Mouse models for pretesting of immunotherapeutic strategies for cancer patients

There are two major reasons for using mouse models for preclinical testing of immunotherapetic strategies before proceeding to clinical trial. First, the requirements of regulatory authorities for toxicity testing and, second, the need of the investigator to convince himself/herself and the grant-giving bodies that proceeding with a clinical trial is scientifically justified. In both cases, the mouse model presents problems specific to a therapy depending on immune effector cells and their products. These are particularly evident in evaluating therapies for cancer patients, where analysis of cellular responses can often be better evaluated in in vitro studies with human peripheral blood leukocytes. However, where mouse models can show an effect on tumour growth, they can be extremely useful for evaluating the mechanisms underlying the effect, as we have found in evaluating tumour rejection of MUC1 expressing tumours. Moreover, strains carrying transgenes of human target antigens allow testing for auto-immunity.

Antibody-based therapies

Preclinical testing in mouse models has been successfully translated into the clinic using a humanised version of the original mouse antibody against the c-erbB2 receptor (Herceptin). Clinical studies with a humanised MUC1 antibody have been approved and initiated, even though the data obtained in mouse models were equivocal. The use of antibodies to deliver toxic agents depends on the efficacy of delivery of the toxic material: when therapy depends on delivering high-dose radioactivity, imaging studies in patients can provide better preclinical testing than the mouse model.

Cell-based therapies

Passive delivery of immune effector cells modified in vitro are in the pipeline for clinical testing. T cells modified with hybrid receptors (with extracelluar antibody sequences) to target tumour antigens, and dendritic cells loaded with tumour antigens are the focus of attention. Our own focus is on the MUC1 antigen in both cases. The use of the mouse model for the T-cell receptor studies may require the development of a parallel set of constructs appropriate to the mouse model, and in vitro studies with human peripheral blood leukocytes may be more useful. In the case of dendritic cells (DC), the mouse DC are taken from the bone marrow or spleen, whereas the source of human DC is either peripheral monocytes stimulated to differentiate into DC or CD34⁺ cells isolated from patients treated with granulocyte–macrophage colony-stimulating factor. Nevertheless, much can be gained from the use of mouse models for evaluating DC-based approaches. Where specific antigens are being explored, mice transgenic for the antigen are preferred.

Active immunisation against tumour antigens

This also includes the use of DCs loaded with specific antigens or tumour lysates. However, simpler delivery of the immunogen would be highly preferable since the good manufacturing practice facilities required for delivery of modified cells are expensive and sites are limited. DNA-based formulations provide several advantages. The sequences are easy to manipulate and production of immunogen can be relatively cheap. The studies in mouse models to be reported here have led to a small trial using MUC1 cDNA in breast cancer patients, and have allowed characterisation of important domains in the antigen and of the components of the immune system important for effective tumour rejection.