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Business


Greater human NK cell


reconstitution was achieved in hIL-15 NOG mice engrafted with human PBMCs versus


conventional NOG mice. The hIL-15 NOG mice survived


seven weeks post-engraftment without signs of GvHD


breakthrough PD-1 inhibitors pembrolizumab (Keytruda®) and nivolumab (Opdivo), as well as PD-L1 and CTLA-4 inhibitors. This antibody- based therapy binds to immune-checkpoint pro- teins expressed on a tumour or on T-cells, enabling the cytotoxic T-cells to target and kill the tumour. The first Nobel Prize in Medicine awarded for can- cer therapy, in 2018, recognised the checkpoint inhibitor research of James P. Allison and Tasuku Honjo – a testament to the groundbreaking nature of this therapeutic approach. The broad utility of checkpoint inhibitors across


multiple tumour types has been well-validated both in the clinic and in the lab, including in- mouse models that have a humanised immune sys- tem coupled with either human tumour cells or patient-derived xenografts (PDXs). Since immuno- oncology depends on the ability to discern how tumours interact with immune cells within the host and the tumour microenvironment, such models have proven highly effective tools for assessing checkpoint inhibitor efficacy. In addition, syngene- ic models – in which a mouse tumour is implanted in an immunocompetent mouse – are facilitating checkpoint inhibitor study by elucidating how immune cell subsets, cytokines or T-cell responses impact tumour growth and how the immune sys- tem regulates tumour progression. As effective as current checkpoint inhibitors


have proven in the lab and in a subset of cancer patients, they are non-efficacious in others. In many cases, it is believed that multiple immune checkpoint pathways are at work simultaneously,


12


so inhibiting a single checkpoint is only partially effective. To overcome this, researchers have explored combining more than one checkpoint inhibitor to determine if synergistic benefit can be achieved in a broader number of patients. Despite the promise of this approach, a key limitation occurs in preclinical development, where the exper- imental new drug must be tested in the context of the fully humanised monoclonal antibody primary drug. Since the primary is human specific, and the new drug may or may not be, the rodent system must harbour compensatory genetic modifications. One way that researchers are overcoming this hur- dle involves essentially humanising a mouse model twice: once to humanise the primary antibody tar- get binding site, and again to humanise the experi- mental new drug target binding site. Scientists are genetically modifying mouse models in this way to enable studying the interactions between check- point inhibitors in a living system with a fully intact immune system. Once the molecular drug targets are humanised, the model can then be sub- ject to syngeneic tumour xenograft studies for test- ing each drug alone and in combination for tumour killing efficacy. This model generation approach is beginning to see traction and has the potential to aid the many pharmaceutical and biotech companies partnering to advance and improve on checkpoint inhibitor therapies. A growing trend in oncology research, and par-


ticularly in lung and breast cancer studies, is the use of relevant biomarkers to predict treatment efficacy, guide treatment selection and monitor outcomes


Drug Discovery World Spring 2019


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