Most notably, HIS patient-derived xenograft (hu-PDX) models have been utilized to assess efficacy and toxicity of immunotherapies in the treatment of a variety of tumor types. Human immune system (HIS) mouse models are increasingly being combined with human xenograft models for the investigation of human immune cell behavior in response to tumors and therapeutics. There is a clear need for well-designed in vitro and in vivo preclinical platforms that can accurately assess both the efficacy and safety of novel agents and individual responses to immunotherapies. These IRAEs range from mild to severe and are thought to be linked to inflammatory damage consequent to non-specific activation of the immune system. Immunotherapies have been linked to numerous immune related adverse events (IRAEs) such as cytokine release syndrome (CRS), pneumonitis, and neuropathy, in addition to late onset rheumatic diseases. Furthermore, the complex heterogeneity of immune systems, both between and within patients over time, significantly impacts the effectiveness and safety of approved immunotherapeutic agents. Preclinical assessment of the safety and toxicity of immunotherapies is heavily reliant on in vivo immunocompetent mouse models that show poor translation of beneficial responses to the clinic. Immunotherapies have significantly improved overall survival (OS) in a wide variety of cancer types, yet immunotherapeutic agents have a notably higher rate of failed clinical trials in comparison to alternative cancer therapeutics. Emerging immunotherapies, such as immune checkpoint inhibitors (ICI) (see Glossary) and Adoptive Cell Therapy (ACT), aim to treat cancer through the activation and enhancement of anti-tumor immunity. Cancer associated inflammation is present at all stages and has been shown to contribute to genomic instability, angiogenesis, epigenetic modifications, induction of cancer cell proliferation and enhancement of anti-apoptotic pathways. Throughout the stages of tumor development, cancer cells evolve to evade destructive immunity, employing mechanisms that mimic peripheral immune tolerance. Immuno-oncology (IO) research has shaped our modern understanding of cancer progression, illuminating the paradoxical role of immune cells in both the induction and elimination of cancer. This review outlines existing preclinical murine models for the study of immuno-oncology, and highlights innovations that can be applied to improve the feasibility and efficacy of autologous models. However, limited access to autologous tissues, short experimental windows, and poor retention of tumor microenvironment and tumor infiltrating lymphocyte components are major challenges affecting the establishment and application of autologous models. Models that comprise of autologous human tumor and human immune cells provide a platform that is more representative of the patient immune-tumor interaction. Whilst overcoming limitations of immunocompetent models, HIS-tumor models often rely on reconstitution with allogeneic immune cells, making it difficult to distinguish between anti-tumor and alloantigen responses. Immunocompromised mice reconstituted with a human immune system (HIS) and engrafted with patient-derived tumor xenografts are a promising novel preclinical model for the study of human tumor-immune interactions. Despite the significant contributions of immunocompetent mouse models to the development and assessment of cancer immunotherapies, they inadequately represent the genetic and biological complexity of corresponding human cancers.
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