Concise Review: Humanized Models of Tumor Immunology in the 21st Century: Convergence of Cancer Research and Tissue Engineering

Abstract

Despite positive testing in animal studies, more than 80% of novel drug candidates fail to proof their efficacy when tested in humans. This is primarily due to the use of preclinical models that are not able to recapitulate the physiological or pathological processes in humans. Hence, one of the key challenges in the field of translational medicine is to "make the model organism mouse more human.'' To get answers to questions that would be prognostic of outcomes in human medicine, the mouse's genome can be altered in order to create a more permissive host that allows the engraftment of human cell systems. It has been shown in the past that these strategies can improve our understanding of tumor immunology. However, the translational benefits of these platforms have still to be proven. In the 21st century, several research groups and consortia around the world take up the challenge to improve our understanding of how to humanize the animal's genetic code, its cells and, based on tissue engineering principles, its extracellular microenvironment, its tissues, or entire organs with the ultimate goal to foster the translation of new therapeutic strategies from bench to bedside. This article provides an overview of the state of the art of humanized models of tumor immunology and highlights future developments in the field such as the application of tissue engineering and regenerative medicine strategies to further enhance humanized murine model systems. STEM CELLS 2015;:1696-1704

Establishment of a Patient-Derived Tumor Xenograft Model and Application for Precision Cancer Medicine

“…[34][35][36] The human bone marrow microenvironment was also established from mesenchymal stem cells etc.…”

Patient-Derived-Tumor-Xenograft: modeling cancer for basic and translational cancer research

“…This totally impairs the possibility to use PDTX models for immunotherapeutic studies and approaches, such as vaccines, immune modulators and activators. To overcome this important issue, humanized mouse have recently emerged [74][75][76][77][78][79]. Different degrees of reconstitution have been applied, including the simple injection of either heterologous or autologous peripheral blood mononuclear cells or alternatively the transplant of CD34-positive human hematopoietic cells.…”

Mouse Models of Tumor Immunotherapy

“…This issue is particularly obvious when modeling diseases where the hematological system is involved, such as infections, autoimmune conditions, and malignancies. To overcome this problem, there has been a great effort in the field to "humanize" experimental mice for a better modeling of human pathophysiological conditions (Holzapfel, Wagner, Thibaudeau, Levesque, & Hutmacher, 2015;Legrand et al, 2009;Rongvaux et al, 2013;Scheer, Snaith, Wolf, & Seibler, 2013).…”

“…gamma chain (γc)-deficient mice, nonobese diabetic (NOD)-severed combined immunodeficiency (SCID)-IL-2 receptor gamma (IL2rg)-deficient mice are commonly used host for xenograft implantation (Aparicio, Hidalgo, & Kung, 2015;Holzapfel et al, 2015;Legrand et al, 2009;Rongvaux et al, 2013). Mouse models xenografted with human tumor tissues are also widely used for immune-based targeted therapy studies, such as anti-VEGF and anti-EGFR mAbs, and adoptive-transferred engineered T cells (Holzapfel et al, 2015;Zhou, Facciponte, Jin, Shen, & Lin, 2014). However, it is notable that an assessment of these classes of therapy is flawed by the lack of intact adaptive immunity in the recipients, including important regulatory T and B cells.…”