Humanized Mouse Models to Evaluate Cancer Immunotherapeutics

Abstract

Immunotherapy is at the forefront of cancer treatment. The advent of numerous novel approaches to cancer immunotherapy, including immune checkpoint antibodies, adoptive transfer of CAR (chimeric antigen receptor) T cells and TCR (T cell receptor) T cells, NK (natural killer) cells, T cell engagers, oncolytic viruses, and vaccines, is revolutionizing the treatment for different tumor types. Some are already in the clinic, and many others are underway. However, not all patients respond, resistance develops, and as available therapies multiply there is a need to further understand how they work, how to prioritize their clinical evaluation, and how to combine them. For this, animal models have been highly instrumental, and humanized mice models (i.e., immunodeficient mice engrafted with human immune and cancer cells) represent a step forward, although they have several limitations. Here, we review the different humanized models available today, the approaches to overcome their flaws, their use for the evaluation of cancer immunotherapies, and their anticipated evolution as tools to help personalized clinical decision-making.

High-content CRISPR screening

“…For example, TCR activation assays use a bead-based method for immune stimulation, which does not adequately recapitulate the complexities of the immunological synapse 271 . These challenges can be addressed by in vivo CRISPR screens 130,133,257,272,273 , either in immunocompetent mice for a focus on murine immune cells, or in immunodeficient or humanized mice with xenotransplanted human immune cells 274 . Such screens may provide insights into tissue-resident immune cells 275 and the role of structural cells such as epithelial cells, endothelial cells and fibroblasts 276 , which have not yet been a focus of in vivo CRISPR screening.…”

Experimental Models of Hepatocellular Carcinoma—A Preclinical Perspective

“…Humanized models (HMs) are generated by engrafting human tumor cells or patientderived xenografts into an immunodeficient rodent host harboring constituents of the human immune system. These novel platforms emerged as a step forward in the preclinical cancer research by reproducing the realistic interactions occurring between the tumor and the immune system [140,141], which make a significant contribution to cancer progression [132]. Regarding the importance of inducing immunodeficiency in mice prior to inoculation, its main role is to facilitate the engraftment and to overcome the rejection of human cancer cells mediated by the murine immune system [140].…”

“…The in vivo reconstitution of the human immune system can be acquired by (i) the intravenous transplantation of human peripheral blood mononuclear cells (PBMCs), which generates the so-called PBL (peripheral blood lymphocyte)-HMs, (ii) the inoculation of CD34+ hematopoietic stem cells (HSCs) leading to the HSC/SRC/SCID-HMs [142], which provides a more complete immune restoration, or (iii) the sub-renal administration of human fetal thymus or fetal liver tissue, followed by the injection of autologous CD34+ HSCs, resulting in the BLT (bone marrow-liver-thymus)-HMs [140,143].…”

Defining the Role of Immunotherapy in the Curative Treatment of Locoregionally Advanced Head and Neck Cancer: Promises, Challenges, and Opportunities

“…For a more detailed information regarding contemporary HNSCC PDXs and human preclinical modelling see (29)(30)(31)(32)(33).…”