Humanized mice for immune checkpoint blockade in human solid tumors

Abstract

Immunotherapy, specifically research involving immune checkpoint blockers (ICBs), has become a popular trend in anticancer research over the last three years. Due to the difficulties and often poor translation of results from in-vitro models, in-vivo models have become more relevant than ever. With the discovery of NOD, Prkdc^scid , and Il2rγ^-/- mutations, patient-derived xenograft (PDX) mouse models were developed, providing an ideal environment for ICBs testing. By implanting a PDX with either CD34⁺ or peripheral blood mononuclear cells, we can create a human immune system capable of mounting a response against tumor burden. These animal models are currently being used to study molecular mechanisms, test drug efficacy, and trial drug combinations. Others have found use for these humanized mouse models as surrogates to represent otherwise uncommon diseases. Limitations remain with regards to what the models are capable of, but in the short amount of time between the development of these models and heightened interest in ICBs, these mice have already shown utility for future developments in the field of immunotherapy.

Keywords: Humanized mice; immune checkpoint blockers; immunotherapy; patient derived xenografts.

Figure 1

The major steps involved in the production of humanized mice. Process (A) demonstrates the humanization process using CD34⁺ hHSCs. After implantation and allowing at least 6 weeks to establish, patient tissue sample can then be grafted. After 6 weeks, humanization can be verified by flow cytometric analysis, ultimately aiming for at least 25% CD45⁺ human cells in the blood. Note that if proceeding with method (A), human PBMCs (hPBMCs) will not be used. Process (B) starts with implantation of patient tumor cells into immunocompromised. Additional experimental therapies may also be used once the mice have been allows to sufficiently humanize and xenograft has been established.

Figure 2

PubMed search results. There has been an increase in the quantity of research being published in the field of ICIs. Data from PubMed was able to be collected as far back as 1997, publications to be released in the year 2020 were excluded from this search result.