Immunotherapy advancements with humanised immune system mouse models

Cancer immunotherapy

This article is sponsored by Taconic.

The cancer therapeutic landscape changed dramatically with the introduction of immune checkpoint inhibitors (ICIs) that target T cells and leverage a patient’s immune system. Success in targeting T cells as immunotherapy has prompted investigators to explore whether other immune cell types can be leveraged to develop efficacious oncology treatments. Throughout these endeavours, humanised immune system (HIS) mouse models have served as important preclinical research tools, helping to drive the immuno-oncology field forward.

T cells spurred early immuno-oncology research

The earliest immunotherapy developments were enabled through preclinical in vitro and in vivo research, the latter using syngeneic rodent models. The next advances employed HIS mouse models – immunodeficient mice engrafted with human hematopoietic stem cells (HSCs), peripheral blood mononuclear cells (PBMCs), or specific immune cell subsets such as natural killer (NK) cells, designed to reconstitute multiple components of the human immune system or specific immune sub-compartments.

When used in immuno-oncology research, HIS models are implanted with human tumour cell xenografts (CDX) derived from immortalised cell lines or patient-derived xenografts (PDX). Early studies demonstrated the value of such models in assessing ICI efficacy. In one example, when HSC-engrafted HIS mice were implanted with tumours from a PDX or a triple-negative breast cancer CDX, then treated with the anti-PD1 pembrolizumab (Keytruda), the growth of the PDX and CDX tumours was significantly impaired. In contrast, tumour growth in non-humanised mice was not impacted by pembrolizumab treatment, indicating that human immune cells were required for anti-tumour efficacy.

ICI therapeutics have become the standard of care for many oncology indications, demonstrating strong efficacy in a subset of cancer patients – particularly those who were previously refractory to other treatments. However, experience has shown that many other patients do not respond at all to ICI therapeutics. ICIs and other T cell-based immunotherapies have other limitations, including risks of immune-related adverse events and the fact that they may not be an option for patients who are immunosuppressed as a result of a first-line cancer treatment. Given these drawbacks, oncology researchers are exploring additional types of T cell-based therapies along with investigating a broader range of cell types and approaches that may prove effective in oncology treatment.

Combination therapies and associated cell types

Chimeric antigen receptor (CAR)-T cell therapy is one such approach gaining attention and focus. CAR-T therapy involves genetically modifying human T cells so they can recognise and kill cells that express the target protein. Preclinical work on this therapy continues, both to assess efficacy and to understand and mitigate risks. In one such study, NOG mice that express human IL-2 cytokine demonstrated the efficacy of CAR-T cell therapy in targeting xenografted uveal and cutaneous melanoma cells with good correlation to results observed in clinical trials. The hIL-2 NOG mouse is a useful host strain for these types of studies as human IL-2 may be necessary to support sufficient engraftment and expansion of tumour infiltrating lymphocytes (TILs), CAR-T, and other cell therapies derived from human T cells.

As researchers broaden their scope with regard to the immune cell types that may be suitable for immunotherapy, many are turning to NK cells. These cells can be leveraged to target tumour cells using germ line-encoded cell surface receptors, in combination with expansion or activation via various methods including NK cell-engager therapies, or engineered to express CARs. Early efforts to engraft NK cells into immune-deficient models suffered from poor cell uptake and a short survival window. By engrafting purified human NK cells derived from PBMCs into a mouse model that transgenically expresses human interleukin 15 (IL-15), researchers at the Central Institute for Experimental Animals (CIEA) demonstrated higher levels of human NK cell reconstitution and a longer survival window, without indications of GvHD. As a result, this IL-15 mouse model has proven a suitable host for assessing NK cell therapeutics.

Expanding on the NOG mouse to better accommodate immune reconstitution

When modelling the interactions between the immune system and tumour cells in early HIS mice, the development of certain human immune cell lineages is restricted. In response, researchers have turned their attention to support for myeloid cell differentiation in order to generate HIS mice with more complete human immune reconstitution. Because they support expanded myeloid lineage development and more complete human immune reconstitution, models like Taconic’s NOG-EXL and huNOG-EXL are ideally suited for studying myeloid-targeting immunotherapies as well as ICIs in combination with other therapies. Experiments using humanised NOG-EXL mice revealed that niraparib, a PARP-1/2 inhibitor, alters the tumour microenvironment and co-treatment with an ICI demonstrated synergistic anti-tumour efficacy.

As immunotherapeutic approaches evolve, HIS models will remain an important tool for the in vivo evaluation of new drugs.

Taconic Biosciences is a fully licensed, global leader in genetically engineered rodent models and services. Specialists in genetically engineered mouse and rat models, microbiome, immuno-oncology mouse models, and integrated model design and breeding services, Taconic continues to develop new models to address unmet needs in immuno-oncology preclinical research.

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