Humanized Mice as an Effective Evaluation System for Peptide Vaccines and Immune Checkpoint Inhibitors

Abstract

Peptide vaccination was developed for the prevention and therapy of acute and chronic infectious diseases and cancer. However, vaccine development is challenging, because the patient immune system requires the appropriate human leukocyte antigen (HLA) recognition with the peptide. Moreover, antigens sometimes induce a low response, even if the peptide is presented by antigen-presenting cells and T cells recognize it. This is because the patient immunity is dampened or restricted by environmental factors. Even if the immune system responds appropriately, newly-developed immune checkpoint inhibitors (ICIs), which are used to increase the immune response against cancer, make the immune environment more complex. The ICIs may activate T cells, although the ratio of responsive patients is not high. However, the vaccine may induce some immune adverse effects in the presence of ICIs. Therefore, a system is needed to predict such risks. Humanized mouse systems possessing human immune cells have been developed to examine human immunity in vivo. One of the systems which uses transplanted human peripheral blood mononuclear cells (PBMCs) may become a new diagnosis strategy. Various humanized mouse systems are being developed and will become good tools for the prediction of antibody response and immune adverse effects.

Role of Human Leukocyte Antigen System as A Predictive Biomarker for Checkpoint-Based Immunotherapy in Cancer Patients

“…Therefore, there has been an interest in investigating whether decreased or complete loss of HLA class I and II molecules as well as defects in the APM molecules might predict the efficacy of ICI-based immunotherapy by impairing naïve T cells activation induced by anti-checkpoint molecules. Several lines of evidence in vivo indicate that HLA class I or II modulation play a major role in the efficacy of ICI-based immunotherapy and various humanized mouse models that reliably reflect the complexity of the human heterogeneous tumour and its TME, have been developed in order to evaluate the potential role of HLA class I and II in predicting the efficacy of ICI-based immunotherapy as well as immune adverse effects for different types of cancer [ 217 ]. In the study of Lechner MG et al, six murine solid tumor models (CT26, 4T1, MAD109, RENCA, LLC, and B16) were used to demonstrate that MHC class I expression on tumor cells is an excellent surrogate marker of the overall tumor immunogenicity level as well as a predictor of response to immunotherapy.…”

Development of a Chimeric Vaccine Against Pseudomonas aeruginosa Based on the Th17-Stimulating Epitopes of PcrV and AmpC

“…The immunogenicity of multi-epitope vaccines may be restricted when applied to humans because of the difference of major histocompatibility complex (MHC) between humans and mice. To bridge this gap, transgenic HLA mice were applied as reliable animal models in pre-clinical investigation of vaccines (44). For example, a vaccine against Coccidioides posadasii was generated using human Th17-driven epitopes (45), and its protective effect was evaluated in humanized HLA-DR4 transgenic mice (46).…”

HLA genotyping meets response to immune checkpoint inhibitors prediction: A story just started

“…The relevance of these biomarkers is reviewed elsewhere (Arora et al, 2019;Havel et al, 2019). Recent development of humanized cancer-derived xenograft mouse models (Kametani et al, 2019) will enable identification and validation of novel biomarkers for response to ICIs. F I G U R E 1 General overview on biomarkers associated with response to immune checkpoint inhibitors (ICIs)…”