An immunology revolution

Dr Santiago Zelenay is using his background in fundamental immunology to understand how the immune system can be used to design better therapies for cancer patients. A recent recipient of the Cancer Research UK (CRUK) Future Leaders in Cancer Research Prize, he shares details of his work and what inspired him to join the cancer community.

Over the years, I’ve become increasingly interested in the idea that the immune system not only constitutes a defence mechanism against infectious microorganisms, such as bacteria and viruses, but that it can also be a powerful barrier to cancer.

The notion that you could treat cancer patients with therapies that harness the power of the immune system has been around for a long time, but it was only over the last ten years that undeniable evidence showed that these therapies can promote profound patient benefit across many different tumour types - to the point that it’s replacing mainstream cancer treatments, like chemotherapy, as the standard of care in some cases.

Immunotherapies, especially those based on the use of the so-called immune checkpoint inhibitors, have really transformed the clinical care of patients with cancer. There has been a revolution in this respect and also in thinking. All this clinical evidence has really eradicated the scepticism that was around the concept that the immune system could block cancer development and progression.

As someone with a background in basic immunology, I got attracted to the idea of working on something that had obvious clinical implications and that could lead to direct patient benefit. I wanted to apply my knowledge in fundamental immunology to cancer biology at a time of renaissance in the cancer immunology field.

This contributed to my decision to move to Manchester and join the CRUK Manchester Institute, an ideal place to continue doing basic research in cancer, but also to focus on the translational aspects too, facilitated by its connection with The Christie hospital, the close interaction with oncologist, clinicians and the access to patient samples.

Dr Santiago Zelenay

Santiago Zelenay is the lead for the Cancer Inflammation and Immunity Group at the Cancer Research UK Manchester Institute and Cancer Immunology lead at the Lydia Becker Institute at The University of Manchester.

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Investigating inflammation

My research group is focused on understanding the principles and rules that regulate the balance between tumour-promoting and tumour-inhibitory inflammation. Inflammation can have a dual role in cancer, promoting or restricting its growth.

This also happens following treatment but little is understood about what determines whether the outcome is good or bad. We study how this happens and whether we can therapeutically change the inflammatory response to make it beneficial.

We ask open fundamental questions in the field. What kicks off the immune response against cancer in the first place, and what prevents this from happening? What is the key for a strong and durable response? How can we therapeutically make an unresponsive tumour respond to immunotherapy?

Through the study of the inflammatory response within tumours, we aim to design new combinations to enhance the efficacy of treatments. Our ultimate goal is to contribute to the design of more efficient therapies for cancer patients.

Research discovery

In asking those basic questions, we found that the use of anti-inflammatory drugs, such as aspirin, can improve the efficacy of immunotherapy in mouse models of cancer. Based on these findings and on further research in patient samples, we have designed a clinical trial to test one of our most promising combinations.

This trial, called ImpALA, will open very soon. Led by Anne Armstrong, a Consultant Medical Oncologist at The Christie, and supported by Breast Cancer Now, and with the Christie as a sponsor, we will test the combination of high-dose aspirin, with a checkpoint inhibitor (avelumab, an anti-PD-L1 antibody), in triple negative breast cancer patients.

The primary trial aim is to determine whether the addition of aspirin enhances the efficacy of avelumab treatment by shifting the inflammatory profile of the tumours towards classic anti-cancer immune pathways, one that would favour cancer control by the immune system.

The general premise is that anti-inflammatory drugs like aspirin, rather than inhibiting tumour inflammation indiscriminately, turn its ‘flavour’ to a good type, one that is associated with higher response rates.

The Manchester advantage

We have an advantage because we’re unique in that we are a community. We may all have very different expertise, but we always point - like an arrow head - together in one direction of travel, and that is to obtain patient benefit.

Comparisons with other places aren’t easy, but from my experience, our interactions with oncologists are unusual in that they’re seamless. This spirit of community where everyone is open to talking and working is connected to a feeling that a new wave of immunologists, cancer biologists and other fundamental researchers are being attracted to work in Manchester.

Besides my interactions with researchers from the CRUK Manchester Institute and clinicians from The Christie, we are very fortunate to have at The University of Manchester a great number of exceptional immunologists. As a group, we interact and collaborate with them in different projects.

Being the Lead of the Cancer Immunology branch of the Lydia Becker Institute of Immunology and Inflammation has helped with meeting others and establishing new collaborations. My interactions with this community have led me to redefine myself. I used to define myself as a pure mouse immunologist, but I feel that’s now changed. They’ve broadened my definition of what I do.