ESMO 2022丨Interview with Professor Samra Turajlic, the Winner of 2022 ESMO Translational Research Award

The 2022 ESMO Translational Research Award was presented to Samra Turajlic from the Royal Marsden NHS Foundation Trust and the Francis Crick Institute, London, UK. Professor Turajlic has performed excellent work on cancer evolution, especially in kidney cancer, and she has been one of the driving forces behind COVID-19 vaccination in cancer patients research coming from the UK. We had the honor to interview Professor Turajlic at this ESMO Congress.

 

 

Oncology Frontier: Congratulations on winning the ESMO Award for Translational Research. Please share us with your feeling of winning this prize.

 

Dr Turajlic: Well, of course, I am delighted for this recognition from ESMO for our team really, not for me. It takes a village to deliver a translational research program. It is very much an interdisciplinary multi-team effort. So, on behalf of our team and our collaborators of course, I am delighted by this prize.

 

Oncology Frontier: Can you introduce your work in the translational research of renal cancer, such as the study of  ADAPTeR and TRACERx Renal, and what enlightenment these studies may bring to the clinic?

 

Dr Turajlic: Thanks for asking me these questions. In the context of the TRACERx Renal study, what we tried to resolve is this incredible clinical diversity that we see in patients who are diagnosed with clear cell renal cell carcinoma - diversity in metastatic efficiency, diversity in clinical outcomes (whether it be from surgery or from treatment) - and yet, on the other side of that clinical diversity, a very simple genetics. This has bewildered all of us in the field for a number of years, and it made us think in the TRACERx Renal Consortium, that perhaps by applying an evolutionary framework of understanding, we could reconcile that diversity of clinical phenotypes. Essentially what we found is that clear cell renal cell carcinoma is characterized by highly conserved patterns of tumor evolution. What I really mean by that is that there are repeatable paths by which genetic mutations occur in a particular order or in combination. It is those patterns of ordering and combinations that produce different evolutionary tempo, different evolutionary outcomes, and different clinical outcomes. This is really the first time in any solid tumor where we have an evolutionary classification that can predict patient outcomes. For us, the next step is to really try and bring this into the clinic, and we are working on different methods by which we might implement this information in the clinic. You also asked me about the ADAPTeR study. This is a prospective phase II clinical trial of nivolumab in clear cell renal cell carcinoma. Trials like this are normally primarily focused on the outcomes, such as response rate, progression-free survival and overall survival, but we were really determined to make biological endpoints a main part of this trial. The reason is that we have this conundrum in clear cell renal cell carcinoma - it is a highly inflamed tumor (more than any other solid tumor type), and yet that inflammation doesn’t pertain a good prognosis like it does in all other solid tumors. It is essentially associated with a negative prognosis. That made us question whether the immune cells inside these primary tumors were really tumor-specific at all. In order to account for all different possibilities of how nivolumab might be acting to produce benefit in these patients, we did a multitude of downstream immunological assays, and the place where we found the signal was PCR sequencing. What we discovered was that patients who benefited from nivolumab, before starting treatment, there was already evidence of expanded T-cell clones, specific antigen-primed clones, which upon binding to nivolumab, expanded further and became cytotoxic. That is how they impacted patient outcomes. In patients who didn’t benefit from nivolumab, there was a paucity of these T-cells, and once we applied nivolumab, the T-cells that were there were replaced by novel T-cell clonotypes, and these patients did not benefit. This tells us two things really. One is that at least some of the immune infiltration in clear cell renal cell carcinoma is tumor-specific; and two, the key to the mechanism of action of nivolumab in this disease is binding and expanding this particular population of T-cells.

 

 

Oncology Frontier: You also led the research on COVID-19 vaccination for cancer patients. As the virus mutates, what measures do you think should be taken to protect cancer patients?

 

Dr Turajlic: Thanks for that question. At the start of the pandemic, we were compelled to set up this study, called CAPTURE, because the pandemic had revealed a huge knowledge gap in the interaction between cancer, immunity and infection. All the decisions we were making about cancer patients, whether we advised them to self-shield or whether we interrupted their cancer therapy, were really just based on an assumption that patients with cancer would be more susceptible to severe COVID-19, and what’s more, the therapies they were on could make this vulnerability even worse. There was a long list of potential therapies that could be implicated in this, and all of these are life-saving therapies. So we were really reluctant to continue with this attitude without generating some evidence. That is why we set up the study. The findings of the study, where we probed both T-cell and B-cell responses initially after infection and then after vaccination, were that, in patients with solid cancers, the immune response was largely preserved, and associated with age, more than the cancer factor (what type of cancer they had, or what type of treatment they were on). Unfortunately, patients with hematological malignancies didn’t fair so well. Their immune response was often blunted, either because of the type of malignancy that they had, or because of the treatment they had received. These data, and other data generated around the world, had helped prioritize patients with blood cancer for further doses of vaccine. But even recently, as we examined the response to four vaccine doses, it seems there is a proportion of these patients that remain highly vulnerable, and we should be aware of that as oncologists. Relative to your question about ongoing evolution of the virus, I think this has relevance to the entire population globally, not just for patients with cancer. Clearly, it will be important to continue monitoring for emerging new variants, because what we and others have shown is that the likelihood of evasion by variants relative to vaccines that patients have received in the past, has been more pronounced with the most recent emerging variants. This is certainly something we will need to keep an eye on and respond to, but I think it will be a population-level response rather than only being applicable to cancer patients.