Humanized mouse models for immuno-oncology research

Abstract

Immunotherapy has emerged as a promising treatment paradigm for many malignancies and is transforming the drug development landscape. Although immunotherapeutic agents have demonstrated clinical efficacy, they are associated with variable clinical responses, and substantial gaps remain in our understanding of their mechanisms of action and specific biomarkers of response. Currently, the number of preclinical models that faithfully recapitulate interactions between the human immune system and tumours and enable evaluation of human-specific immunotherapies in vivo is limited. Humanized mice, a term that refers to immunodeficient mice co-engrafted with human tumours and immune components, provide several advantages for immuno-oncology research. In this Review, we discuss the benefits and challenges of the currently available humanized mice, including specific interactions between engrafted human tumours and immune components, the development and survival of human innate immune populations in these mice, and approaches to study mice engrafted with matched patient tumours and immune cells. We highlight the latest advances in the generation of humanized mouse models, with the aim of providing a guide for their application to immuno-oncology studies with potential for clinical translation.• Next-generation humanized mouse models are being generated to better recapitulate the development of human innate and adaptive immunity. The development and use of novel humanized mouse platforms will accelerate the discovery and testing of new immunotherapies for patients with cancer.Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Preclinical proof of concept for VivoVec, a lentiviral-based platform for in vivo CAR T-cell engineering

“…Vehicletreated animals exhibited a slight reduction in B cells over the study period, consistent with past reports that circulating B-cell levels gradually reduce over time in CD34humanized mice. 23 Circulating CAR T cells were detected in a UB-VV100 dose-dependent manner but not in mice treated with the control CAR encoding vector, suggesting antigen-dependent expansion of CAR T cells. The detection of B-cell depletion (day 11) prior to the detection of circulating CAR T cells in the peripheral blood (day 18) may be due to B-cell killing in sites other than the peripheral blood or may reflect occluded or reduced detection of surface CAR after engagement with cognate antigen.…”

Combining preclinical tools and models to unravel tumor complexity: Jump into the next dimension

“…Murine model still represent the most widely used mammalian in cancer research representing an indispensable platform for the de velopment of novel methods of prevention, diagnosis, and treatment before going into clinical trial (31, 45). Humanized murine models established transplanting human-derived hematopoietic stem cells (HSCs) or peripheral blood mononuclear cells (PBMCs) into immunodeficient mice can be used as a system in which human tumors grown in the presence of a competent human immune system (46). This model allows studying immune-tumor crosstalk also determining the different immune cells that infiltrate the TME.…”

Patient-derived xenografts or organoids in the discovery of traditional and self-assembled drug for tumor immunotherapy

“…Humanized PDX models have provided a tremendous boost to the study of tumor pathogenesis and drug development. However, there are still limitations of humanized PDX models: 1) the time period required to build PDX models from patients is long and may take up to 6 months (or longer), 2) the high cost and low throughput, 3) lack of maturation of innate immune cells, coupled with insufficient ability to generate antigen-specific antibodies, 4) limited education of T cells in absence of murine thymus, 5)deficient HLA molecules, and 6) the difficulty in generating lymph node structures and germinal centers( 31 ). These limitations have led to several ongoing efforts to develop novel humanized preclinical models and platforms to develop therapeutic strategies that enhance response to immunotherapy.…”