The introduction of immunotherapy has dramatically improved the outlook for patients with several types of cancer that previously had very low survival rates. However, this outlook has yet to occur for primary bone cancer patients.
This new research project awarded to Dr Olivier Pardo at Imperial College London, working in collaboration with Professor Dominique Heymann at the University of Nantes in France aims to test new innovative drug combinations that could make immunotherapy an effective treatment option for osteosarcoma, one of the most common forms of primary bone cancer, and improve survival rates which haven't improved in over 30 years.
How does the immune system behave?
T cells are a key part of our immune system. To prevent them from being activated all the time and destroy healthy cells, T cells have proteins on their surface, that when activated, can turn off the immune response. These are named checkpoint proteins.
Cancer cells also have proteins on their surface that interact with the checkpoint proteins, switching off the immune response; as a result of this interaction, the T cells do not recognise and kill cancer cells.
Drugs that prevent the interaction between the checkpoint proteins and the proteins on the cancer cells are called checkpoint inhibitors. They prevent the immune system being switched off, allowing the T cells to recognise and attack the cancer cells.
What role do immunotherapies play?
The introduction of checkpoint immunotherapies such as pembrolizumab has provided a major breakthrough in the treatment of several common cancers with previously poor survival rates (e.g., melanoma, lung cancer). However, osteosarcoma patients appear fairly unresponsive to pembrolizumab.
What are the aims of the project and what do we already know?
The aim of this research is to understand why osteosarcoma behaves differently and potentially adjust existing immunotherapy treatment so that osteosarcoma patients can benefit.
Research previously carried out by Dr Pardo suggests that a protein named FGF2 (basic fibroblast growth factor) which is abundant in the serum of osteosarcoma patients may make osteosarcoma cells resistant to immunotherapy by in turn inhibiting the activity of another protein called interferon gamma, which facilitates the destruction of cancer cells when they are attacked by immune cells.
Dr Pardo will investigate how FGF2 decreases the activity of interferon gamma and how this hinders the activation of the immune system against osteosarcoma.
The team will examine if inhibition of FGF2 in osteosarcoma enhances the response to checkpoint inhibitor immunotherapy. Importantly, drugs that inactivate FGF2 have been used in the clinic for other cancers and could be re-purposed for osteosarcoma patients. A key objective of this research will be to test FGFR inhibitors/immune checkpoint inhibitors combinations in a preclinical model of osteosarcoma, to determine if these drugs enable immunotherapy to be effective.
Dr Pardo, said:
The work in my lab has for many years focused on the role of FGF2 in resistance to treatment in various cancers. However, we have only now realised that FGF2 may influence the way the immune system interacts with cancer cells. We intend to demonstrate that targeting FGF2 enables osteosarcoma cells to be eliminated by the immune system, a project that we would not have been able to initiate without the support of the Bone Cancer Research Trust.
Professor Heymann added why the importance of collaboration in osteosarcoma is needed:
Bone sarcomas are rare, mineralized and highly heterogeneous malignant entities making them difficult to analyse and then less attractive for pharmaceutical companies. Facing this observation, international scientific networks are mandatory for allowing the sharing of expertise and facilitating the access to biological models and samples. The Bone Cancer Research Trust strongly supports this international networking in the field of bone sarcomas.
Dr Viqui Vinader, Research Manager at the Bone Cancer Research Trust, said:
Using drugs that are already in the clinic for other indications can significantly reduce the time needed to reach osteosarcoma patients, as many questions have already been answered; for example, their toxicity, how the body handles the drugs and therefore how safe they are for patients. It also means that supply of the drugs may already be available, and clinicians already know how best to administer them to patients to maximise their effect. This project is extremely exciting and wouldn’t be possible without the funds raised by our incredible supporters, who we cannot thank enough.
Find out more about the research project below.