While we hope for all clinical trials to be successful, unfortunately this is not always the case. In many instances, using the information from unsuccessful trials is just as important.

Immunotherapy is a relatively new type of cancer treatment that enables the body’s immune system to find and destroy cancer cells. While chemotherapy works to kill cancer cells, immunotherapy uses drugs called checkpoint inhibitors to harness the body’s own immune system to fight cancer.

While some cancer types respond well to immunotherapies, many cancers, including most colorectal cancers, remain resistant to current immunotherapies.

“Immunotherapies have revolutionised the way some cancers are treated. However, there are also cancers where immunotherapy just doesn’t work as well,” says Dr Amr Allam, Postdoctoral Research Fellow at the ONJCRI.

“In 2021, colorectal cancer affected over 15,000 Australians. If detected early, many patients can have positive outcomes after undergoing surgery and chemotherapy treatment. However, in 50% of patients, the cancer will progress, and devastatingly the survival rate drops to approximately 12 months when the cancer is detected at late stages. Immunotherapies provide promising results in treating some types of colorectal cancers, but most patients currently remain unresponsive to immunotherapy,” he explains.

“The immune system can detect some cancer cells easier than others. For instance, if a tumour harbours many mutations, then the immune system can detect it easier. But there are many other factors that contribute to this and that we do not understand that well,” says Dr Allam.

Dr Allam, who currently works in the Cancer and Immunity Program at the ONJCRI is using data and samples from a previous clinical trial for colon cancer to work out why this might be the case, and how we can use this information to inform future research and improve current immunotherapy approaches for this disease.

“My current work is based on a previous clinical trial. The trial was run in 2018 and used a drug called Napabucasin that attempted to improve response to an immune checkpoint inhibitor, called Nivolumab, in patients with advanced colorectal cancer. The trial unfortunately revealed a low response rate, but it did allow us to collect a large number of samples from patients before, during and at the end of the trial. I am now comparing the various immune cell types in these samples to better understand why some patients responded and many did not. This will inform us how we should aim to alter the response of a patient’s immune system so that this person then responds to immunotherapy and how we would test this in a future clinical trial,” says Dr Allam.

“A better understanding of the interplay between cancer cells and the surrounding normal and immune cells will also help us to identify biomarkers, which will enable us to predicate in the future which patients are likely to respond. Also, this can provide better approach to stratify patients, ensuring the best therapy tailored for a specific patient at an individual level.”

“Asking questions like, does the microenvironment change after treatment? Or, do we see better activity in the immune cells? Or, do we see changes in tumour structures? all help us get a better understanding of what happens between normal cells and cancer cells that collectively make up the so called tumour microenvironment. We are also using statistical analysis to understand if patients would have benefited if they could be treated in the earlier stages of their disease,” says Dr Allam.

These questions have led to Dr Allam to investigate how combining drugs that targeting the tumour microenvironment with immunotherapy treatment could improve patient outcomes.

“Using a variety of preclinical models, we are now exploring how such combination therapies can stop the progression of tumours. Our research is at very exciting exploratory stages and already shows some positive results. We have learnt that targeting a key molecule called STAT3, either genetically or pharmacologically, lowers the metastatic burden in our preclinical models. STAT3 plays an integral role in promoting “features” of cancer, namely cancer cell survival, proliferation, migration to distant organs survival, and cancer cell evasion of the immune system. This is likely to be an important finding because thus far metastatic colorectal cancer is currently very difficult to treat.” explains Dr Allam.

“There is no ‘one-size-fits all’ with cancer treatment so being able to take observations in patients back to the lab like we have in this instance is crucial to ensure progress in this area of research and eventually translated our findings from the laboratory into the clinic to provide the best possible treatment for cancer patients.”