Forsøksdyr: Evaluating the efficacy of immunotherapy and combinatorial treatment regimes in mouse models of cancer

Godkjenningsdato 14.11.2018

Godkjenningsperiode 15.11.2018-14.11.2022

The last few years have seen major improvements in cancer therapeutics, in particular with the rise of immuno-oncology, leading to increased survival for cancer patients. Nonetheless, clinical trials of checkpoint inhibitors in several cancer types, for example breast cancer, have not shown dramatic results. Further, in those cancers in which checkpoint inhibitors have been approved, only a subset of patients responds to treatment. In this study, we aim to explore combinatorial treatment regimes and finding prognostic markers for therapy response. This study aims to increase our current understanding of which patients that might benefit from checkpoint inhibitors and elucidate possible treatment combinations that could lead to improved survival.

Animals will be exposed to radiation and be given medications such as chemotherapy or checkpoint inhibitors, which may lead to toxicities. Dosages for these exposures will be kept at levels securing treatment effects and at the same time minimising side effects. Mice may undergo procedures such as tissue transplantation and fine needle aspiration biopsies, for which they will be anaesthetised and closely monitored afterwards. Mice will also undergo minimally burdensome standard procedures such as ear clipping for identification, which do not cause a marked reduction in animal welfare.

In this project we will use up to 1250 mice, including immunodeficent mice for PDX models, 5 transgenic strains and FVB/N wild type mice for allograft transplantations and maintenance of transgenic strains. The transgenic strains will be used for lineage tracing experiments and determining effects of GLI1 and LGR5 transgene expression on applied treatment regimes. We are responsible for the breeding of the mice, except the immunodeficient mice for PDX models. The experimental transgenic mice harbour several transgenes and require a substantial amount of breeding to obtain the desired genotypes. The mice that do not obtain the desired experimental genotypes are used for further breeding to minimize the amount of included animals.

The immune system is very complex and cannot be mimicked outside a living organism. Tissue cultures (immortalised cell lines, primary cultures and organoids) cannot mimic the interplay between the various cell populations of the immune system and the effect of induced immune responses cannot be determined without a system harbouring several types of immune cells and tumours. Thus, in vivo models have to be used for studies including complex immune responses. We have conducted statistical power analyses to determine the minimum number of experimental animals required in order to address the purpose of the experiment. In addition, we use best current practices and follow closely literature and other publications for novel methods in order to reduce the total number of animals used. We use anaesthetics and analgesics in the event of invasive procedures, and when possible deliver medications by minimally uncomfortable methods such as through enriched chow or osmotic pumps. We use refined procedures for mammary fat pad transplantations and mammary gland intraductal injection of DMBA, rather than systemic treatment via oral gavage.