHC class I in patients) but not on murine cells.
Lastly, there are humanized tumor models in which human xenograft models such as human cell lines are injected into immunocompromised hosts such as athymic (nude) or severe combined immunodeficient (SCID) animals. This model provides a great degree of clinical relevance for the development of anti-tumor therapies. The degree of immune deficiency in the murine host determines the applicability of this model. There are recent developments with NOD/SCID IL2ry chain knockout (NSG) mouse that allows not only engraftment of human cancer cell lines but also primary patient-derived xenograft (PXD). This model recapitulates the complexity of human disease very well, but implantation has a low success rate Further, these immunodeficient mice can accept both a human tumor graft and a human immune system graft, enabling more direct experimentation than syngeneic animal models.
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