Forsøksdyr: Potentiation of immune therapy by inhibiting AXL signalling

Godkjenningsdato 23.12.2020

Godkjenningsperiode 23.12.2020-22.12.2024

The mechanisms by which cancer cells stay hidden from the immune system are now more widely understood. This has led to an expansion of immune oncology agents being developed and this is the fastest growing sector of the cancer drug market. These novel therapeutics use the patient's immune system to target the death of cancer cells. Resistance to these drugs however has been identified in clinical studies. These resistance mechanisms are mediated by the cellular epithelial to mesenchymal transition (EMT). The receptor tyrosine kinase AXL plays an important role in mediating EMT and facilitating tumor immune escape. AXL also plays a crucial role in the immune cells of the innate lineage and functions to dampen the immune response. In this manner AXL activation promotes a pro-tumorigenic microenvironment.

The aim of this project is to explore the anti-tumorigenic potential of combining therapy targeting EMT/AXL signaling pathways with clinically approved immune checkpoint inhibitors alone and in combination with chemotherapy in syngeneic cancer models of breast, lung, melanoma and AML. Further, the role AXL plays in the immune cells and in the cancer cells needs further investigation in order to unravel the fundamental mechanisms resulting in the observed potentiation of immune therapy by inhibiting AXL.

BerGenBio has developed small molecule inhibitors and targeting antibodies against AXL and other proteins important in maintenance of EMT. In support of our pre-clinical program to take these inhibitors into the clinic, the aim of these studies is to investigate strategies for combination treatment regimes to enhance the effect of immune therapies for drug resistant and less immunogenic cancers. We are applying for the use of a maximum of 960 C57Bl/6 mice (WT and huAXL-KI mice), 400 BalbC, 320 DBA/2 and 160 CH3 mice to be able to investigate the efficacy of AXL inhibitors alone and in combination with immune therapy in multiple indications including cancers of the skin, breast and lung.

Replacement, Reduction and Refinement
An extensive amount of in vitro studies have been performed to validate our drug targets and select indications where EMT is an important resistance development to identify the indications and cell lines that needs validation in mouse models. As cell culture studies can not replace the complexity of a mouse model in response to drug treatment, in vitro results needs validation in mouse models as pre-clinical proof of concept. This is in particularly true for studies where combinations with immune therapy is investigated.
For subcutaneous models, two tumors will be utilized per mouse. For tumor growth analysis, measurements of the same animals will be used across the time. The personnel performing the procedures of animal handling, cell injection and subsequent administration of drugs to the animals and that are responsible for the well being of the mice are well trained and experienced in these methods.