Potentiation of immune therapy by AXL signalling inhibition and chemotherapy
1 Purpose: The aim of this project is to explore the anti-tumorigenic potential of combining therapy targeting EMT/AXL signalling 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
2 Distress: Animals are not expected to suffer pain or discomfort during experimental procedure. Mice will be implanted with tumor cells that can form metastasis. Therefore some discomfort and pain will occur. Common side effects of the chemotherapeutics (Doxorubicin and STING agonist) used in this study will be noted in the scoring sheet for the animal. Animals that show too much distress during the monitoring will be sacrificed. .
3 Expected benefits: Using mice models, we aim to study mechanism that involves AXL overexpression and immune evasion in cancer. This will be followed by an efficacy study and therefore this project will contribute the pre-clinical effort of Bergenbio to use bemcentinib in combination with chemotherapy and immunotherapy.
In support of our pre-clinical program of BergenBio to develop Axl inhibitors and take these inhibitors into the clinic, the aim of these studies is to investigate strategies for combination treatment regimens to enhance the effect of immune therapies for drug resistant and less immunogenic cancers.
4 Number of animals and what kind
We are applying for the use of a maximum of 1040 C57Bl/6 mice (wt and huAXL-KI mice), 900 BalbC, 320 DBA/2 and 320 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.
5 how to adhere to 3R
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 cannot 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 are 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.
2 Distress: Animals are not expected to suffer pain or discomfort during experimental procedure. Mice will be implanted with tumor cells that can form metastasis. Therefore some discomfort and pain will occur. Common side effects of the chemotherapeutics (Doxorubicin and STING agonist) used in this study will be noted in the scoring sheet for the animal. Animals that show too much distress during the monitoring will be sacrificed. .
3 Expected benefits: Using mice models, we aim to study mechanism that involves AXL overexpression and immune evasion in cancer. This will be followed by an efficacy study and therefore this project will contribute the pre-clinical effort of Bergenbio to use bemcentinib in combination with chemotherapy and immunotherapy.
In support of our pre-clinical program of BergenBio to develop Axl inhibitors and take these inhibitors into the clinic, the aim of these studies is to investigate strategies for combination treatment regimens to enhance the effect of immune therapies for drug resistant and less immunogenic cancers.
4 Number of animals and what kind
We are applying for the use of a maximum of 1040 C57Bl/6 mice (wt and huAXL-KI mice), 900 BalbC, 320 DBA/2 and 320 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.
5 how to adhere to 3R
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 cannot 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 are 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.